Aryl or heteroaryl substituted carbamate compound as well as derivative and application thereof

Abstract

The present invention relates to compounds of formula (I), pharmaceutical compositions comprising said compounds, and uses of said pharmaceutical compositions in the treatment and / or prevention of diseases, disorders or conditions associated with AMPK kinase.

Description

Aryl or heteroaryl substituted carbamate compounds and their derivatives and uses

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202311128222.7 filed on August 31, 2023 and Chinese patent application CN202411118554.1 filed on August 14, 2024, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present application relates to aryl or heteroaryl substituted carbamate compounds and derivatives thereof, pharmaceutical compositions comprising the compounds or derivatives, and the use of the pharmaceutical compositions for treating and / or preventing diseases, disorders or conditions associated with AMPK kinase. Background Art

[0004] AMPK (adenosine monophosphate (AMP)-activated protein kinase) is a serine / threonine protein kinase. It is a heterotrimeric complex composed of an α subunit containing the kinase domain and two regulatory subunits (β- and γ-). AMPK is regulated by the upstream kinases LKB1 (liver kinase B1) and CAMKK2 (calcium / calmodulin-dependent protein kinase kinase 2). Phosphorylation of Thr174 in the activation loop (T-loop) of the α subunit (Thr172 in α2) leads to a 500- to 1000-fold increase in activity. AMPK acts as a metabolic switch, and its activation affects lipid, cholesterol, carbohydrate, and amino acid metabolism, as well as mitochondrial function, autophagy, and cell growth.

[0005] Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus, is a chronic metabolic disease characterized by hyperglycemia, insulin deficiency, and insulin resistance. In addition to genetic factors, lifestyle habits and dietary patterns greatly influence the incidence of type 2 diabetes. Currently, the main drugs used to treat type 2 diabetes include biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 analogs. However, all currently used therapeutic drugs have certain side effects, so there is a need to develop hypoglycemic drugs with novel mechanisms of action to meet the needs of diabetic patients.

[0006] AMPK reduces lipid storage by phosphorylating multiple substrates. These pathways work together to promote fatty acid oxidation while inhibiting fatty acid and cholesterol synthesis. AMPK may also indirectly control the rate of fatty acid oxidation by regulating mitochondrial function. In addition to regulating fatty acid metabolism and indirectly affecting carbohydrate metabolism, AMPK also directly regulates carbohydrate metabolism pathways through various mechanisms. Activating AMPK can promote cellular glucose uptake by enhancing the translocation and expression of GLUT proteins. AMPK agonists have been reported to significantly lower blood glucose levels in mice, returning them to normal levels. Therefore, AMPK agonists have the potential to lower blood glucose (Cell Metabolism 25, 1147–1159, ACS Med. Chem. Lett. 2018, 9, 1, 39–44).

[0007] International patent application WO2013153479A2 discloses indole carboxylic acid compounds with AMPK agonist activity: US patent application US20150203450A1 discloses azaindole derivatives with AMPK agonist activity: These compounds all have fused bicyclic heteroaromatic rings. Similarly, WO2012116145, WO2014031441, WO2014031445 and WO2014139388 disclose indole or benzimidazole derivatives having fused bicyclic heteroaromatic rings, which are said to have AMPK agonist activity.

[0008] Tamura et al. attempted to use compound 11 (a heteroaryl-substituted carbamate compound) as an AMPK agonist, but no AMPK agonist activity was detected: Tamura et al. pointed out that existing AMPK agonists all have fused bicyclic heteroaromatic rings, and therefore believed that the aromatic bicyclic ring is necessary for AMPK agonist activity (Yuusuke Tamura et al., Identification of novel indole derivatives as highly potent AMPK activators with anti-diabetic profiles, Bioorganic & Medicinal Chemistry Letters, Vol. 68, 15 July 2022, 128769).

[0009] There is a need to develop novel AMPK agonist compounds for treating diseases, disorders or conditions associated with AMPK kinase.

[0010] Summary of the Invention

[0011] The present invention provides novel AMPK agonist compounds for treating and / or preventing diseases, disorders or conditions associated with AMPK kinase. In some embodiments, the compounds of the present invention have an aromatic substituted carbamate structure. The inventors surprisingly discovered that such compounds have excellent AMPK agonist activity. The compounds of the present invention have better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less prone to drug resistance and other more excellent properties.

[0012] In one aspect, the present invention provides a compound of formula (I) as defined below:

[0013] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0014] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0015] In another aspect, the present invention provides the use of a compound of formula (I) of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention in the preparation of a medicament as an AMPK agonist.

[0016] In another aspect, the present invention provides the use of a compound of formula (I) of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing diseases, disorders or conditions associated with AMPK kinase.

[0017] In another aspect, the present invention provides a compound of formula (I) of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention for the preparation of a medicament for treating and / or preventing diseases, disorders or conditions that can be treated and / or prevented by activating AMPK.

[0018] In another aspect, the present invention provides a method for treating and / or preventing a disease, disorder or condition associated with AMPK kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) of the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0019] In another aspect, the present invention provides a method for treating and / or preventing a disease, disorder or condition that can be treated and / or prevented by activating AMPK, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) of the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0020] In some embodiments, the disease, disorder or condition is preferably selected from type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease and alopecia. DETAILED DESCRIPTION

[0021] definition

[0022] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0023] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0024] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0025] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 2-6 Alkyl", "C 2-5 Alkyl" and "C 1-4 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term "C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0026] As used herein, the term "alkylene" refers to a group obtained by further losing one hydrogen atom from an "alkyl" as defined above. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms. For example, "C 1-6 Alkylene", "C 2-6 Alkylene", "C 2-5 Alkylene" and "C 1-4 Alkylene". "C 1-6 Examples of "alkylene" include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene and n-hexylene. The term "C 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0027] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above.

[0028] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6Alkenyl", such as "C 2-4 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0029] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 Alkynyl", such as "C 2-4 The alkynyl group is, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-2-butynyl and 2-methyl-3-pentynyl. The term "alkynylene" is the corresponding divalent group, including, for example, "C 2-6 Alkynylidene", "C 2-4 Specific examples include, but are not limited to, -C≡C-, -CH2C≡C-, -C≡C-CH2-, -CH2-C≡C-CH2-, pentynylene, hexynylene, and the like.

[0030] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0031] As used herein, the terms "carbocycle" and "carbocyclyl" mean a ring or ring system in which all ring members are C atoms, which may be saturated ("cycloalkyl"), partially unsaturated (e.g., having one or more double bonds within the ring, i.e., "cycloalkenyl"), or aromatic ("aryl"). Carbocycles have, for example, 3-12 (suitably 3-10, 3-8, 3-7, 3-6, 4-6, or 5-6) ring carbon atoms.

[0032] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer 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 fused hydrocarbon ring having, for example, 3-12 (suitably having 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. , which include but are not limited to (ylidene) cyclopropyl (ring), (ylidene) cyclobutyl (ring), (ylidene) cyclopentyl (ring), (ylidene) cyclohexyl (ring), (ylidene) cycloheptyl (ring), (ylidene) cyclooctyl (ring), (ylidene) cyclononyl (ring), (ylidene) cyclobutenyl (ring), (ylidene) cyclopentenyl (ring), (ylidene) cyclohexenyl (ring), (ylidene) cycloheptenyl (ring), (ylidene) cyclooctenyl (ring), (ylidene) cyclononenyl (ring), etc. In some embodiments, cycloalkyl includes aryl-fused cycloalkyl, as long as the entire ring system is non-aromatic, for example

[0033] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.). The cycloalkyl group has 3-15 carbon atoms, suitably 3-12, 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6 carbon atoms. For example, the term "C 3-6 Cycloalkyl" and "C 3-6 "Cycloalkylene" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0034] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds within the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6.

[0035] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monocyclic or bicyclic ring structures having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(═O), S(═O)2, and NR', wherein R' is a suitable substituent, such as H, alkyl, etc. The heterocycle can be attached to the rest of the molecule through any of the carbon atoms or, if present, the nitrogen atom. In particular, a 3-12 membered heterocycle is a group having 3-12 (e.g., 3-10, 3-8, 3-7, 3-6, 4-11, 4-9, 4-7, 4-6, 5-12, 5-6, 6-10, 6-9, 6-8, 7-11, or 8-12) carbon atoms and heteroatoms in the ring. Examples include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl. Heterocyclic groups include aryl or heteroaryl fused heterocyclic groups, as long as the entire ring system is non-aromatic, for example

[0036] As used herein, the heterocycles described above include nitrogen-containing heterocycles, oxygen-containing heterocycles, and sulfur-containing heterocycles. For example, a "nitrogen-containing heterocycle" has at least one nitrogen atom, which may also optionally have one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O). The nitrogen-containing heterocycle is attached to the rest of the molecule via the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, a 3- to 12-membered nitrogen-containing heterocycle is a group having 3-12 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridinyl), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, and the like. An "oxygen-containing heterocycle" has at least one oxygen atom, which may optionally have one or more (e.g., one, two, three, or four) ring members selected from N, C=O, S, S=O, and S(=O)2. The oxygen-containing heterocycle is preferably a saturated oxygen-containing monocyclic or bicyclic ring. In particular, the 3- to 12-membered oxygen-containing heterocycle is a group having 3-12 carbon atoms and heteroatoms (at least one of which is an oxygen atom) in the ring, including but not limited to a three-membered oxygen-containing heterocycle (such as an oxirane group), a four-membered oxygen-containing heterocycle (such as an azetidinyl group), a five-membered nitrogen-containing heterocycle (such as a tetrahydrofuranyl group, a dihydrofuranyl group), a six-membered oxygen-containing heterocycle (such as a tetrahydropyranyl group, a morpholinyl group), an 8- to 10-membered fused bicyclic oxygen-containing heterocycle (such as )wait.

[0037] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 "Aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl (benzene ring) or naphthyl.

[0038] As used herein, the terms "heteroaryl" and "heteroaromatic ring" refer to monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring systems having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O)2. One or more ring carbon atoms in a heteroaryl group may be replaced by C(O). A heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzo furanyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, triazolopyridinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

[0039]

[0046] The term "oxo" or "oxo," as used herein, is defined as =0.

[0040] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0041] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0042] As used herein, the term "haloalkenyl" refers to an alkenyl group substituted with one or more (such as 1 to 3) the same or different halogen atoms, as defined herein. 2-8 Halogenated alkenyl, "C 2-6 Halogenated alkenyl" and "C 2-4The term "haloalkenyl" refers to haloalkenyl groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, and 2 to 4 carbon atoms, respectively.

[0043] As used herein, the term "haloalkynyl" refers to an alkynyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms, the alkenyl group being as defined herein. 2-8 Haloalkynyl", "C 2-6 Haloalkynyl" and "C 2-4 The term "haloalkynyl" refers to haloalkynyl groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, and 2 to 4 carbon atoms, respectively.

[0044] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0045] If a group is described as "optionally substituted with" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0046] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0047] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0048] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0049] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, such substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0050] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) can be substituted in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0051] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0052] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0053] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0054] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0055] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0056] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0057] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention may exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0058] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0059] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0060] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0061] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0062] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0063] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0064] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0065] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0066] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0067] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0068] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0069] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0070] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0071] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0072] Compound

[0073] In one aspect, the present invention provides compounds of formula (I):

[0074] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:

[0075] X 1 is selected from -C(=O)-, -C(=S)-, and -CH2-;

[0076] L 1 Selected from -O-, -S-, -NR c -and-CR a R b -;

[0077] L 2 Selected from -O-, -S-, -NR c -、-CR a R b -、-O-CR a R b -and-S-CR a R b -;

[0078] Alternatively, -L 1 -X 1 -L 2 - as a whole is -NH-;

[0079] R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace;

[0080] R 1a Independently selected from halogen, -OH, -CN, oxo, -COOR c 、-C(=O)NHRc 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 1-6 Alkylene -OH, -OC 1-6 Alkylene-OH, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-COOR c 、-C 1-6 Alkylene-C(=O)NHR c 、-S(=O)2-C 1-6 Alkyl and

[0081] R a and R b Each occurrence is independently selected from H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 3-6 Cycloalkyl;

[0082] R c independently selected at each occurrence from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0083] Ring A Selected from benzene ring and 5-6 membered aromatic heterocyclic ring, each of the benzene ring and 5-6 membered aromatic heterocyclic ring is optionally substituted by 1, 2 or 3 R A Substituted, wherein the R A Independently selected from H, D, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 4-6 Carbocyclyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0084] L 3 Selected from bond, -O-, -S-, -NR L3 -, -C(=O)-NR L3 -、-C(=O)-O-、-C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR L3 -、-C 1-6 Alkylene-S-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-;

[0085] R L3 Selected from H, D and C 1-6 alkyl;

[0086] R 2 Selected from C 6-10 Aryl, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group and 5-10 membered heteroaryl group, the C 6-10 Aryl, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon groups, 4-10 membered heterocyclic groups and 5-10 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4 or 5 groups each independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group substitution;

[0087] R 2a 、R 2b 、R 2c 、R 2d and R 2e Each independently selected from H, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2 or more R; and

[0088] R is independently selected from: H, halogen, -OH, -CN, -NH2, oxo, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C substituted by 1 or 2 OH 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyleneoxy-C 1-6 Alkoxy, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-10 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -N=S(=O)R s1 R s2 、-NH-S(=O)2C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-4-10 membered heterocyclic group, -S(=O)2NH-C 1-6 Alkyl, -S(=O)2NH-C 3-10 Cycloalkyl, -C 3-10 Cycloalkylene-COOH, -C(=O)-4-10 membered heterocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2 or more independently selected C 1-6 Alkyl, -NH2, =NH and oxo substituents, said C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2 or more independently selected from halogen, -OH, -CN, -NH2, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN and -C 1-6 Alkylene-NH2 substituents, and R s1 and R s2 Each is C 1-6 Alkyl, or R s1 and R s2 Together with the S atom to which they are attached, they form a 4-6 membered heterocycloalkyl group; provided that:

[0089] (1) The compound of formula (I) is not the following compound:

[0090] (include ), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; b; and

[0091] (2) When ring A is a thiazole ring, L 3 -NR L3 -, and R 2 When L is a substituted or unsubstituted phenyl group, 1 Not-CR a R b -;

[0092] (3) When -L 1 -X 1 -L 2 When - as a whole is -NH-, for And R 2 C 6-10 Aryl, wherein the bond designated "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0093] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:

[0094] X 1 is selected from -C(=O)-, -C(=S)-, and -CH2-;

[0095] L 1 Selected from -O-, -S-, -NR c -and-CR a R b -;

[0096] L 2 Selected from -O-, -S-, -NR c -、-CR a R b -、-O-CR a R b -and-S-CR a R b -;

[0097] R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace;

[0098] R 1a Independently selected from halogen, -OH, -CN, oxo, -COOR c 、-C(=O)NHR c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 1-6 Alkylene-OH, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-COOR c 、-C 1-6 Alkylene-C(=O)NHR c 、-S(=O)2-C 1-6 Alkyl and

[0099] R a and R b Each occurrence is independently selected from H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 3-6 Cycloalkyl;

[0100] R c independently selected at each occurrence from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0101] Ring A Selected from benzene ring and 5-6 membered aromatic heterocyclic ring, each of the benzene ring and 5-6 membered aromatic heterocyclic ring is optionally substituted by 1, 2 or 3 R A Substituted, wherein the R A independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6Haloalkynyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 4-6 Carbocyclyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0102] L 3 Selected from bond, -O-, -S-, -NR L3 -, -C(=O)-NR L3 -、-C(=O)-O-、-C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR L3 -、-C 1-6 Alkylene-S-, -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-;

[0103] R L3 Selected from H, D and C 1-6 alkyl;

[0104] R 2 Selected from C 6-10 Aryl, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group and 5-10 membered heteroaryl group, the C 6-10 Aryl, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon groups, 4-10 membered heterocyclic groups and 5-10 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4 or 5 groups each independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group substitution;

[0105] R 2a 、R 2b 、R 2c 、R 2d and R 2e Each independently selected from H, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2 or more R; and

[0106] R is independently selected from: H, halogen, -OH, -CN, -NH2, oxo, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C substituted by 1 or 2 OH 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyleneoxy-C 1-6 Alkoxy, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-10 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -N=S(=O)R s1 R s2 、-NH-S(=O)2C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-4-10 membered heterocyclic group, -S(=O)2NH-C 1-6 Alkyl, -S(=O)2NH-C 3-10 Cycloalkyl, -C 3-10 Cycloalkylene-COOH, -C(=O)-4-10 membered heterocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2 or more independently selected C 1-6 Alkyl, -NH2, =NH and oxo substituents, said C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2 or more independently selected from halogen, -OH, -CN, -NH2, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN and -C 1-6 Alkylene-NH2 substituents, and R s1 and Rs2 Each is C 1-6 Alkyl, or R s1 and R s2 Together with the S atom to which they are attached, they form a 4-6 membered heterocycloalkyl group;

[0107] The conditions are:

[0108] (1) The compound of formula (I) is not the following compound:

[0109] (include ), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; b; and

[0110] (2) When ring A is a thiazole ring, L 3 -NR L3 -, and R 2 When L is a substituted or unsubstituted phenyl group, 1 Not-CR a R b -.

[0111] In some embodiments, the present invention provides compounds of formula (I), wherein: when ring A is a thiazole ring and L 3 If R does not exist, 2 Not an unsubstituted biphenyl.

[0112] In some embodiments, the present invention provides a compound of formula (I), wherein ring A is selected from a benzene ring and a 5-6 membered aromatic heterocycle, wherein the benzene ring and the 5-6 membered aromatic heterocycle are each optionally substituted by 1, 2 or 3 R A Substituted, the R A independently selected from H, D, F, Cl, Br, -OH, -NH2, -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, phenyl, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2; wherein, when applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6carbocyclyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.

[0113] In some preferred embodiments, ring A is selected from a benzene ring and a 5-6 membered aromatic heterocycle, wherein the benzene ring and the 5-6 membered aromatic heterocycle are each optionally substituted by 1, 2 or 3 R A Substituted, the R A independently selected from H, D, F, Cl, Br, -OH, -NH2, -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2; wherein, when applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 carbocyclyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.

[0114] In some more preferred embodiments, ring A is selected from a benzene ring and a 5-6 membered aromatic heterocycle, wherein the benzene ring and the 5-6 membered aromatic heterocycle are each optionally substituted by 1, 2 or 3 R A Substituted, the R A independently selected from H, D, F, Cl, -OH, -NH2, -CN, methyl, ethyl, isopropyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, methoxy, ethoxy, isopropoxy, tert-butoxy, -CF3, -OCF3, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -NHCH3 and -N(CH3); wherein, when applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 Carbocyclic group.

[0115] In some embodiments, ring A is selected from a benzene ring and a 5-6 membered aromatic heterocyclic ring, wherein the benzene ring and the 5-6 membered aromatic heterocyclic ring are each optionally substituted by 1, 2 or 3 R A replace.

[0116] In some embodiments, ring A is selected from phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl and pyridinyl, wherein each of the phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl and pyridinyl groups is optionally substituted with 1 or 2 R A replace.

[0117] In some embodiments, ring A is selected from phenyl, thienyl, imidazolyl, thiazolyl, wherein each of the phenyl, thienyl, imidazolyl, thiazolyl groups is optionally substituted with 1 or 2 R A replace.

[0118] In some embodiments, Ring A is selected from thienyl, which is optionally substituted with 1 or 2 R A replace.

[0119] In some embodiments, Ring A is selected from: wherein any of the above groups is optionally substituted by 1, 2 or 3 (preferably 1 or 2, more preferably 1) R A substituted, and wherein the bond identified by "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0120] In some more preferred embodiments, Ring A is selected from: wherein any of the above groups is optionally substituted with 1, 2 or 3 R A Replace, and where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 carbocyclyl; and wherein the bond identified by "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0121] In a further more preferred embodiment, Ring A is It is optionally replaced by 1 or 2 R A Substitution, where applicable, of two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 Carbocyclic group, thereby forming a group selected from As the ring A; and wherein the bond identified by "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0122] In some embodiments, Ring A is selected from: wherein any of the above groups is optionally replaced by 1 or 2 R A replace.

[0123] In some embodiments, Ring A is selected from: wherein any of the above groups is optionally replaced by 1 RA replace.

[0124] In some embodiments, Ring A is selected from It is optionally replaced by 1 R A replace.

[0125] A preferred embodiment is wherein the ring A is surrounded by 1 or 2 R A Those compounds of formula (I) which are substituted.

[0126] In a further more preferred embodiment, Ring A is selected from:

[0127] In some embodiments, Ring A is selected from:

[0128] In some embodiments, Ring A is selected from:

[0129] In some embodiments, Ring A is selected from The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0130] In some embodiments, the R A Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 carbocyclyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.

[0131] In some embodiments, the R A Independently selected from H, D, halogen, -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclyl, phenyl; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 Carbocyclic group.

[0132] In some embodiments, the R A independently selected from H, D, halogen (eg, F, Cl), -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, phenyl group.

[0133] In some embodiments, the R A independently selected from H, halogen (such as Cl), C 1-4 Alkyl, C 3-4 Cycloalkyl, phenyl.

[0134] In some embodiments, the R A independently selected from H, halogen (such as Cl), C 1-4 In some embodiments, the R A Each independently selected from F, Cl, Br, -OH, -NH2, -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, -NH(C 1-4 alkyl) and -N(C 1-4 Alkyl)2.

[0135] In some preferred embodiments, the R A Each is independently selected from F, Cl, -OH, -NH2, -CN, methyl, ethyl, isopropyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, methoxy, ethoxy, isopropoxy, tert-butoxy, -CF3, -OCF3, cyclopropyl, cyclobutyl, oxetanyl, azetidyl, -NHCH3 and -N(CH3)2.

[0136] In some embodiments, the R A Each is independently selected from H, D, F, Cl, -CN, methyl, ethyl, isopropyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, methoxy, ethoxy, isopropoxy, tert-butoxy, -CF3, -OCF3, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and phenyl.

[0137] In some more preferred embodiments, the R A Each is independently selected from F, Cl, -CN, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, ethoxy, -OCF3, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.

[0138] In some embodiments, the R A Each is independently selected from H, F, Cl, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, and phenyl.

[0139] In some embodiments, the R A Each is independently selected from Cl or methyl.

[0140] In some embodiments, the ring A is selected from: The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0141] In some particularly preferred embodiments, the ring A is selected from: The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0142] In some embodiments, the ring A is selected from:

[0143] In some embodiments, the ring A is selected from:

[0144] In some embodiments, the ring A is selected from:

[0145] In some embodiments, the ring A is selected from

[0146] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-1):

[0147] Preferably, Partially selected Preferably, Partially selected Preferably Preferably Preferably More preferred The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0148] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-2):

[0149] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0150] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-3'):

[0151] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-4'):

[0152] Preferably, Partially selected Preferably, Partially selected Preferably More preferably The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0153] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-5'):

[0154] Preferably, for The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0155] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-6'):

[0156] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-7'):

[0157] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0158] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-8):

[0159] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0160] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-9):

[0161] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0162] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-10):

[0163] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0164] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-11):

[0165] Preferably, Part of Preferably More preferably The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0166] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-12):

[0167] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0168] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-13):

[0169] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0170] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-14):

[0171] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0172] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-15):

[0173] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0174] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-16):

[0175] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0176] In some embodiments, the present invention provides a compound of formula (I) having a structure shown in formula (I-17):

[0177] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0178] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-18):

[0179] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0180] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-19):

[0181] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0182] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-20):

[0183] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0184] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-21):

[0185] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0186] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-22):

[0187] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0188] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-23'):

[0189] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0190] In some embodiments, the present invention provides a compound of formula (I), which has a structure shown in formula (I-23):

[0191] Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

[0192] In some embodiments, the present invention provides a compound of the present invention as described above, wherein L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-6 Alkylene-O-*, #-C 1-6 Alkylene-NR L3 -*,#-C 1-6 Alkylene-S-*, -C1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-, wherein the bond marked with "#" is connected to R 2 The bond marked with "*" is connected to ring A.

[0193] In some embodiments, L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-6 Alkylene-O-*, #-C 1-6 Alkylene-NR L3 -*,#-C 1-6 Alkylene-S-*, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-, wherein the bond marked with "#" is connected to R 2 The bond marked with "*" is connected to ring A.

[0194] In some embodiments, L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-4 Alkylene-O-*, #-C 1-4 Alkylene-NR L3 -*,#-C 1-4 Alkylene-S-*, -C 2-4 Alkenylene- and -C 2-4 Alkynylidene-, wherein the bond marked with "#" is connected to R 2 are connected, and the bond marked with "*" is connected to ring A.

[0195] In some preferred embodiments, L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*,#-C 1-4 Alkylene-O-*, #-C 1-4 Alkylene-NR L3 -*,#-C 1-4 Alkylene-S-*, -C 1-4 Alkylene-, -C 2-4 Alkenylene- and -C 2-4 Alkynylidene-, wherein the bond marked with "#" is connected to R 2 are connected, and the bond marked with "*" is connected to ring A.

[0196] In some embodiments, L 3 Selected from bond, -S-, -O-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-(CH2) n -O-*、#-(CH2) n -NR L3 -*、#-(CH2) n -S-*, vinylene, propenylene, ethynylene and propynylene, where the bond marked with "#" is connected to R 2 The bond marked with "*" is connected to ring A, and n is selected from 1 and 2.

[0197] In some more preferred embodiments, L 3 Selected from bond, -S-, -O-, -NR L3 -、#-C(=O)-NR L3 -*、#-(CH2) n -O-*、#-(CH2) n -NR L3 -*、#-(CH2) n -S-*, vinylene, propenylene, ethynylene and propynylene, where the bond marked with "#" is connected to R 2 The bond marked with "*" is connected to ring A, and n is selected from 1 and 2.

[0198] In some embodiments, L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-4 Alkylene-NR L3 -* and -C 2-4 Alkynylidene-, wherein the bond marked with "#" is connected to R 2 The bond marked with "*" is connected to Ring A. In some embodiments, L 3 Selected from bonds, -C 2-4 Alkynylene- (e.g., ethynylene and propynylene).

[0199] In some embodiments, L 3 Selected from a bond, an ethynylene group.

[0200] In some embodiments, R L3 Selected from H, D and C 1-4 alkyl.

[0201] In some preferred embodiments, R L3is selected from H, D, -CH3, -CH2CH3 and -CH(CH3)2.

[0202] In some more preferred embodiments, R L3 For H.

[0203] In some more preferred embodiments, L 3 is selected from the group consisting of a bond, -O-, -S-, -NH-, #-C(=O)-NH-*, #-CH2-NH-*, #-CH2-O-*, #-CH2-S-* and -C≡C-, wherein the bond marked with "#" is the same as R 2 The bond marked with "*" is connected to ring A.

[0204] In some more preferred embodiments, L 3 is selected from a bond, -O-, -S-, -NH-, #-C(=O)-NH-*, #-CH2-NH-* and -C≡C-, wherein the bond marked with "#" is connected to R2, and the bond marked with "*" is connected to ring A.

[0205] In a further more preferred embodiment, L 3 is the key.

[0206] In some embodiments, the present invention provides a compound of the present invention as described above, wherein R 2 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group and C 9-10 Saturated or partially unsaturated cyclic hydrocarbon group, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group or C 9-10 The saturated or partially unsaturated cyclic hydrocarbon group is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0207] In some embodiments, R 2 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group and C 9-10 Partially unsaturated cyclic hydrocarbon group, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group or C 9-10 Partially unsaturated cyclic hydrocarbon groups are optionally substituted by 1, 2, 3, 4, or 5 independently selected R 2a 、R 2b 、R 2c、R 2d and R 2e The group is substituted.

[0208] In some embodiments, R 2 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl are optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0209] In some embodiments, R 2 Selected from C 3-6 Cycloalkyl, phenyl, 9-membered heteroaryl, the C 3-6 Cycloalkyl, phenyl, 9-membered heteroaryl are optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0210] In some embodiments, R 2 phenyl, 9-membered heteroaryl, wherein the phenyl, 9-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0211] In some preferred embodiments, R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindanyl and 1,2,3,4-tetrahydronaphthyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindanyl and 1,2,3,4-tetrahydronaphthyl. Pentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindanyl and 1,2,3,4-tetrahydronaphthyl are each optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from R 2a 、R 2b 、R 2c 、R 2dand R 2e The group is substituted.

[0212] In some more preferred embodiments, R 2 is selected from cyclopropyl, cyclobutyl, phenyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, indolyl, dihydroindole, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl, wherein the cyclopropyl, cyclobutyl, phenyl, thienyl, thiazolyl, oxazolyl, pyridinyl, indolyl, dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl are each optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0213] In some embodiments, R 2 is selected from cyclopropyl, cyclobutyl, phenyl, thienyl, pyridyl, indolyl, dihydroindole, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl, wherein the cyclopropyl, cyclobutyl, phenyl, thienyl, pyridyl, indolyl, dihydroindole, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl are each optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0214] In some embodiments, R 2 is selected from cyclopropyl, cyclobutyl, phenyl, indolyl, wherein the cyclopropyl, cyclobutyl, phenyl, indolyl are each optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group is substituted.

[0215] In some embodiments, R 2 is selected from phenyl and indolyl, wherein the phenyl and indolyl are each optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2eThe group is substituted.

[0216] In some more preferred embodiments, R 2 Selected from:

[0217] In some embodiments, R 2 Selected from

[0218] In some embodiments, R 2 Selected from

[0219] In some embodiments, R 2 Selected from

[0220] In some embodiments, R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, 4-6 membered monocyclic heterocyclyl, 8-10 membered biheterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2 or 3 R groups.

[0221] In some embodiments, R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclic group, phenyl and 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl, 4-6 membered monocyclic heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2 or 3 R groups.

[0222] In some preferred embodiments, R 2a 、R 2b 、R 2c 、R 2d and R 2e Each of the following groups is independently selected from H, F, Cl, Br, -OH, -CN, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydrotriazolyl, phenyl, imidazolyl, pyrazolyl, thienyl, furyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl, the methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydrotriazolyl, Phenyl, imidazolyl, pyrazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl are each optionally substituted with 1, 2 or 3 R groups.

[0223] In some embodiments, R 2a 、R 2b 、R 2c 、R 2d and R 2eEach is independently selected from H, F, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, Phenyl and pyridyl, the -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, Phenyl and pyridyl are each optionally substituted with 1, 2 or 3 R groups.

[0224] In some more preferred embodiments, R 2a 、R 2b 、R 2c 、R 2d and R 2e Each is independently selected from H, F, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, Phenyl and pyridyl, the -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, Phenyl and pyridyl are each optionally substituted with 1, 2 or 3 R groups.

[0225] In some embodiments, R 2a 、R 2b 、R 2c 、R 2d and R 2eEach of them is independently selected from H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, cyclopropyl, cyclobutyl, phenyl, pyridinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, and piperidinyl, and the -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, cyclopropyl, cyclobutyl, phenyl, pyridinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, and piperidinyl are each optionally substituted by 1, 2 or 3 R.

[0226] In some embodiments, R is selected from the group listed in groups (1)-(3):

[0227] (1)H, halogen, -OH, -CN, -NH2, oxo, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, -C substituted by 1 or 2 OH 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyleneoxy-C 1-4 Alkoxy, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N=S(=O)R s1 R s2 、-NH-S(=O)2C 1-4 Alkyl, -S(=O)2-C 1-4 Alkyl, -S(=O)2-4-6 membered heterocyclic group, -S(=O)2NH-C 1-4 Alkyl, -S(=O)2NH-C 3-6 Cycloalkyl, -C 3-6 Cycloalkylene-COOH and -C(=O)-4-6 membered heterocyclic group, wherein R s1 and R s2 Each is C 1-4 Alkyl, or R s1 and R s2 Together with the S atom to which they are attached, they form a 4-6 membered heterocycloalkyl group;

[0228] (2) 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or more independently selected from C 1-4 Alkyl, -NH2, =NH and oxo substituents; and

[0229] (3) phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2 or more independently selected from halogen, -OH, -CN, -NH2, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -CN and -C 1-4 The substituent of the alkylene group -NH2 is substituted.

[0230] In some embodiments, R is selected from H, -NH2, -OH, -C substituted with 1 OH 1-4 Alkyl, C 1-4 Alkyl, -S(=O)2-C 1-4 Alkyl, 4-6 membered heterocyclic group.

[0231] In some preferred embodiments, R is selected from the groups listed in groups (1) to (3):

[0232] (1) H, halogen, -OH, -CN, -NH2, oxo, -COOH, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -CH2OH, -ethylene-OH, methoxy, ethoxy, propoxy, butoxy, -methyleneoxy-methoxy, -methyleneoxy-ethoxy, -methyleneoxy-propoxy, -ethyleneoxy-methoxy, -ethyleneoxy-ethoxy, -ethyleneoxy-propoxy, -C(=O)-NH-methyl, -C(=O)-NH-ethyl, -C(=O)-NH-propyl, -C(=O)-NH-butyl, -N=S(=O)(methyl)2, -N=S(=O)(methyl)(ethyl), -N=S(=O)(methyl)(propyl), -N=S(=O)(methyl)(butyl), -N=S(=O)(ethyl)2, -N=S(=O)(ethyl)(propyl), -(NH) p -W-methyl, -(NH) p -W-ethyl, -(NH) p -W-propyl, -(NH) p -W-butyl, -W-NH-cyclopropyl, -W-oxetanyl, -W-azetidinyl, -W-tetrahydrofuranyl, -W-pyrrolidinyl, -W-tetrahydropyranyl, -W-piperidinyl, -W-morpholinyl, -cyclopropylene-COOH and wherein each W is independently C(=O) or S(=O)2, and each p is independently 0 or 1;

[0233] (2) oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydropyrazolyl, dihydroimidazolyl, and dihydrotriazolyl, wherein each of the oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydropyrazolyl, dihydroimidazolyl, and dihydrotriazolyl groups is optionally substituted with one, two, or more substituents independently selected from the group consisting of methyl, ethyl, propyl, tert-butyl, -NH2, =NH, and oxo; and

[0234] (3) phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl, wherein each of the phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl groups is optionally substituted by one, two or more groups independently selected from halogen, -OH, -CN, -NH2, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -CN and -C 1-4 The substituent of the alkylene group -NH2 is substituted.

[0235] In some preferred embodiments, R is selected from the groups listed in groups (1), (2'), and (3):

[0236] Where (1) and (3) are as described above;

[0237] (2′) oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyrazolyl, dihydroimidazolyl and dihydrotriazolyl, wherein each of the oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyrazolyl, dihydroimidazolyl and dihydrotriazolyl groups is optionally substituted with 1, 2 or more substituents independently selected from methyl, ethyl, propyl, tert-butyl, —NH , —NH and oxo.

[0238] In some more preferred embodiments, R is selected from the group consisting of: H, F, -OH, -CN, -NH2, oxo, -COOH, -CH3, -CH2OH, -OCH3, -OCH2CH2OCH3, -C(=O)CH3, -C(=O)NHCH3, -NHC(=O)CH3, -N=S(=O)(CH3)2, -NH-S(=O)2CH3、-S(=O)2CH3、

[0239] In some embodiments, R is H, -NH2, -OH, -CH2OH, -CH3, -S(=O)2CH3, In some embodiments, R is H, -OH, -CH2OH, -CH3, -S(=O)2CH3, In an even more preferred embodiment, R is H.

[0240] In some embodiments, R 2 Selected from:

[0241] In some particularly preferred embodiments, R 2 Selected from:

[0242] In some embodiments, R 2 Selected from

[0243] In some embodiments, R 2 Selected from

[0244] In some embodiments, the compounds of the present invention have structures shown in formula (II-1) to (II-9):

[0245] In some embodiments, the present invention provides a compound having a structure represented by formula (II-1).

[0246] In some embodiments, the present invention provides a compound having a structure represented by formula (II-2).

[0247] In some embodiments, the present invention provides a compound having a structure represented by formula (II-3).

[0248] In some embodiments, the present invention provides a compound having a structure represented by formula (II-4).

[0249] In some embodiments, the present invention provides a compound having a structure represented by formula (II-5).

[0250] In some embodiments, the present invention provides a compound having a structure represented by formula (II-6).

[0251] In some embodiments, the present invention provides a compound having a structure represented by formula (II-7).

[0252] In some embodiments, the present invention provides a compound having a structure represented by formula (II-8).

[0253] In some embodiments, the present invention provides a compound having a structure represented by formula (II-9).

[0254] In some embodiments, the present invention provides compounds having structures shown in formulas (I-24) to (I-33):

[0255] In some embodiments, the present invention provides the compound having the structure shown in formula (I-24).

[0256] In some embodiments, the present invention provides the compound having the structure shown in formula (I-25).

[0257] In some embodiments, the present invention provides the compound having the structure shown in formula (I-26).

[0258] In some embodiments, the present invention provides the compound having the structure shown in formula (I-27).

[0259] In some embodiments, the present invention provides the compound having the structure shown in formula (I-28).

[0260] In some embodiments, the present invention provides the compound having the structure shown in formula (I-29).

[0261] In some embodiments, the present invention provides the compound having the structure shown in formula (I-30).

[0262] In some embodiments, the present invention provides the compound having the structure shown in formula (I-31).

[0263] In some embodiments, the present invention provides the compound having the structure shown in formula (I-32).

[0264] In some embodiments, the present invention provides the compound having the structure shown in formula (I-33).

[0265] In some such embodiments, X 1 In other embodiments, X 1 In other embodiments, X 1 It is -CH2-.

[0266] In some such embodiments, X 1 is selected from -C(=O)-, -C(=S)-; preferably, X 1Selected from -C(=O)-.

[0267] In some embodiments, the present invention provides a compound of the present invention as described above, wherein R a and R b Each occurrence is independently selected from H, D, F, Cl, Br, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy and C 3-4 Cycloalkyl.

[0268] In some preferred embodiments, R a and R b Each occurrence is independently H.

[0269] In some embodiments, the present invention provides a compound of the present invention as described above, wherein R c independently selected at each occurrence from H, D, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-4 Cycloalkyl.

[0270] In some preferred embodiments, R c H and C independently at each occurrence 1-4 Alkyl, preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, more preferably H and methyl.

[0271] In some embodiments, the present invention provides a compound of the present invention as described above, wherein L 1 Selected from -O-, -S-, -NR c -and-CR a R b -.

[0272] In some embodiments, the present invention provides a compound of the present invention as described above, wherein L 1 Selected from -O-, -NR c -and-CR a R b -.

[0273] In some embodiments, L 1 Selected from-NR c -.

[0274] In some preferred embodiments, L 1 Selected from -O-, -S-, -NH, -N(CH3)- and -CH2-.

[0275] In some embodiments, L1 Selected from -NH-.

[0276] In some embodiments, the present invention provides a compound of the present invention as described above, wherein L 2 Selected from -O-, -S-, -NR c -、-CR a R b -、#-O-CR a R b -* and #-S-CR a R b -*, where the key marked with "#" is the same as X 1 Connect, the key marked with "*" and R 1 connect.

[0277] In some embodiments, L 2 Selected from -O-, -CR a R b -.

[0278] In some embodiments, L 2 Selected from -O-.

[0279] In some preferred embodiments, L 2 is selected from -O-, -S-, -NH-, -N(CH3)-, -CH2-, #-O-CH2-* and #-S-CH2-*, wherein the bond marked with "#" is 1 Connect, the key marked with "*" and R 1 connect.

[0280] In some more preferred embodiments, L 2 Selected from -O-, -S-, -NH-, -N(CH3)-, -CH2- and #-O-CH2-*, wherein the bond marked with "#" is 1 Connect, the key marked with "*" and R 1 connect.

[0281] In some embodiments, L 2 Selected from -O-, -CH2-.

[0282] In some embodiments, the present invention provides a compound of the present invention as described above, wherein -L 1 -X 1 -L 2 - Partially selected from: -NH-, wherein the bond identified by "c" is connected to ring A, and the bond identified by "d" is connected to R 1 connect.

[0283] In some embodiments, -L1 -X 1 -L 2 - Partially selected

[0284] In some embodiments, -L 1 -X 1 -L 2 - Partially selected -NH-.

[0285] In some embodiments,

[0286] In some embodiments, the present invention provides the compound of formula (I), which has the structure shown in formula (III'):

[0287] wherein X is selected from O or S; preferably X is selected from O.

[0288] In some embodiments, the present invention provides the compound of formula (I), which has the structure shown in formula (III):

[0289] In some embodiments, the present invention provides the compound of formula (I), which has the structure shown in formula (III-1):

[0290] In some embodiments, the present invention provides compounds having structures shown in formulas (III-A) to (III-F):

[0291] In some embodiments, the present invention provides the compound having the structure shown in formula (III-A).

[0292] In some embodiments, the present invention provides the compound having the structure shown in formula (III-B).

[0293] In some embodiments, the present invention provides the compound having the structure shown in Formula (III-C).

[0294] In some embodiments, the present invention provides the compound having the structure shown in Formula (III-D).

[0295] In some embodiments, the present invention provides the compound having the structure shown in Formula (III-E).

[0296] In some embodiments, the present invention provides the compound having the structure shown in Formula (III-F).

[0297] In some embodiments, the present invention provides the compound of formula (I), which has the structure shown in formula (III-2) or (III-3):

[0298] In some embodiments, the compound of formula (I) of the present invention has a structure represented by formula (III-G) or (III-H):

[0299] In some embodiments, the compound of formula (I) of the present invention has a structure represented by formula (III-I) or (III-J):

[0300] In some embodiments, the present invention provides a compound of the present invention as described above, wherein R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclic group, 8-10 membered fused bicyclic heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclyl, 8-10 membered fused bicyclic heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace.

[0301] In some preferred embodiments, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic nitrogen-containing heterocyclic group, 4-6 membered monocyclic oxygen-containing heterocyclic group, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic nitrogen-containing heterocyclic group, 4-6 membered monocyclic oxygen-containing heterocyclic group, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, phenyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace.

[0302] In some embodiments, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace.

[0303] In some embodiments, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, wherein any of the above groups is optionally substituted by 1, 2 or 3 R1a replace.

[0304] In some embodiments, R 1 Selected from C 3-6 Cycloalkyl, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace.

[0305] In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, phenyl and (Preferred ), wherein any of the above groups is optionally replaced by 1, 2 or 3 R 1a replace.

[0306] In some more preferred embodiments, R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, piperidinyl, phenyl and (Preferred ), wherein any of the above groups is optionally replaced by 1, 2 or 3 R 1a replace.

[0307] In some embodiments, R 1 Selected from n-propyl, cyclopentyl, cyclohexyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, phenyl and (Preferred ), wherein any of the above groups is optionally replaced by 1, 2 or 3 R 1a replace.

[0308] In some embodiments, R 1 Selected from n-propyl, cyclopentyl, cyclohexyl and (Preferred ), wherein any of the above groups is optionally replaced by 1, 2 or 3 R 1a replace.

[0309] In some embodiments, R 1 Selected from cyclopentyl and (Preferred ), wherein any of the above groups is optionally replaced by 1, 2 or 3 R 1a replace.

[0310] In some embodiments, R 1 Selected from (Preferred ), which is optionally replaced by 1, 2 or 3 R 1a replace.

[0311] In some embodiments, R 1 A group selected from Groups (1)-(2):

[0312] (1) methyl, ethyl and n-propyl, each of which is optionally substituted with 1, 2 or 3 R 1a replace;

[0313] (2) (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred More preferred ), (Preferred ),

[0314] In some more preferred embodiments, R 1 A group selected from Groups (1)-(2):

[0315] (1) methyl, ethyl and n-propyl, each of which is optionally substituted with 1, 2 or 3 R 1a replace;

[0316] (2) (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ),

[0317] In some embodiments, R 1 Selected from: (Preferred ), (Preferred More preferred ), wherein s is selected from 0, 1 or 2.

[0318] In some embodiments, s is selected from 2.

[0319] In some embodiments, R 1 Selected from: (Preferred More preferred ).

[0320] In some embodiments, R 1 Selected from (Preferred More preferred ).

[0321] In some embodiments, each R 1a Independently selected from halogen, -OH, -CN, oxo, -COOR c 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -C 1-4 Alkylene -OH, -OC 1-4 Alkylene-OH, -C 1-4 Alkylene-COOH, -S(=O)2-C 1-4 Alkyl and

[0322] In some embodiments, each R 1a independently selected from halogen, -OH, -CN, oxo, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -C 1-4 Alkylene-OH, -C 1-4 Alkylene-COOH, -S(=O)2-C1-4 alkyl and

[0323] In some preferred embodiments, each R 1aindependently selected from halogen, -OH, oxo, -COOH, C1-4 alkyl, -C1-4 alkylene-OH, -C1-4 alkylene-COOH, -S(=O)2-C 1-4 Alkyl and

[0324] In some more preferred embodiments, each R 1a independently selected from F, Cl, Br, -OH, oxo, -COOH, methyl, ethyl, isopropyl, tert-butyl, -CH2-OH, -CH2CH2-OH, -C(CH3)2-OH, -CH2-COOH, -CH2CH2-COOH, -C(CH3)2-COOH, -S(=O)2-CH3 and

[0325] In some embodiments, each R 1a Independently selected from -OH, -COOR c 、-C 1-4 Alkylene-OH.

[0326] In some embodiments, each R 1a Independently selected from -OH, -C 1-2 Alkylene-OH.

[0327] In some embodiments, each R 1a independently selected from Cl, -OH, -CN, oxo, -COOH, -COOEt, methyl, ethyl, -CH2-OH, -CH2CH2-OH, -OCH2CH2-OH, -C(CH3)2-OH, -CH2-COOH, -CH2CH2-COOH, -C(CH3)2-COOH, -S(=O)2-CH3 and

[0328] In some more preferred embodiments, each R 1a independently selected from Cl, -OH, oxo, -COOH, methyl, ethyl, -CH2-OH, -CH2CH2-OH, -C(CH3)2-OH, -CH2-COOH, -CH2CH2-COOH, -C(CH3)2-COOH, -S(=O)2-CH3 and

[0329] In some embodiments, each R 1a Independently selected from -OH, -CH2-OH, -COOH, -COOEt.

[0330] In some embodiments, each R 1a Independently selected from -OH, -CH2-OH, -COOH.

[0331] In some embodiments, each R 1a Independently selected from -OH, -CH2-OH.

[0332] In some embodiments, each R 1a are independently selected from -OH.

[0333] In some embodiments, R 1 Selected from:

[0334] In some particularly preferred embodiments, R 1 Selected from:

[0335] In some embodiments, R 1 Selected from:

[0336] In some embodiments, R 1 Selected from:

[0337] In some embodiments, R 1 Selected from:

[0338] In some embodiments, R 1 Selected from:

[0339] In some embodiments, R 1 Selected from:

[0340] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from: (Preferred ), (Preferred ).

[0341] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0342] In some embodiments, -L 1 -X 1 -L2 -R 1 Some selected from:

[0343] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0344] In a further preferred embodiment, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0345] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0346] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0347] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0348] In some embodiments, -L 1 -X 1 -L 2 -R 1 Some selected from:

[0349] In some embodiments, the present invention provides the compound, or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, wherein the compound has a structure represented by any one of Formulas (IV-1) to (IV-4):

[0350] (Preferred ), (Preferred ).

[0351] In some embodiments, the present invention provides the compound, or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, wherein the compound has a structure represented by any one of Formulas (IV-5) to (IV-8):

[0352] (Preferred ), (Preferred ).

[0353] In some embodiments, the present invention provides the compound, or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, wherein the compound has a structure represented by any one of Formulas (V-1) to (V-9):

[0354] (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ).

[0355] In some embodiments, the present invention provides the compound, or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, wherein the compound has a structure represented by any one of Formulas (VI-1) to (VI-14):

[0356] (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ),

[0357] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0358] Preferred More preferred

[0359] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0360] Preferred More preferred

[0361] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0362] Preferred More preferred

[0363] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from the following formulas:

[0364] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from the following formulas:

[0365] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0366] Preferred

[0367] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0368] Preferred

[0369] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0370] Preferred

[0371] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0372] Preferred

[0373] In some embodiments, the present invention provides a compound of formula (I) having a structure selected from one of the following formulae:

[0374] Preferred

[0375] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0376] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0377] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following Table 1:

[0378] Table 1:

[0379] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 1 to Compound 11, Compound 13 to Compound 15, Compound 17 to Compound 24, Compound 28 to Compound 44, Compound 50 to Compound 139, Compound 142 to Compound 203, and Compound 208.

[0380] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 1 to Compound 10, Compound 13, Compound 14, Compound 17 to Compound 24, Compound 28 to Compound 33, Compound 40, Compound 41, Compound 43, Compound 44, Compound 51 to Compound 136, Compound 139, and Compound 208.

[0381] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 11, Compound 15, and Compound 42.

[0382] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 195, Compound 196, and Compound 198.

[0383] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 199, Compound 200, Compound 201, Compound 202, and Compound 203.

[0384] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 137 and Compound 138.

[0385] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 142, Compound 143, and Compound 144.

[0386] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 145, Compound 146, Compound 147, and Compound 148.

[0387] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 149, Compound 150, and Compound 151.

[0388] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from compound 152.

[0389] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from compound 153.

[0390] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 154 to Compound 165.

[0391] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 166 to Compound 168.

[0392] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 34 to Compound 39, Compound 50, Compound 183 to Compound 194, and Compound 197.

[0393] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 169 to Compound 175.

[0394] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 176 to Compound 180.

[0395] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 181 and Compound 182.

[0396] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 1, Compound 3 to Compound 11, Compound 19, Compound 21, Compound 23, Compound 24, Compound 38, Compound 50, Compound 51.

[0397] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 3, Compound 5 to Compound 9, Compound 19, Compound 21, Compound 23, Compound 50 and Compound 51.

[0398] In some embodiments, the present invention provides a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is selected from Compound 1, Compound 2, Compound 53, Compound 54, Compound 55, and Compound 56.

[0399] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 3 to Compound 10, Compound 14, Compound 18, Compound 19, Compound 21 to Compound 24, Compound 40, Compound 41, Compound 43, Compound 44, Compound 51, Compound 57 to Compound 63, Compound 80 to Compound 82, Compound 85 to Compound 87, Compound 91, Compound 92 to Compound 96, Compound 99, Compound 101, Compound 103, Compound 104, Compound 136.

[0400] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 34, Compound 35, Compound 37, Compound 38, Compound 187, Compound 188, Compound 189, and Compound 190.

[0401] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 36, Compound 39, Compound 50, Compound 191 to Compound 194.

[0402] Preparation method of compound

[0403] The compounds according to the present invention can be synthesized using one of the following synthetic routes as needed.

[0404] Synthesis Route 1

[0405] Compounds 1-1 and 1-2 undergo curtius rearrangement to obtain intermediate 1-3, and intermediate 1-3 undergoes Suzuki coupling reaction with 1-4 to obtain a compound of formula (I); Ring A, L 1 , L 2 , L 3 、X 1 、R 1 and R 2 Each is as defined above.

[0406] Synthesis Route 2

[0407] Compounds 2-1 and 1-2 undergo condensation reaction with triphosgene to obtain intermediate 1-3, and intermediate 1-3 undergoes Suzuki coupling reaction with 1-4 to obtain a compound of formula (I); Ring A, L 1 , L 2 , L 3 、X 1 、R 1 and R 2 Each is as defined above.

[0408] Synthesis Route 3

[0409] Compounds 1-1 and 1-2 undergo a curtius rearrangement reaction to obtain intermediate 1-3, and intermediate 1-3 undergoes a Suzuki coupling reaction with 3-2 to obtain a compound of formula (I); Ring A, L 1 , L 2 , L 3 、X 1 、R 1 and R 2 Each is as defined above.

[0410] Synthesis Route 4

[0411] Wherein, compound 4-1 undergoes sonogashira coupling reaction with 4-2 to obtain intermediate 4-3, and intermediate 4-3 undergoes curtius rearrangement reaction with 1-2 to obtain compound of formula (I); Ring A, L 1 , L 2 , L 3 、X 1 、R 1 and R 2 Each is as defined above.

[0412] Pharmaceutical compositions and uses

[0413] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0414] In another aspect, the present invention provides a compound of the present invention as described above, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or the pharmaceutical composition of the present invention for the preparation of a medicament.

[0415] In another aspect, the present invention provides a method for activating AMPK kinase, comprising contacting the AMPK kinase with a compound of the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate, or pharmaceutically acceptable salt thereof. In some embodiments, the method is performed in vitro or ex vivo. In other embodiments, the method is performed in vivo.

[0416] In another aspect, the present invention provides use of a compound of the present invention as described above, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention in the preparation of a medicament as an AMPK agonist.

[0417] In some embodiments, the compound of the present invention, the pharmaceutical composition of the present invention, or the medicament is used to treat and / or prevent a disease, disorder or condition associated with AMPK kinase.

[0418] In some embodiments, the compound of the invention, the pharmaceutical composition of the invention, or the medicament is used to treat and / or prevent a disease, disorder, or condition that can be treated and / or prevented by activating AMPK.

[0419] In another aspect, the present invention also provides a method for treating and / or preventing diseases, disorders or conditions associated with AMPK kinase, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention as described above, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0420] In another aspect, the present invention also provides a method for treating and / or preventing diseases, disorders or conditions that can be treated and / or prevented by activating AMPK, comprising administering to a subject in need thereof an effective amount of a compound of the present invention as described above, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0421] In another aspect, the present invention provides a compound of the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in treating and / or preventing a disease, disorder or condition associated with AMPK kinase.

[0422] In another aspect, the present invention provides a compound of the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in treating and / or preventing diseases, disorders or conditions that can be treated and / or prevented by activating AMPK.

[0423] In some embodiments, the disease, disorder or condition is selected from type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease and alopecia. In some embodiments, the disease, disorder or condition is alopecia.

[0424] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0425] As used herein, unless otherwise indicated, the terms "treat," ...

[0426] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0427] In other embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0428] Example

[0429] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0430] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0431] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0432] Thin layer chromatography separation and purification were performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF 254 produced in Yantai).

[0433] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0434] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0435] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0436] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0437] Synthesis Example

[0438] Example 1: Synthesis of Compound 1

[0439] Step 1: To a 50 mL reaction flask at room temperature, 1a (4.00 g, 19.32 mmol), N,N-dimethylformamide (30 mL), and N-chlorosuccinimide (3.87 g, 28.98 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 50°C for 16 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain intermediate 1b. LC-MS: m / z: 240.8 (M+H) + .

[0440] Step 2: To a 250 mL reaction flask at room temperature, 1b (200 mg, 0.82 mmol), 1c (605 mg, 4.12 mmol), dioxane (10 mL), diphenylphosphoryl azide (274 mg, 1.00 mmol), and triethylamine (335 mg, 3.32 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography to yield intermediate 1d. LC-MS: m / z: 384.0 (M+H) + .

[0441] Step 3: Under nitrogen, 1d (55 mg, 0.14 mmol), 1e (32.95 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (11.68 mg, 0.01 mmol), potassium carbonate (59.29 mg, 0.43 mmol), dioxane (2 mL), and water (0.4 mL) were added to an 8 mL microwave tube. The reaction was complete after two hours at 100°C. The reaction solution was then concentrated under reduced pressure to obtain the crude product, which was then isolated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 1. LC-MS: m / z: 452.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.42(d,J=8.3Hz,2H),7.37(d,J=8.4Hz,2H),6.52( s,1H),5.08(q,J=5.9Hz,1H),4.94(d,J=6.3Hz,1H),4.70(s,1H),4.64(t,J=5.1Hz,1H),4 .30(t,J=4.9Hz,1H),4.12(s,1H),3.96(dd,J=9.5,6.2Hz,1H),3.78(dt,J=15.3,8.5Hz,2 H),3.55(d,J=4.1Hz,2H),3.40(d,J=8.6Hz,1H),0.85(t,J=2.9Hz,2H),0.79-0.73(m,2H).

[0442] Example 2: Synthesis of Compound 2

[0443] Step 1: To a 25 mL single-necked vial, add 2a (450 mg, 1.62 mmol), dioxane hydrochloride solution (3 mL), and dioxane (9 mL). Allow to react at room temperature for 3 hours until complete. Concentrate the reaction mixture under reduced pressure to yield 2b. LC-MS: m / z: 178.0 (M+H) + .

[0444] Step 2: To a 25 mL single-necked bottle, 2b (288 mg, 1.62 mmol), 2c (1.24 mg, 3.24 mmol), triethylamine (982.0 mg, 9.71 mmol), dichloromethane (10 mL) and triphosgene (479.97 mg, 1.62 mmol) were added in sequence. The nitrogen atmosphere was replaced and the reaction was allowed to proceed overnight at room temperature until the reaction was complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (7 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column to obtain intermediate 2d. LC-MS: m / z: 610.2 (M+Na) + . 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.70-7.66(m,2H),7.63-7.59(m,2H),7 .49-7.42(m,6H),6.93(d,J=1.9Hz,1H),6.45(d,J=1.9Hz,1H),5.06(q,J=5.7 Hz,1H),4.56(t,J=5.1Hz,1H),4.18(q,J=6.5,4.9Hz,2H),3.99-3.93(m,1H), 3.90-3.84(m,1H),3.69(t,J=7.3Hz,1H),3.53(t,J=8.0Hz,1H),1.02(s,9H).

[0445] Step 3: Under nitrogen protection, 2d (60 mg, 0.1 mmol), 1e (55.90 mg, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (24.97 mg, 0.03 mmol), potassium carbonate (70.44 mg, 0.51 mmol), dioxane (5 mL), and water (1 mL) were added to a 25 mL single-necked flask. The reaction was completed after 16 hours at 90°C. The crude product was then concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to obtain intermediate 2e. LC-MS: m / z: 656.4 (M+H) + .

[0446] Step 4: Add 2e (30 mg, 0.05 mmol), tetrabutylammonium fluoride in tetrahydrofuran (90 uL, 0.09 mmol), and tetrahydrofuran (2 mL) to a 25 mL single-necked flask. Replace the atmosphere with nitrogen and allow the reaction to proceed overnight at room temperature until completion. Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18-10μm-19*250mm) was separated and purified to prepare compound 2. LC-MS: m / z: 418.1 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=8.2Hz,2H),7.31(d,J=8.0Hz,2H),7.19(s ,1H),6.89(s,1H),5.08(q,J=5.9Hz,1H),4.97(d,J=6.4Hz,1H),4.70(t,J=5. 5Hz,1H),4.64(t,J=5.2Hz,1H),4.31(t,J=5.0Hz,1H),4.15-4.10(m,1H),4. 00-3.96(m,1H),3.82-3.75(m,3H),3.54(d,J=5.5Hz,2H),0.86-0.73(m,4H).

[0447] Example 3: Synthesis of Compound 3

[0448] Step 1: To a 250 mL reaction flask at room temperature, 3a (1000 mg, 4.14 mmol), 1c (3026 mg, 20.71 mmol), dioxane (80 mL), diphenylphosphoryl azide (1368 mg, 4.97 mmol), and triethylamine (629 mg, 6.21 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo, and the resulting residue was purified on a silica gel column to yield intermediate 3b. LC-MS: m / z: 384.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.37(s,1H),6.41(s,1H),5.08(q,J=5.8Hz,1H),4.63(t,J=5.1Hz,1H),4. 29(t,J=4.9Hz,1H),4.15-4.08(m,1H),3.98-3.92(m,1H),3.82-3.72(m,2H),3.38(t,J=8.5Hz,1H).

[0449] Step 2: At room temperature, 3b (80 mg, 0.21 mmol), 1e (68.43 mg, 0.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (16.99 mg, 0.02 mmol), potassium carbonate (86.23 mg, 0.62 mmol), dioxane (3 mL), and water (0.60 mL) were added to a 10 mL microwave tube. The mixture was reacted at 100°C for two hours under nitrogen protection. After the reaction, the reaction solution was filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 3. LC-MS: m / z: 452.1 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.48(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),6.49(s ,1H),5.08(q,J=5.9Hz,1H),4.94(d,J=6.4Hz,1H),4.70(t,J=5.7Hz,1H),4.64(t,J=5.1H z,1H),4.30(t,J=4.9Hz,1H),4.17-4.08(m,1H),3.97(dd,J=9.5,6.2Hz,1H),3.83-3.71( m,2H),3.55(d,J=5.7Hz,2H),3.39(t,J=8.5Hz,1H),0.91-0.81(m,2H),0.81–0.72(m,2H).

[0450] Example 4: Synthesis of Compound 4

[0451] Under nitrogen, an 8 mL microwave tube was charged with 3b (100 mg, 0.26 mmol), 4a (61.78 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19.02 mg, 0.03 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (2 mL), and water (0.4 mL). The reaction was complete after two hours at 100°C under microwave conditions. The product was then concentrated under reduced pressure to obtain the crude product, which was then separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 4. LC-MS: m / z: 458.1 (M+H). + ,1 H NMR (400MHz, CDCl3) δ7.73 (d, J = 8.4Hz, 2H), 7.68-7.55 (m, 4H), 7.51-7.38 (m ,3H),7.36(t,J=7.3Hz,1H),6.53(s,1H),5.25(q,J=6.2Hz,1H),4.74(t,J=5. 1Hz,1H),4.56(t,J=5.2Hz,1H),4.35(q,J=6.0Hz,1H),4.21(dd,J=9.4,6.4H z,1H),4.01(dd,J=9.3,6.0Hz,1H),3.90(t,J=8.2Hz,1H),3.75-3.58(m,1H).

[0452] Example 5: Synthesis of Compound 5

[0453] Under nitrogen protection, 3b (100 mg, 0.26 mmol), 5a (80.23 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19.02 mg, 0.03 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (2 mL), and water (0.4 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours at 100°C under microwave conditions. The product was then concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 5. LC-MS: m / z: 435.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.74(d,J=1.8Hz,1H),7.51(d,J=8.6Hz,1H), 7.38(d,J=3.1Hz,1H),7.34(dd,J=8.5,1.8Hz,1H),6.62-6.37(m,2H),5.08(q,J=6. 0Hz,1H),4.94(d,J=6.5Hz,1H),4.64(t,J=5.1Hz,1H),4.30(t,J=4.9Hz,1H),4.19- 4.06(m,1H),3.98(dd,J=9.4,6.2Hz,1H),3.90-3.65(m,5H),3.40(t,J=8.5Hz,1H).

[0454] Example 6: Synthesis of Compound 6

[0455] Under nitrogen protection, 3b (100 mg, 0.26 mmol), 6a (77.0 mg, 0.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (21 mg, 0.03 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (2 mL), and water (0.5 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours at 100°C under microwave conditions. The product was then concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was separated and purified to obtain compound 6. LC-MS: m / z: 474.0 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ11.20 (s, 1H), 9.66 (s, 1H), 7.62 (d, J = 1.5Hz, 4H), 7.30 (dd ,J=7.6,1.7Hz,1H),7.20-7.15(m,1H),6.96(d,J=8.0Hz,1H),6.89(t,J=7.5Hz,1H) ,6.53(s,1H),5.12-5.07(m,1H),4.95(s,1H),4.65(t,J=5.1Hz,1H),4.30(t,J=4.9 Hz,1H),4.13(s,1H),3.99-3.96(m,1H),3.83-3.75(m,2H),3.40(t,J=8.5Hz,,1H).

[0456] Example 7: Synthesis of Compound 7

[0457] At room temperature, 3b (100 mg, 0.26 mmol), 7a (85.54 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (21.23 mg, 0.03 mmol), potassium carbonate (107.79 mg, 0.78 mmol), dioxane (3.00 mL), and water (0.60 mL) were added to a 10 mL microwave tube. The mixture was microwaved at 100°C for two hours under nitrogen protection. After the reaction, the reaction solution was filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18-10μm-19*250mm) to separate and purify to obtain compound 7. LC-MS: m / z: 434.2 (M+H-18) + , 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),7.55(s,4H),6.51(s,1H),5.54(s,1H),5.08(q,J=6.0Hz,1H),4.94(d,J=6.4Hz,1H),4.64(t,J=5.1Hz, 1H),4.30(t,J=4.9Hz,1H),4.17–4.09(m,1H),3.97(dd,J=9.5,6.2Hz,1H),3.83–3.74(m,2H),3.39(t,J=8.5Hz,1H),2.44–2.36(m,2H),2.32–

[0458] 2.23(m,2H),1.98–1.87(m,1H),1.72–1.60(m,1H).

[0459] Example 8: Synthesis of Compound 8

[0460] Step 1: Add 8a (1 g, 4.52 mmol), 1c (3.31 g, 22.62 mmol), diphenylphosphoryl azide (1.49 mg, 5.43 mmol), triethylamine (0.92 g, 9.05 mmol) and dioxane (20 mL) to a 25 mL single-necked bottle. Replace the nitrogen atmosphere and react at 90 ° C for 15 hours to complete the reaction. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column to obtain intermediate 8b. LC-MS: m / z: 364.0 (M+H) + .

[0461] Step 2: Under nitrogen protection, 8b (100 mg, 0.27 mmol), 8c (88.83 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (22.42 mg, 0.03 mmol), potassium carbonate (94.86 mg, 0.69 mmol), dioxane (2 mL), and water (0.4 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours at 100°C under microwave conditions. The product was then concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18-10μm-19*250mm) was separated and purified to obtain compound 8. LC-MS: m / z: 432.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ7.33-7.28(m,4H),6.42(s,1H),5.07-5.02(m,1H), 4.97-4.84(m,1H),4.71-4.64(m,1H),4.62(t,J=5.2Hz,1H),4.30(t,J=4.8H z,1H),4.14-4.09(m,1H),3.99-3.95(m,1H),3.81-3.71(m,2H),3.54(s,2H ),3.39(t,J=8.4Hz,1H),2.17(s,3H),8.54-8.29(m,2H),0.76-0.73(m,2H).

[0462] Example 9: Synthesis of Compound 9

[0463] Under nitrogen, an 8 mL microwave tube was charged with 3b (100 mg, 0.26 mmol), 9a (64.6 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19.02 mg, 0.03 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (2 mL), and water (0.4 mL). The reaction was complete after two hours at 100°C under microwave conditions. The product was then concentrated under reduced pressure to afford the crude product, which was then separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to afford compound 9. LC-MS: m / z: 467.2 (M+H). + . 1H NMR (400MHz, CDCl3) δ7.55(d,J=8.4Hz,1H),7.33(s,1H),6.94(d,J=8.6Hz,1H),6.49(s,1H),5.23(dd,J=12.0,6.4Hz,1H),4.73(t,J=5.0Hz,1 H),4.55(t,J=5.1Hz,1H),4.34(d,J=6.0Hz,1H),4.24–4.14(m,1H),4.01(dd,J=9.3,6.0Hz,1H),3.88(s,5H),3.72–3.62(m,1H),3.22(s,4H).

[0464] Example 10: Synthesis of Compound 10

[0465] At room temperature, 3b (100 mg, 0.26 mmol), 10a (47.41 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (21.23 mg, 0.03 mmol), potassium carbonate (107.79 mg, 0.78 mmol), dioxane (3.00 mL), and water (0.60 mL) were added to a 10 mL microwave tube. The mixture was reacted at 100°C for two hours under nitrogen protection. After the reaction, the reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was separated and purified to obtain compound 10. LC-MS: m / z: 412.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.50(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.48(s,1H),5.08(q,J=6.0Hz,1H),4.94(d,J=6.4Hz,1 H),4.63(t,J=5.1Hz,1H),4.30(t,J=4.9Hz,1H),4.16–4.08(m,1H),3.97(dd,J=9.4,6.2Hz,1H),3.82–3.73(m,5H),3.39(t,J=8.5Hz,1H).

[0466] Example 11: Synthesis of Compound 11

[0467] Step 1: To a 250 mL reaction flask at room temperature, 3a (500 mg, 2.07 mmol), 11a (788 mg, 10.35 mmol), dioxane (20 mL), diphenylphosphoryl azide (684 mg, 2.48 mmol), and triethylamine (314 mg, 3.11 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times and stirred at 90°C for 16 hours. After completion of the reaction, the reaction solution was concentrated in vacuo, and the resulting residue was purified on a silica gel column to yield compound 11b. LC-MS: m / z: 313.9 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.16(s,1H),6.39(s,1H),4.56(t,J=5.1Hz,1H),4.19(t,J=6.5Hz,2H),3.53-3.46(m,2H),1.81-1.73(m,2H).

[0468] Step 2: At room temperature, 11b (100 mg, 0.32 mmol), 1e (104.59 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (25.96 mg, 0.03 mmol), potassium carbonate (131.79 mg, 0.95 mmol), dioxane (3 mL), and water (0.60 mL) were added to a 10 mL microwave tube. The mixture was microwaved at 100°C for two hours under nitrogen protection. After the reaction, the reaction mixture was filtered, and the crude filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was separated and purified to obtain compound 11 (61.60mg, 0.16mmol). LC-MS: m / z: 382.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.48(d,J=8.2Hz,2H),7.36(d,J=8.1Hz,2H),6.48(s,1H),4.70(t,J=5.6Hz,1H),4.56(t,J=5.1Hz,1H), 4.19(t,J=6.5Hz,2H),3.55(d,J=5.7Hz,2H),3.50(q,J=5.9Hz,2H),1.82-1.73(m,2H),0.85(q,J=4.2,3.6Hz,2H),0.76(q,J=4.6,4.2Hz,2H).

[0469] Example 12: Synthesis of Compound 12

[0470] Step 1: To a 25 mL single-necked vial at room temperature, add 12a (200 mg, 0.90 mmol) and dissolve in extra-dry tetrahydrofuran (3.0 mL). Add N,N'-carbonyldiimidazole (290 mg, 1.80 mmol). Incubate at 60°C under nitrogen for 1 hour until the reaction is complete. The reaction solution containing intermediate 12b is used directly in the next reaction without purification.

[0471] Step 2: To the reaction system containing intermediate 12b, 1c (200 mg, 1.35 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.60 mmol) were added at room temperature and allowed to react at 60°C under nitrogen for 1 hour. The reaction was complete. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 12c. LC-MS: m / z: 378.0 (M+H). + .

[0472] Step 3: At room temperature, 12c (55 mg, 0.15 mmol), 8c (133.47 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (10.63 mg, 0.01 mmol), potassium carbonate (40.15 mg, 0.29 mmol), dioxane (3.0 mL) and water (0.6 mL) were added to a 25 mL single-necked bottle in sequence. After nitrogen replacement three times, the reaction solution was reacted at 90°C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain the crude product, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, chromatographic column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 12. LC-MS: m / z: 446.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),7.73(d,J=2.2Hz,1H),7.45(dd,J=8.5,2.2Hz,1H),7.36(d,J=8.5Hz, 2H),7.31(d,J=8.4Hz,3H),5.07(q,J=6.2Hz,1H),4.93(d,J=6.4Hz,1H),4.70(t,J=5.6Hz,1H),4.64(t,J=5 .0Hz,1H),4.32(t,J=4.8Hz,1H),4.14(m,1H),3.99(dd,J=9.2,6.3Hz,1H),3.81(dd,J=8.1,6.8Hz,1H),3.7 5(dd,J=9.2,6.5Hz,1H),3.56(d,J=5.7Hz,2H),3.42(t,J=8.5Hz,1H),0.91–0.83(m,2H),0.80–0.71(m,2H).

[0473] Example 13: Synthesis of Compound 13

[0474] Step 1: At room temperature, 13a (200 mg, 0.97 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (8.0 mL). Triethylamine (0.54 mL, 3.86 mmol), diphenylphosphoryl azide (531.68 mg, 1.93 mmol), and 1c (564.68 mg, 3.86 mmol) were then added sequentially. The atmosphere was purged with nitrogen three times, and the reaction mixture was allowed to react at 90°C overnight. After completion of the reaction, the reaction mixture was poured into water (70 mL) and extracted with ethyl acetate (7 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain intermediate 13b. LC-MS: m / z: 352.0 (M+H). + .

[0475] Step 2: At room temperature, 13b (60 mg, 0.17 mmol), 8c (39.48 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (12.54 mg, 0.02 mmol), potassium carbonate (47.36 mg, 0.34 mmol), dioxane (3.0 mL) and water (0.6 mL) were added to a 25 mL single-necked bottle in sequence. After nitrogen substitution three times, the reaction solution was reacted at 90°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 13. LC-MS: m / z: 418.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.50–7.41(m,2H),7.37–7.30(m,2H),7.28(d,J=1.5Hz,1H),7. 14(s,1H),5.05(q,J=6.2Hz,1H),4.92(d,J=6.4Hz,1H),4.69(t,J=5.7Hz,1H),4.63(t,J=5.1Hz,1H),4 .31(t,J=4.8Hz,1H),4.13(m,1H),3.99(dd,J=9.2,6.4Hz,1H),3.80(dd,J=8.1,6.8Hz,1H),3.72(dd, J=9.2,6.6Hz,1H),3.54(d,J=5.6Hz,2H),3.41(t,J=8.5Hz,1H),0.89–0.82(m,2H),0.78–0.70(m,2H).

[0476] Example 14: Synthesis of Compound 14

[0477] Under nitrogen, 3b (100 mg, 0.26 mmol), 14a (54.64 mg, 0.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19.02 mg, 0.03 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (2 mL), and water (0.4 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours at 100°C under microwave conditions. The product was then concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 14. LC-MS: m / z: 451.2 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 7.37 (d, J = 8.4Hz, 2H), 6.58 (d, J = 8. 8Hz,2H),6.44(s,1H),5.08-5.04(m,1H),4.93(d,J=6.4Hz,1H),4.63(t,J=4 .8Hz,1H),4.30(t,J=4.8Hz,1H),4.15-4.08(m,1H),3.98-3.94(m,1H),3.8 1-3.72(m,2H),3.39(t,J=8.4Hz,1H),3.26-3.23(m,4H),1.97-1.93(m,4H).

[0478] Example 15: Synthesis of Compound 15

[0479] At room temperature, 11b (100 mg, 0.32 mmol), 15a (66.75 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (25.96 mg, 0.03 mmol), potassium carbonate (131.79 mg, 0.95 mmol), dioxane (3 mL), and water (0.60 mL) were added to a 10 mL microwave tube. The mixture was microwaved at 100°C for two hours under nitrogen protection. After the reaction, the reaction mixture was filtered, and the crude filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 15. LC-MS: m / z: 364.9 (M+H) + . 1HNMR(400MHz,DMSO-d6)δ8.01(s,1H),7.74(s,1H),7.50(d,J=8.6Hz,1H),7.40–7.28(m,2H), 6.48(s,2H),4.57(s,1H),4.19(d,J=6.8Hz,2H),3.81(s,3H),3.51(s,2H),1.83-1.69(m,2H).

[0480] Example 16: Synthesis of Compound 16

[0481] Step 1: At room temperature, 16a (200 mg, 0.98 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (10.0 mL). 1c (570.27 mg, 3.90 mmol), diphenylphosphoryl azide (1073.90 mg, 3.90 mmol), and triethylamine (0.54 mL, 3.90 mmol) were then added. The mixture was purged and reacted at 90°C overnight under nitrogen. The reaction was complete. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain intermediate 16b. LC-MS: m / z: 350.1 (M+H). + .

[0482] Step 2: At room temperature, 16b (130 mg, 0.4 mmol), 8c (115.82 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58.85 mg, 0.08 mmol), potassium carbonate (111.15 mg, 0.80 mmol), dioxane (8.0 mL) and water (1.6 mL) were added to a 50 mL single-necked bottle. The mixture was purged and reacted at 90°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain a crude product, which was then purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 16. LC-MS: m / z: 416.2 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.75(s,1H),8.76(s,1H),7.47–7.40(m,4H),4.98(d,J=5.2Hz,1H),4.63–4.55(m,1H),4.26(s,2H) ,4.10(s,2H),3.91(s,2H),3.75(s,2H),3.70(s,3H),3.58(s,2H),0.90(dd,J=6.4,4.8Hz,2H),0.80(dd,J=6.4,4.8Hz,2H).

[0483] Example 17: Synthesis of Compound 17

[0484] Step 1: At room temperature, 1a' (3 g, 18.45 mmol), [bis(trifluoroacetoxy)iodo]benzene (4.30 g, 9.96 mmol), elemental iodine (2.34 g, 9.22 mmol), and carbon tetrachloride (50 mL) were added to a 100 mL single-necked flask. The reaction was allowed to proceed for five hours at room temperature until complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried three times with petroleum ether / dichloromethane (V:V = 10:1) to obtain intermediate 17a. LC-MS: m / z: 288.8 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.58 (s, 1H).

[0485] Step 2: To a 25 mL single-necked vial was added 17a (300 mg, 1.04 mmol), 17b (127.46 mg, 1.25 mmol), bistriphenylphosphine palladium dichloride (72.99 mg, 0.10 mmol), cuprous iodide (39.61 mg, 0.21 mmol), N,N-diisopropylethylamine (201.62 mg, 1.56 mmol), and tetrahydrofuran (10 mL). The reaction was allowed to proceed at room temperature for 16 hours, and the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain intermediate 17c. LC-MS: m / z: 263.0 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ7.66(s,1H),7.62-7.59(m,2H),7.50-7.45(m,3H).

[0486] Step 3: To a 25 mL single-necked vial were added 17c (200 mg, 0.76 mmol), 1c (556.28 mg, 3.81 mmol), dioxane (15 mL), triethylamine (115.55 mg, 1.14 mmol), and diphenylphosphoryl azide (251.41 mg, 0.91 mmol). The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 17. LC-MS: m / z: 406.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),7.55-7.50(m,2H),7.45-7.40(m,3H),6.49(s,1H),5.11(q,J=5.8Hz,1H),4.95(d,J=6.4Hz,1H), 4.65(t,J=5.1Hz,1H),4.29(t,J=4.9Hz,1H),4.16-4.08(m,1H),3.96(dd,J=9.5,6.1Hz,1H),3.83-3.75(m,2H),3.38(t,J=8.5Hz,1H).

[0487] Example 18: Synthesis of Compound 18

[0488] Step 1: To a 50 mL single-necked flask at room temperature were added 18a (1500 mg, 7.65 mmol), 18b (1314 mg, 15.30 mmol), 2,2'-bipyridine (1195 mg, 7.65 mmol), sodium carbonate (1622 mg, 15.30 mmol), anhydrous copper acetate (1390 mg, 7.65 mmol), and 1,2-dichloroethane (20 mL). The atmosphere was purged with nitrogen three times and the reaction was complete after 16 hours at 70°C. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate 18c. LC-MS: m / z: 236.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.73(d,J=1.9Hz,1H),7.51(dt,J=8.7,0.7Hz,1H),7.37(d,J=3.2Hz,1H),7.28(dd,J=8 .6, 2.0Hz, 1H), 6.38 (dd, J=3.1, 0.8Hz, 1H), 3.43 (tt, J=7.2, 3.7Hz, 1H), 1.09-1.02 (m, 2H), 0.96-0.90 (m, 2H).

[0489] Step 2: To a 25 mL single-necked flask at room temperature, 18c (1500 mg, 6.35 mmol), potassium acetate (1870 mg, 19.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (519 mg, 0.64 mmol), bipyralidoborane (1936 mg, 7.62 mmol), and dioxane (20 mL) were added. The reaction was complete after 16 hours at 80°C. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate 18d. LC-MS: m / z: 284.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.56-7.47(m,2H),7.31(d,J=3.2Hz,1H),6.43(d,J=3.1Hz,1H),3.46-3.39(m,1H),1.30(s, 12H),1.09-1.02(m,2H),0.96–0.90(m,2H).

[0490] Step 3: Under nitrogen protection, 18d (100 mg, 0.26 mmol), 3b (88.35 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (21.23 mg, 0.03 mmol), potassium carbonate (107.79 mg, 0.78 mmol), dioxane (3 mL), and water (0.6 mL) were added to an 8 mL microwave tube. The reaction was completed after 2 hours of microwave reaction at 100°C. The solid was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 18. LC-MS: m / z: 461.1 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.73(s,1H),7.62(d,J=8.5Hz,1H),7.40-7.34(m,2H ),6.50(s,1H),6.45(d,J=3.2Hz,1H),5.08(q,J=6.0Hz,1H),4.94(d,J=6.4Hz,1H),4.64(t, J=5.1Hz,1H),4.30(t,J=4.9Hz,1H),4.17-4.09(m,1H),3.97(dd,J=9.4,6.2Hz,1H),3.85-3 .71(m,2H),3.49-3.43(m,1H),3.40(t,J=8.5Hz,1H),1.10-1.04(m,2H),0.99-0.93(m,2H).

[0491] Example 19: Synthesis of Compound 19

[0492] Step 1: Under nitrogen, a 100 mL single-necked flask was charged with 19a (1.1 g, 3.89 mmol), 19b (1 g, 3.53 mmol), palladium acetate (80 mg, 0.35 mmol), potassium phosphate (2.25 g, 10.6 mmol), dioxane (20 mL), and water (4 mL). The reaction was allowed to proceed at 100°C for 15 hours, after which the reaction was complete. After completion of the reaction, the temperature was lowered, the mixture was filtered, and the filtrate was concentrated under reduced pressure to yield the crude product, which was then purified on a silica gel column to afford intermediate 19c. 1 H NMR (400MHz, CDCl3) δ8.06-7.98(m,2H),7.78-7.70(m,2H),7.67-7.58(m,2H),7.48(d,J=8.5Hz,2H),3.09(s,3H).

[0493] Step 2: Under nitrogen, to a 15 mL single-necked vial was added 19c (200 mg, 0.64 mmol), pinacol diboron (195.8 mg, 0.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (47.03 mg, 0.06 mmol), potassium acetate (126.15 mg, 1.29 mmol), and dioxane (2 mL). The reaction was heated to 90°C for 15 hours, after which the reaction was complete. After completion of the reaction, the reaction was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to afford intermediate 19d. 1H NMR (400MHz, CDCl3) δ8.04-7.97(m,2H),7.96-7.88(m,2H),7.82-7.77(m,2H),7.66-7.59(m,2H),3.09(s,3H),1.37(s,12H).

[0494] Step 3: Under nitrogen, an 8 mL microwave tube was charged with 19d (71.72 mg, 0.20 mmol), 3b (70 mg, 0.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13.32 mg, 0.02 mmol), potassium carbonate (62.88 mg, 0.45 mmol), dioxane (2 mL), and water (0.4 mL). The reaction was heated to 100°C for 2 hours until complete. After completion, the reaction mixture was cooled and poured into water (10 mL). Extraction was performed with ethyl acetate (2 mL x 3). The organic phase was washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then isolated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 19. LC-MS: m / z: 536.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.03-7.98(m,4H),7.87-7.85(m,2H),7.76-7.74(m,2H),6.55(s,1H),5.10(q,J=5.9Hz ,1H),4.96(s,1H),4.65(t,J=5.1Hz,1H),4.31(t,J=4.9Hz,1H),4.13(m,1H),3.98(dd,J=9.5,6.2Hz,1H),3.79(m,2H),3.41(m 1H),3.27(s,3H).

[0495] Example 20: Synthesis of Compound 20

[0496] Step 1: Under nitrogen protection at room temperature, 20a (2.2 g, 10.00 mmol), 20b (1.71 mL, 12.00 mmol), cuprous iodide (0.04 g, 0.20 mmol), bis(triphenylphosphine)palladium dichloride (0.07 g, 0.10 mmol), and tetrahydrofuran (30 mL) were added to a 100 mL single-necked flask. Triethylamine (12 mL) was added under stirring. The reaction was complete after 16 hours at room temperature. The reaction solution was then filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 20c. LC-MS: m / z: 191.1 (M+H) + .

[0497] Step 2: To a 100 mL single-necked flask at room temperature, add 20c (2.5 g, 13.14 mmol) and tetrahydrofuran (15 mL). Add tetrabutylammonium fluoride (11 mL, 1.0 M) with stirring. After three hours at room temperature, the reaction is complete. The reaction solution is then filtered and concentrated under reduced pressure to yield the crude product, which is then purified on a silica gel column to afford intermediate 20d. 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),7.30(dd,J=7.6,1.7Hz,1H),7.22-7.15(m,1H),6.87(dd,J=8.2,1.2Hz,1H),6.79-6.74(m,1H),4.12(s,1H).

[0498] Step 3: Under nitrogen, 1a' (1 g, 6.15 mmol), 1c (4.49 g, 30.75 mmol), diphenylphosphoryl azide (2.03 g, 7.38 mmol), triethylamine (0.93 g, 9.22 mmol), and dioxane (60 mL) were added to a 100 mL single-necked flask. The reaction was complete after 16 hours at 90°C. The reaction solution was then filtered and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate 20e. LC-MS: m / z: 306.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),6.94(d,J=1.9Hz,1H),6.46(d,J=1.9Hz,1H),5.06(q,J=6.0Hz,1H),4.93(d,J=6.5Hz,1H ),4.62(t,J=5.1Hz,1H),4.29(t,J=4.9Hz,1H),4.15-4.10(m,1H),3.98-3.94(m,1H),3.81-3.72(m,2H),3.38(t,J=8.5Hz,1H).

[0499] Step 4: At room temperature, 20e (1.11 g, 3.63 mmol), silver nitrate (0.74 g, 4.36 mmol), iodine (1.01 g, 3.99 mmol), dimethyl sulfoxide (5 mL), and acetonitrile (20 mL) were added to a 100 mL single-necked flask. The reaction was completed after two hours at room temperature. The reaction solution was poured into a saturated sodium thiosulfate solution (100 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried three times with petroleum ether / dichloromethane (V:V = 5:1) to obtain intermediate 20f. LC-MS: m / z: 432.0 (M+H) + .

[0500] Step 5: Under nitrogen protection at room temperature, 20f (100 mg, 0.23 mmol), 20d (41.06 mg, 0.35 mmol), cuprous iodide (8.82 mg, 0.05 mmol), bis(triphenylphosphine)palladium dichloride (16.26 mg, 0.02 mmol), and tetrahydrofuran (4 mL) were added to a 25 mL single-necked flask. Triethylamine (1 mL) was added under stirring. The reaction was completed after 16 hours at room temperature. The reaction solution was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 20. LC-MS: m / z: 421.8 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),7.70-7.63(m,1H),7.60(d,J=8.0Hz,1H),7.36-7.24(m,3H),6.59(s,1H),5.12(q,J=5.9Hz,1H),4 .96(d,J=6.4Hz,1H),4.66(t,J=5.2Hz,1H),4.31(t,J=4.9Hz,1H),4.19-4.08(m,1H),4.00-3.96(m,1H),3.85-3.73(m,2H),3.41(m,1H).

[0501] Example 21: Synthesis of Compound 21

[0502] Step 1: Under nitrogen protection at 0°C, 21a (3.9 g, 25.16 mmol) and 21b (10 mL) were added to a 100 mL single-necked flask. Aluminum chloride (3.35 g, 25.13 mmol) was added under stirring. The reaction was completed after 24 hours at room temperature. The reaction solution was poured into ice water (100 mL) and extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 21c. LC-MS: m / z: 274.8 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.95-7.87(m,2H),7.75-7.68(m,2H),3.68(t,J=6.3Hz,2H),3.05(t,J=6.8Hz,2H),1.87-1.70(m,4H).

[0503] Step 2: To a 250 mL single-necked flask at 0°C, add 21c (3 g, 10.95 mmol) and methanol (30 mL), followed by the slow addition of sodium borohydride (624 mg, 16.42 mmol). Allow to react for two hours at room temperature until the reaction is complete. The crude product is then concentrated under reduced pressure and purified by silica gel column chromatography to yield intermediate 21d. LC-MS: m / z: 277.1 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ7.55-7.45(m,2H),7.34-7.25(m,2H),5.28(d,J=4.5Hz,1H),4. 52(dt,J=7.1,5.0Hz,1H),3.59(t,J=6.6Hz,2H),1.78-1.53(m,4H),1.50-1.26(m,2H).

[0504] Step 3: At room temperature, 21d (100 mg, 0.36 mmol), tetrahydrofuran (0.3 mL), and tert-butanol (3 mL) were added to a 25 mL single-necked flask, followed by potassium tert-butoxide (121.04 mg, 1.08 mmol). The reaction was complete after four hours at room temperature. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 21e. LC-MS: m / z: 241.0 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ7.54-7.46(m,2H),7.34-7.24(m,2H),4.31-4.28(m,1H),4.04-3.99(m,1H ),3.57-3.46(m,1H),1.90-1.73(m,2H),1.71-1.58(m,1H),1.59-1.50(m,2H),1.42-1.30(m,1H).

[0505] Step 4: To a 25 mL single-necked vial at room temperature was added 21e (200 mg, 0.83 mmol), pinacol diboron (252.92 mg, 1.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (60.73 mg, 0.08 mmol), potassium acetate (244.37 mg, 2.49 mmol), and dioxane (5 mL). The reaction was complete after 16 hours at 80°C. The reaction mixture was then filtered to obtain the crude product 21f, which was directly carried out in the next step. LC-MS: m / z: 289.2 (M+H) + .

[0506] Step 5: Under nitrogen protection, 21f (89.91 mg, 0.31 mmol), 3b (100 mg, 0.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (21.23 mg, 0.03 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (3 mL) and water (0.75 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours of microwave reaction at 100°C. The reaction solution was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 21. LC-MS: m / z: 465.9 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.17(s,1H),7.57-7.50(m,2H),7.39(d,J=8.3Hz,2H),6.50(s ,1H),5.08(q,J=6.0Hz,1H),4.94(d,J=6.4Hz,1H),4.64(t,J=5.1Hz,1H),4.37-4.28(m ,2H),4.16-4.09(m,1H),4.05-3.93(m,2H),3.84-3.72(m,2H),3.57-3.49(m,1H),3.39 (t,J=8.5Hz,1H),1.84(t,J=14.9Hz,2H),1.65(s,1H),1.55(s,2H),1.47-1.37(m,1H).

[0507] Example 22: Synthesis of Compound 22

[0508] Under nitrogen, a 10 mL microwave tube was charged with 3 (70 mg, 0.15 mmol), 18b (39.92 mg, 0.46 mmol), palladium acetate (10.43 mg, 0.05 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (25.44 mg, 0.06 mmol), potassium phosphate (65.76 mg, 0.31 mmol), dioxane (1 mL), and toluene (1 mL). The reaction was complete after 2 hours at 100°C. The product was then concentrated under reduced pressure to obtain the crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 22. LC-MS: m / z: 458.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),7.40(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2H),6.14(s,1H),5.04(q, J=6.1Hz,1H),4.92(d,J=6.5Hz,1H),4.68(t,J=5.6Hz,1H),4.62(t,J=5.1Hz,1H),4.29(t,J=4.9Hz,1H), 4.17-4.06(m,1H),3.96(dd,J=9.3,6.3Hz,1H),3.78(t,J=6.0Hz,1H),3.73(dd,J=9.4,6.2Hz,1H),3.55( d,J=5.7Hz,2H),3.39(m,1H),1.95-1.89(m,1H),0.91-0.81(m,4H),0.78-0.71(m,2H),0.59-0.49(m,2H).

[0509] Example 23: Synthesis of Compound 23

[0510] Step 1: To a 100 mL single-necked flask at 0°C, add 23a (1 g, 6.89 mmol), p-toluenesulfonyl chloride (1.445 g, 7.58 mmol), and dichloromethane (25 mL). Triethylamine (1.39 g, 13.78 mmol) was added under stirring. The reaction was complete after 16 hours at room temperature. The reaction solution was poured into ice water (200 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 23b. LC-MS: m / z: 300.0 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ7.51-7.44(m,2H),7.11(d,J=7.9Hz,2H),4.28-4.23(m,2H),3.77(d,J=4.7Hz,2H),3.67(t,J=6.5 Hz,1H),3.58(s,1H),3.51(d,J=5.0Hz,2H),3.09(q,J=7.8Hz,2H),2.47-2.37(m,2H),2.29(s,3H),1.18(d,J=7.3Hz,2H).

[0511] Step 2: At room temperature, 23b (161.67 mg, 0.54 mmol), 23c (100 mg, 0.45 mmol), potassium carbonate (186.57 mg, 1.35 mmol) and N,N-dimethylformamide (3 mL) were added to a 50 mL single-necked bottle. The reaction temperature was raised to 70°C for five hours until the reaction was complete. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 23d. LC-MS: m / z: 348.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.63-7.55(m,2H),6.95-6.88(m,2H),4.03(t,J=6.4H z,2H),3.58-3.55(m,4H),2.41-2.32(m,6H),1.90-1.85(m,2H),1.27(s,12H).

[0512] Step 3: Under nitrogen, 23d (91 mg, 0.26 mmol), 3b (100.79 mg, 0.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (21.40 mg, 0.03 mmol), potassium carbonate (90.54 mg, 0.66 mmol), dioxane (3 mL), and water (0.75 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours of microwave reaction at 100°C. The reaction solution was then filtered, and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 23. LC-MS: m / z: 525.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.52-7.44(m,2H),7.05-6.96(m,2H),6.4 8(s,1H),5.08(q,J=6.0Hz,1H),4.63(t,J=5.1Hz,1H),4.30(t,J=4.9Hz,1H),4. 16-4.08(m,1H),4.04(t,J=6.4Hz,2H),3.99-3.95(m,1H),3.82-3.73(m,2H),3. 57(t,J=4.6Hz,4H),3.40(d,J=8.5Hz,2H),2.45-2.33(m,6H),1.92-1.85(m,2H).

[0513] Example 24: Synthesis of Compound 24

[0514] Step 1: To a 100 mL three-necked flask at 25°C was added 24a (1 g, 3.62 mmol), paraformaldehyde (1.47 g, 18.08 mmol), tetrahydrofuran (10 mL), and methanol (10 mL). Sodium triacetoxyborohydride (1.53 g, 7.23 mmol) was then added in three batches. The reaction was complete after 15 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield intermediate 24b. LC-MS: m / z: 254.0 (M+H) + .

[0515] Step 2: Under nitrogen, to a 15 mL single-necked vial was added 24b (400 mg, 1.57 mmol), pinacol diboron (479.6 mg, 1.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (115.15 mg, 0.16 mmol), potassium acetate (308.9 mg, 3.15 mmol), and dioxane (4 mL). The reaction was heated to 90°C for 15 hours, after which the reaction was complete. After completion of the reaction, the reaction was cooled, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product, which was then purified by silica gel column chromatography to afford intermediate 24c. 1 H NMR (400MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.24(d,J=8.0Hz,2H),3.04(d,J=11.2Hz,2H),2.51(t d,J=10.9,5.0Hz,1H),2.37(s,3H),2.13(td,J=11.2,3.8Hz,2H),1.93–1.76(m,4H),1.33(s,12H).

[0516] Step 3: Under nitrogen, an 8 mL microwave tube was charged with 24c (43.08 mg, 0.14 mmol), 3b (50 mg, 0.13 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (9.51 mg, 0.01 mmol), potassium carbonate (44.91 mg, 0.32 mmol), dioxane (2 mL), and water (0.4 mL). The reaction was heated to 100°C for 2 hours until complete. After completion, the reaction mixture was cooled and poured into water (20 mL). Extraction was performed with ethyl acetate (3 mL x 3). The organic phase was washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 24. LC-MS: m / z: 479.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.23(s,1H),7.54-7.45(m,2H),7.32(d,J=8.4 Hz,2H),6.49(s,1H),5.07(m,1H),4.92(s,1H),4.63(t,J=5.1Hz,1H),4.30(t,J=4.9 Hz,1H),4.15-4.09(m,1H),3.96(dd,J=9.5,6.2Hz,1H),3.82-3.74(m,2H),3.41-3.9 7(m,4H),2.89(d,J=10.9Hz,2H),2.22(s,3H),2.05-1.95(m,2H),1.80-1.62(m,4H).

[0517] Example 25: Synthesis of Compound 25

[0518] Step 1: To a 25 mL single-necked vial at room temperature, add 25a (1000 mg, 5.59 mmol) and dissolve in ultra-dry tetrahydrofuran (15.0 mL). Add N,N'-carbonyldiimidazole (1811.43 mg, 11.17 mmol). Incubate at 80°C under nitrogen for 1 hour until the reaction is complete. After completion, the reaction solution containing intermediate 25b is used directly in the next reaction without further treatment.

[0519] Step 2: To the reaction solution containing intermediate 25b, 1c (1225.38 mg, 8.38 mmol) and N,N-diisopropylethylamine (3.71 mL, 22.36 mmol) were added at room temperature and reacted at 80°C under nitrogen for 1 hour. The reaction was complete. After the reaction, the reaction solution was concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain intermediate 25c. LC-MS: m / z: 351.0 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),7.27(s,1H),5.11(q,J=5.6Hz,1H),4.95(d,J=6.4Hz,1H),4.70–4.62(m,1H),4.27(t,J=4.8H z,1H),4.15–4.04(m,1H),3.92(dd,J=9.8,5.9Hz,1H),3.81(dd,J=9.8,5.2Hz,1H),3.76(dd,J=7.9,7.0Hz,1H),3.42–3.36(m,1H).

[0520] Step 3: At room temperature, 25c (80 mg, 0.23 mmol), 8c (65.62 mg, 0.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (33.34 mg, 0.05 mmol), potassium carbonate (62.97 mg, 0.46 mmol), dioxane (10.0 mL) and water (2.0 mL) were added to a 25 mL single-necked bottle in sequence. After nitrogen was replaced three times, the reaction solution was reacted at 90°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 25. LC-MS: m / z: 419.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.99 (s, 1H), 7.76 (d, J = 8.4Hz, 2H), 7.52 (s, 1H), 7.33 (d ,J=8.4Hz,2H),5.11(q,J=5.6Hz,1H),4.94(d,J=6.8Hz,1H),4.69–4.66(m,2H),4. 28(t,J=5.2Hz,1H),4.10(m,1H),3.94(dd,J=9.6,6.0Hz,1H),3.86–3.70(m,2H),3 .55(d,J=5.7Hz,2H),3.42(t,J=8.6Hz,1H),0.89–0.82(m,2H),0.79–0.71(m,2H).

[0521] Example 26: Synthesis of Compound 26

[0522] Step 1: To a 25 mL single-necked vial at room temperature, add 26a (1000 mg, 5.18 mmol) and dissolve in ultra-dry tetrahydrofuran (15.0 mL). Add N,N'-carbonyldiimidazole (1679.79 mg, 10.36 mmol). Incubate at 80°C under nitrogen for 1 hour until the reaction is complete. After completion, the reaction solution containing intermediate 26b is used directly in the next reaction without further treatment.

[0523] Step 2: 1c (1135.51 mg, 7.77 mmol) and N,N-diisopropylethylamine (0.86 mL, 5.18 mmol) were added to the reaction system containing intermediate 26b at room temperature and reacted at 80°C under nitrogen for 1 hour. The reaction was complete. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain intermediate 26c. LC-MS: m / z: 367.0 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),5.10(q,J=5.6Hz,1H),4.94(d,J=6.4Hz,1H),4.68–4.61(m,1H),4.27(t,J =4.8Hz,1H),4.14–4.04(m,1H),3.92(dd,J=10.0,6.0Hz,1H),3.82–3.74(m,2H),3.45–3.35(m,1H),2.24(s,3H).

[0524] Step 3: At room temperature, 26c (90 mg, 0.25 mmol), 8c (70.98 mg, 0.37 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (36.06 mg, 0.05 mmol), potassium carbonate (68.12 mg, 0.49 mmol), dioxane (10.0 mL) and water (2.0 mL) were added to a 25 mL single-necked bottle in sequence. After nitrogen was replaced three times, the reaction solution was reacted at 90°C for 2 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 26. LC-MS: m / z: 433.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),7.58–7.45(m,2H),7.40–7.28(m,2H),5.10( q,J=5.6Hz,1H),4.93(d,J=6.4Hz,1H),4.70–4.65(m,2H),4.28(t,J=5.0Hz,1H),4. 13–4.06(m,1H),3.93(dd,J=9.6,6.0Hz,1H),3.82–3.75(m,2H),3.56(d,J=5.8Hz,2 H),3.41(dd,J=9.2,8.0Hz,1H),2.43(s,3H),0.89–0.83(m,2H),0.80–0.71(m,2H).

[0525] Example 27: Synthesis of Compound 27

[0526] Step 1: To a 25 mL single-necked vial at room temperature, add 27a (870 mg, 4.08 mmol), dissolve in ultra-dry tetrahydrofuran (12.0 mL), and add N,N'-carbonyldiimidazole (1321.63 mg, 8.15 mmol). Incubate at 80°C under nitrogen for 1 hour, and the reaction is complete. After completion, the reaction solution containing intermediate 27b is used directly in the next reaction without further treatment.

[0527] Step 2: To the reaction solution containing intermediate 27b, 1c (894.38 mg, 6.12 mmol) and N,N-diisopropylethylamine (2.70 mL, 16.32 mmol) were added at room temperature and reacted at 80°C under nitrogen for 1 hour. The reaction was complete. After the reaction, the reaction solution was concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain intermediate 27c. LC-MS: m / z: 385.0 (M+H).+ .

[0528] Step 3: At room temperature, 27c (73 mg, 0.19 mmol), 8c (54.53 mg, 0.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (27.70 mg, 0.20 mmol), potassium carbonate (52.33 mg, 2.00 mmol), dioxane (8.0 mL) and water (1.6 mL) were added to a 25 mL single-necked bottle in sequence. After nitrogen replacement three times, the reaction solution was reacted at 90°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain a crude product, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, chromatographic column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 27. LC-MS: m / z: 453.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),7.76(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),5.13 (q,J=5.6Hz,1H),4.95(d,J=6.5Hz,1H),4.71(t,J=5.6Hz,1H),4.69–4.65(m,1H),4.27( t,J=4.9Hz,1H),4.10(dt,J=11.8,6.6Hz,1H),3.92(dd,J=9.8,5.8Hz,1H),3.86–3.74(m ,2H),3.57(d,J=5.6Hz,2H),3.40(t,J=8.6Hz,1H),0.90–0.84(m,2H),0.81–0.75(m,2H).

[0529] Example 28: Synthesis of Compound 28

[0530] Step 1: Under nitrogen, tetrahydrofuran (10 mL) and compound 28a (2.0 g, 28.53 mmol) were added to a 100 mL three-necked flask. Compound 28b (68 mL, 0.5 mol / L) was added at 0°C, and the temperature was raised to 25°C for 2 hours until the reaction was complete. The reaction solution was poured into ice water (30 mL) and extracted three times with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 28c. LC-MS: m / z: 97.1 (M+1). + .

[0531] Step 2: Under nitrogen, tetrahydrofuran (4 mL), 28c (66.81 mg, 0.70 mmol), 20f (100 mg, 0.23 mmol), cuprous iodide (8.82 mg, 0.05 mmol), and bis(triphenylphosphine)palladium dichloride (16.26 mg, 0.02 mmol) were added to a 50 mL single-necked flask. Triethylamine (1 mL) was added under stirring. The reaction was completed after 16 h at 25°C. The reaction solution was filtered, and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 28. LC-MS: m / z: 400.0 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ6.41(s,1H),5.93(s,1H),5.08(q,J=5.9Hz,1H),4.94(d,J=6.4Hz,1H),4.63(t,J=5.1Hz,1H),4.29(t,J=4.9Hz,1 H),4.15-4.08(m,1H),3.97-3.93(m,1H),3.81-3.73(m,2H),3.40-3.33(m,2H),2.37-2.30(m,2H),2.23-2.14(m,2H),1.80-1.73(m,2H).

[0532] Example 29: Synthesis of the hydrochloride salt of compound 29

[0533] Step 1: Under nitrogen protection, tetrahydrofuran (20 mL), 29a (1.09 mL, 8.48 mmol) and n-butyllithium (3.39 mL, 8.48 mmol) were added to a 100 mL three-necked flask. After reacting at -70°C for 0.5 hours, a solution of 29b (1.57 g, 8.48 mmol) in tetrahydrofuran (5 mL) was slowly added to the above reaction solution. The reaction was completed after reacting at -70°C for 2 hours. Saturated ammonium chloride solution (20 mL) was slowly added to the above solution. The reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column to obtain compound 29c. LC-MS: m / z: 364.0 (M+Na) + . 1H NMR(400MHz,DMSO-d6)δ7.81(d,J=4.0Hz,2H),7.61(d,J=4.0Hz,2H),4.62(brs,1 H),3.22(t,J=4.0Hz,2H),2.98(d,J=8.0Hz,2H),1.94-1.91(m,2H),1.42(s,9H).

[0534] Step 2: Methanol (20 mL), 29c (1 g, 2.92 mmol), and sodium borohydride (0.55 g, 14.61 mmol) were added to a 100 mL three-necked flask at 0°C. After reacting at 25°C for 15 hours, the reaction solution was quenched with saturated ammonium chloride (100 mL), water was added, and the mixture was extracted with methyl tert-butyl ether (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 29d. LC-MS: m / z: 366.0 (M+Na) + .

[0535] Step 3: Under nitrogen protection, 29d (0.50 g, 1.45 mmol), dichloromethane (10 mL) and triethylsilyl hydride (1.65 g, 14.61 mmol) were added to a 100 mL three-necked flask. Boron trifluoride etherate (0.50 g, 11.62 mmol) was added to the above solution at 0°C. After reacting at 25°C for 15 hours, the above reaction solution was washed with saturated sodium bicarbonate solution (20 mL). The organic phase was concentrated under reduced pressure to obtain a residue, which was dissolved in 30 mL of ethyl acetate and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 29e. LC-MS: m / z: 228.0 (M+H) + .

[0536] Step 4: To a 100 mL three-necked flask, add 29e (0.33 g, 1.45 mmol), tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (1.58 g, 7.23 mmol). After reacting at 25°C for 5 hours, the reaction mixture was added to water (50 mL). Extraction was performed with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain intermediate 29f. LC-MS: m / z: 272.0 (M-55). + .

[0537] Step 5: Under nitrogen, a 100 mL three-necked flask was charged with 29f (1.4 g, 1.25 mmol), potassium acetate (0.31 g, 3.12 mmol), dioxane (14 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.09 g, 0.12 mmol), and pinacol diboron (0.49 g, 1.87 mmol). After reacting at 90°C for 15 hours, the reaction mixture was added to water (100 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain compound 29g. LC-MS: m / z: 398.2 (M+23) + .

[0538] Step 6: Under nitrogen, to a 100 mL three-necked flask were added 29 g (120 mg, 0.31 mmol), 3b (117.10 mg, 0.31 mmol), potassium carbonate (107.79 mg, 0.78 mmol), dioxane (2 mL), water (0.4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.83 mg, 0.03 mmol). After reacting at 100°C for 2 hours, the reaction mixture was added to water (100 mL). Extraction was performed with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to yield Intermediate 29h. LC-MS: m / z: 575.2 (M+23). + .

[0539] Step 7: To a 100 mL three-necked flask, add 29h (100 mg, 0.18 mmol), dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL, 6.71 mmol). After reacting at 25°C for 1 hour, the reaction solution was concentrated to obtain a crude product, which was separated and purified using HPLC (mobile phase: A: 0.05% HCl / H2O; B: ACN, column: Waters-SunFire-C18-10μm-19*250mm) to obtain the hydrochloride salt of compound 29. LC-MS: m / z: 453.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.20 (s, 1H), 7.76 (s, 3H), 7.51 (d, J = 8.0Hz, 2H), 7.29 (d, J=8.0Hz,2H),6.50(s,1H),5.10-5.05(m,1H),4.97(d,J=4.0Hz,1H),4.64-4.62(m ,1H),4.31-4.30(m,1H),4.14-4.12(m,1H),4.11-3.94(m,1H),3.80-3.74(m,2H), 3.41-3.39(m,1H),2.78(t,J=4.0Hz,2H),2.62(t,J=4.0Hz,2H),1.66-1.53(m,4H).

[0540] Example 30: Synthesis of Compound 30

[0541] Step 1: Under nitrogen, dioxane (4 mL), 29d (300 mg, 0.87 mmol), potassium acetate (256 mg, 2.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (63 mg, 0.09 mmol), and pinacol diboron (442 mg, 1.74 mmol) were added to a 100 mL three-necked flask. After reacting at 100°C for 15 hours, the reaction mixture was added to water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 30a. LC-MS: m / z: 414.2 (M+Na) + .

[0542] Step 2: Under nitrogen, dioxane (2 mL), 30a (100 mg, 0.26 mmol), potassium carbonate (89.83 mg, 0.65 mmol), water (0.4 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19.02 mg, 0.03 mmol), and 3b (132.26 mg, 0.34 mmol) were added to a 100 mL three-necked flask. After reacting at 100°C for 2 hours, the reaction solution was added to water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain intermediate 30b. LC-MS: m / z: 591.2 (M+Na) + .

[0543] Step 3: To a 100 mL three-necked flask, 30b (45 mg, 0.08 mmol), dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL, 6.71 mmol) were added. After reacting at 25°C for 2 hours, the reaction solution was concentrated to obtain a crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 30. LC-MS: m / z: 451.2 (M-OH) + . 1 H NMR(400MHz,DMSO-d6)δ7.53-7.49(m,2H),7.44-7.24(m,2H),6.49(s,1H),5.1 0-5.06(m,1H),4.94(d,J=8.0Hz,1H),4.63(t,J=8.0Hz,1H),4.30(d,J=8.0Hz, 1H),4.14-4.10(m,2H),4.07-3.95(m,1H),3.82-3.74(m,2H),3.39-3.32(m,1H ),3.04-2.89(m,2H),2.13-2.12(m,1H),1.81-1.73(m,2H),1.52-1.49(m,1H).

[0544] Example 31: Synthesis of the hydrochloride salt of compound 31

[0545] Step 1: Under nitrogen, dichloromethane (15 mL), 31a (1 g, 5.71 mmol), 4-dimethylaminopyridine (0.35 g, 2.85 mmol), p-toluenesulfonyl chloride (2.18 g, 11.41 mmol), and triethylamine (1.73 g, 17.13 mmol) were added to a 100 mL three-necked flask. After reacting at 25°C for 15 hours, the above solution was added to water (100 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain intermediate 31b. LC-MS: m / z: 352.2 (M+Na) + .

[0546] Step 2: To a 100 mL three-necked flask, add N,N-dimethylformamide (4 mL), 31b (200 mg, 0.61 mmol), and 31c (160.34 mg, 0.73 mmol). After reacting at 70°C for 15 hours, the reaction solution was added to water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain intermediate 31d. LC-MS: m / z: 400.2 (M+Na) + . 1 H NMR (400MHz, CDCl3) δ7.76-7.72(m,2H),6.90-6.86(m,2H),4.74(s,1H),4.04(d ,J=8.0Hz,2H),3.33-3.30(m,2H),1.99-1.95(m,2H),1.44(s,9H),1.33(s,12H).

[0547] Step 3: Under nitrogen, a 100 mL three-necked flask was charged with 31d (100 mg, 0.26 mmol), potassium carbonate (89.83 mg, 0.65 mmol), dioxane (2 mL), water (0.4 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19.02 g, 0.03 mmol), and 3b (98.09 mg, 0.26 mmol). After reacting at 100°C for 2 hours, the reaction mixture was added to water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to obtain intermediate 31e. LC-MS: m / z: 577.2 (M+Na). + .

[0548] Step 4: To a 100 mL three-necked flask, dichloromethane (2.5 mL), 31e (80 mg, 0.14 mmol), and trifluoroacetic acid (0.5 mL, 6.71 mmol) were added. After reacting at 25°C for 2 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using HPLC (mobile phase: A: 0.05% HCl / H2O; B: ACN, column: Waters-SunFire-C18-10μm-19*250mm) to obtain the hydrochloride salt of compound 31. LC-MS: m / z: 455.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.00(s,3H),7.52-7.49(m,2H),7.04-7.02(m,2H),6.49(s,1H),5.09-4.97(m,2H),4.63(d,J=4.0H z,1H),4.29(d,J=8.0Hz,1H),4.14-4.09(m,3H),3.98-3.94(m,1H),3.81-3.73(m,2H),3.37(s,1H),2.98-2.93(m,2H),2.07-2.00(m,2H).

[0549] Example 32: Synthesis of the formate salt of compound 32

[0550] Step 1: Under nitrogen, tetrahydrofuran (2 mL), 32a (200 mg, 0.93 mmol), and di-tert-butyl dicarbonate (244 mg, 1.12 mmol) were added to a 100 mL three-necked flask. After reacting at 25°C for 15 hours, the solution was concentrated under reduced pressure to yield intermediate 32b. LC-MS: m / z: 336.0 (M+Na) + . 1 H NMR (400MHz, CDCl3) δ7.41-7.37(m,2H),7.07-7.03(m,2H),4.51(s,1H),3.13(t,J=8.0Hz,2H),2.59(t,J=8.0Hz,2H),1.82-1.74(m,2H)1.44(s,9H).

[0551] Step 2: Under nitrogen, dioxane (10 mL), 32b (270 mg, 0.86 mmol), potassium acetate (168.66 mg, 1.72 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (63 mg, 0.09 mmol), and pinacol diboron (240 mg, 0.95 mmol) were added to a 30 mL three-necked flask. After reacting at 90°C for 15 hours, the reaction mixture was added to water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 32c as a colorless oil. LC-MS: m / z: 384.2 (M+Na) + . 1H NMR(400MHz, CDCl3) δ7.71(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,2H),4.50(s,1H),3 .14(s,2H),2.65(t,J=8.0Hz,2H),1.84-1.79(m,2H),1.44(s,9H),1.33(s,12H).

[0552] Step 3: Under nitrogen, to a 100 mL three-necked flask were added dioxane (6 mL), water (1.2 mL), 32c (90 mg, 0.23 mmol), potassium carbonate (0.84 mg, 0.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17 mg, 0.02 mmol), and 3b (84.54 mg, 0.23 mmol). After reacting at 100°C for 2 hours, the reaction mixture was filtered and the filtrate was dried to obtain intermediate 32d.

[0553] Step 4: To a 100 mL three-necked flask, dichloromethane (2.5 mL), 32d (126.13 mg, 0.23 mmol), and trifluoroacetic acid (0.5 mL, 6.71 mmol) were added. After reacting at 25°C for 2 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain the formate salt of compound 32. LC-MS: m / z: 439.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),7.52(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),6.50(s,1H),5.10-5.06(m,1H),4.98(s,1H),4.63(d,J=8. 0Hz,1H),4.30(d,J=8.0Hz,1H),4.15-4.11(m,3H),3.99-3.95(m,1H), 3.82-3.74(m,2H),3.39(s,1H),2.75-2.50(m,4H),1.84-1.79(m,2H).

[0554] Example 33: Synthesis of Compound 33

[0555] Step 1: Under nitrogen, tetrahydrofuran (40 mL) and 33a (5.0 g, 26.85 mmol) were added to a 250 mL three-necked flask. Lithium aluminum tetrahydride (67.13 mL, 1.0 mol / L) was added with stirring at 0°C. The temperature was then raised to 25°C for 2 hours, leading to completion. A small amount of Na2SO4·10H2O was added to the reaction solution, and the reaction was stirred until bubbling ceased. The reaction solution was filtered, dried over anhydrous sodium sulfate, filtered again, and the filtrate was concentrated under reduced pressure to yield intermediate 33b. LC-MS: m / z: 103.0 (M+1). + .

[0556] Step 2: Under nitrogen protection, tetrahydrofuran (80 mL) and 33b (2.0 g, 19.58 mmol) were added to a 250 mL three-necked flask. Sodium hydroxide (0.47 g, 19.58 mmol) was added under stirring at 0°C. After stirring for 30 minutes, tert-butyldiphenylsilyl chloride (5.36 g, 19.58 mmol) was added. The mixture was then heated to room temperature and reacted for 2 hours until the reaction was complete. The reaction solution was slowly poured into ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain intermediate 33c. LC-MS: m / z: 323.2 (M-17) + . 1 H NMR(400MHz,DMSO-d6)δ7.64-7.58(m,4H),7.48-7.40(m,6H),4.44(t,J=5.5Hz,1H),3 .60(s,2H),3.41(d,J=5.5Hz,2H),1.00(s,9H),0.41-0.34(m,2H),0.34-0.28(m,2H).

[0557] Step 3: Add 33c (1.5 g, 4.40 mmol) and dichloromethane (30 mL) to a 100 mL single-necked bottle, and add Dess-Martin periodinane (1.87 g, 4.4 mmol) under stirring at 0°C. Then, the temperature was raised to 25°C for 2 hours until the reaction was complete. The reaction solution was filtered, and the filtrate was added with water (50 mL) and extracted three times with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 33d. LC-MS: m / z: 361.2 (M+23) + .

[0558] Step 4: To a 100 mL single-necked flask, 33d (1.33 g, 3.93 mmol), carbon tetrabromide (2.61 g, 7.86 mmol), and dichloromethane (10 mL) were added. Triphenylphosphine (4.12 g, 15.72 mmol) was added under stirring at 0°C for 2 hours, and the reaction was complete. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the intermediate. The intermediate was then dissolved in tetrahydrofuran (15 mL), and n-butyllithium (2.36 mL, 2.5 mol / L) was added at -78°C. The reaction was stirred for 1 hour, and the reaction was complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain intermediate 33e. LC-MS: m / z: 335.1 (M+H) + .

[0559] Step 5: Under nitrogen, tetrahydrofuran (6 mL), 33e (174.38 mg, 0.52 mmol), 20f (150 mg, 0.35 mmol), cuprous iodide (13.24 mg, 0.07 mmol), and bistriphenylphosphine palladium dichloride (24.39 mg, 0.03 mmol) were added to a 50 mL single-necked flask. Triethylamine (1.5 mL) was added under stirring. The reaction was completed after 16 hours at 25°C. The solid was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain intermediate 33f. LC-MS: m / z: 638.2 (M+1) + .

[0560] Step 6: Under nitrogen, 33f (50 mg, 0.08 mmol) and tetrahydrofuran (2 mL) were added to a 25 mL single-necked flask. Tetrabutylammonium fluoride (0.2 mL, 1.0 mol / L) was added under stirring. The reaction was complete after 3 hours at 25°C. The solid was then filtered, and the filtrate was separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 33. LC-MS: m / z: 399.9 (M+1). + . 1H NMR (400MHz, DMSO) δ11.17(s,1H),6.36(s,1H),5.07(q,J=5.9Hz,1H),4.95(t,J=6.4Hz,2H),4.62(t,J=5.1Hz,1H),4 .28(t,J=4.9Hz,1H),4.10(q,J=7.0Hz,1H),3.96-3.92(m,1H),3.81-3.72(m,2H),3.41(s,3H),0.88(d,J=3.4Hz,4H).

[0561] Example 34: Synthesis of Compound 34

[0562] Step 1: To a 50 mL reaction flask at room temperature, dioxane (20 mL), 3a (500 mg, 2.07 mmol), 34a (1782 mg, 10.35 mmol), diphenylphosphoryl azide (684 mg, 2.48 mmol), and triethylamine (314 mg, 3.10 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 90°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified on a silica gel column to yield intermediate 34b. LC-MS: m / z: 410.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),6.38(s,1H),4.68-4.56(m,1H),4.06(q,J=7.1H z,2H),2.38-2.29(m,1H),2.04-1.91(m,4H),1.52-1.37(m,4H),1.18(t,J=7.1Hz,3H).

[0563] Step 2: Under nitrogen protection, dioxane (8 mL), water (1.6 mL), 34b (500 mg, 1.22 mmol), 5a (376 mg, 1.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (89 mg, 0.12 mmol) and potassium carbonate (505 mg, 3.65 mmol) were added to a 20 mL microwave tube. The reaction was completed after 2 hours of microwave reaction at 100 ° C. The solid was then filtered and the reaction was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 34. LC-MS: m / z: 460.9 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),7.73(d,J=2.1Hz,1H),7.50(d,J=8.6H z,1H),7.38(d,J=3.1Hz,1H),7.33(dd,J=8.6,1.8Hz,1H),6.48(d,J=2.3Hz, 1H),6.47(s,1H),4.67-4.56(m,1H),4.06(q,J=7.1Hz,2H),3.81(s,3H),2.3 9-2.30(m,1H),2.06-1.91(m,4H),1.54-1.38(m,4H),1.18(t,J=7.1Hz,3H).

[0564] Example 35: Synthesis of Compound 35

[0565] Under nitrogen, a 10 mL reaction flask was charged with 34 (100 mg, 0.22 mmol), methanol (2 mL), and 20% aqueous potassium hydroxide solution (2 mL). The reaction was complete after 16 hours at 50°C. The solid was then filtered, and the filtrate was separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 35. LC-MS: m / z: 433.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),10.88(s,1H),7.73(d,J=1.8Hz,1H),7.50(d,J=8.6Hz,1H),7.38(d,J=3.1Hz,1H),7.33(d d,J=8.5,1.8Hz,1H),6.48(d,J=6.5Hz,2H),4.66-4.55(m,1H),3.81(s,3H),2.28-2.19(m,1H),2.06-1.91(m,4H),1.51-1.36(m, 4H).

[0566] Example 36: Synthesis of Compound 36

[0567] Under nitrogen protection, 34 (130 mg, 0.28 mmol) and tetrahydrofuran (3 mL) were added to a 10 mL reaction flask. A solution of lithium aluminum tetrahydride in tetrahydrofuran (1N, 0.4 mL) was added dropwise to the reaction flask at 0°C, and the reaction was completed after 16 hours at 25°C. The solid was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 36. LC-MS: m / z: 418.9 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),7.73(d,J=1.7Hz,1H),7.50(d,J=8.6Hz,1H) ,7.38(d,J=3.1Hz,1H),7.33(dd,J=8.5,1.7Hz,1H),6.48(dd,J=3.1,0.8Hz,1H),6 .46(s,1H),4.60-4.52(m,1H),4.44(t,J=5.3Hz,1H),3.81(s,3H),3.23(t,J=5.7H z,2H),2.05-1.99(m,2H),1.82-1.76(m,2H),1.39-1.30(m,3H),1.06-0.97(m,2H).

[0568] Example 37: Synthesis of Compound 37

[0569] Under nitrogen protection, dioxane (12 mL), water (2.4 mL), 34b (600 mg, 1.46 mmol), 1e (481 mg, 1.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (107 mg, 0.15 mmol), and potassium carbonate (606 mg, 4.38 mmol) were added to a 20 mL microwave tube. The reaction was completed after 2 hours of microwave reaction at 100°C. The solid was then filtered, and the reaction solution was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 37. LC-MS: m / z: 478.1 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.47(d,J=8.4Hz,2H),7.36(d,J=8.4 Hz,2H),6.46(s,1H),4.70(t,J=5.7Hz,1H),4.66-4.56(m,1H),4.06(q,J=7 .1Hz,2H),3.55(d,J=5.6Hz,2H),2.40-2.29(m,1H),2.06-1.88(m,4H),1.5 4-1.37(m,4H),1.18(t,J=7.1Hz,3H),0.88-0.81(m,2H),0.81-0.74(m,2H).

[0570] Example 38: Synthesis of Compound 38

[0571] Under nitrogen, a 10 mL reaction flask was charged with 37 (80 mg, 0.17 mmol), methanol (2 mL), and 20% aqueous potassium hydroxide solution (2 mL). The reaction was complete after 16 hours at 50°C. The solid was then filtered, and the filtrate was separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 38. LC-MS: m / z: 450.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.47(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),6.46(s,1H),4.69(s,1H),4.63- 4.55(m,1H),3.55(s,2H),2.22(s,1H),2.04-1.91(m,4H),1.51-1.36(m,4H),0.87-0.81(m,2H),0.81-0.74(m,2H).

[0572] Example 39: Synthesis of Compound 39

[0573] Under nitrogen protection, 37 (130 mg, 0.27 mmol) and tetrahydrofuran (4 mL) were added to a 10 mL reaction flask. A solution of lithium aluminum tetrahydride in tetrahydrofuran (1N, 0.4 mL) was added dropwise to the reaction flask at 0°C, and the reaction was completed after 16 hours at 25°C. The solid was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C18 -10μm-19*250mm) was analyzed and purified to obtain compound 39. LC-MS: m / z: 435.9 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.47(d,J=8.5Hz,2H),7.36(d,J=8.4Hz,2H) ,6.46(s,1H),4.70(t,J=5.6Hz,1H),4.60-4.52(m,1H),4.44(t,J=5.3Hz,1H),3.5 5(d,J=5.7Hz,2H),3.22(t,J=5.8Hz,2H),2.02(d,J=11.5Hz,2H),1.79(d,J=13.2H z,2H),1.40-1.28(m,3H),1.08-0.96(m,2H),0.89-0.81(m,2H),0.81-0.73(m,2H).

[0574] Example 40: Synthesis of Compound 40

[0575] Toluene (1.5 mL), compound 3 (100 mg, 0.22 mmol), 40a (164 mg, 2.21 mmol), palladium acetate (5 mg, 0.02 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (9 mg, 0.02 mmol), potassium phosphate (141 mg, 0.66 mmol), and dioxane (1.5 mL) were added to a 10 mL microwave tube at room temperature. The reaction was complete after 2 hours of microwave reaction at 100°C. The solid was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 40. LC-MS: m / z: 446.2.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.79(s,1H),7.33(d,J=8.4Hz,2H),7.26(d,J=8.3Hz,2H),6.49(s,1H),5 .05(q,J=6.1Hz,1H),4.92(d,J=6.5Hz,1H),4.68(t,J=5.7Hz,1H),4.62(t,J=5.1Hz,1H),4.30(t, J=4.8Hz,1H),4.17-4.07(m,1H),4.01-3.93(m,1H),3.82-3.71(m,2H),3.54(d,J=5.7Hz,2H),3.4 0(t,J=8.5Hz,1H),2.57-2.51(m,2H),1.12(t,J=7.5Hz,3H),0.87-0.80(m,2H),0.80-0.73(m,2H).

[0576] Example 41: Synthesis of Compound 41

[0577] At room temperature, dioxane (1.5 mL), toluene (1.5 mL), 3 (100 mg, 0.22 mmol), 41a (54 mg, 0.44 mmol), palladium acetate (10 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (18 mg, 0.04 mmol), and potassium phosphate (141 mg, 0.66 mmol) were added to a 10 mL microwave tube. The reaction was complete after 2 hours of microwave reaction at 100°C. The solid was then filtered, and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 41. LC-MS: m / z: 494.2.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.33-7.07(m,9H),6.61(s,1H),5.09(q,J=6.0Hz,1H),4.94(d,J=6.4Hz,1H),4.72-4.61(m,2H),4.31(d, J=5.1Hz,1H),4.18-4.09(m,1H),4.03-3.94(m,1H),3.85-3.73(m,2H), 3.52(d,J=5.6Hz,2H),3.42(t,J=8.5Hz,1H),0.82(s,2H),0.72(s,2H).

[0578] Example 42: Synthesis of Compound 42

[0579] To a 100 mL round-bottom flask at room temperature was added dioxane (30 mL), water (6 mL), 11b (1000 mg, 3.18 mmol), 6a (1224 mg, 4.13 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (260 mg, 0.32 mmol), and potassium carbonate (1318 mg, 9.54 mmol). The atmosphere was purged with nitrogen three times, and the reaction was complete at 90°C for 16 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (30 ml x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane / methanol) to obtain a crude product, which was separated and purified by high-performance liquid chromatography (mobile phase: A: 0.1% FA / H2OB:ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 42. LC-MS: m / z: 403.9 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),9.69(s,1H),7.65-7.60(m,4H),7.30(dd,J=7.6,1.7Hz,1H),7.20-7.15(m,1H),6.96(dd,J=8. 1,1.2Hz,1H),6.89(td,J=7.4,1.2Hz,1H),6.52(s,1H),4.59(s,1H),4.21(t,J=6.5Hz,2H),3.51(t,J=6.2Hz,2H),1.85-1.74(m,2H).

[0580] Example 43: Synthesis of Compound 43

[0581] At room temperature, water (0.5 mL), toluene (1.5 mL), dioxane (1.5 mL), 3 (140 mg, 0.31 mmol), 43a (133 mg, 1.55 mmol), palladium acetate (14 mg, 0.06 mmol), tricyclohexylphosphine (35 mg, 0.12 mmol), and cesium carbonate (303 mg, 0.93 mmol) were added to a 10 mL microwave tube. The reaction was complete after 2 hours of microwave reaction at 110°C. The solid was then filtered, and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 43. LC-MS: m / z: 458.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.28(s,4H),6.47(s,1H),5.10-5.03(m,2H), 4.96-4.89(m,2H),4.68(t,J=5.6Hz,1H),4.63(t,J=5.1Hz,1H),4.30(t,J=4.9Hz,1 H),4.17-4.08(m,1H),4.01-3.92(m,1H),3.82-3.72(m,2H),3.54(d,J=5.6Hz,2H), 3.40(t,J=8.5Hz,1H),1.82(d,J=1.2Hz,3H),0.86-0.80(m,2H),0.80-0.73(m,2H).

[0582] Example 44: Synthesis of Compound 44

[0583] Methanol (5 mL), 43 (50 mg, 0.11 mmol), and 10% palladium / carbon (12 mg, 0.11 mmol) were added to a 10 mL reaction flask. The atmosphere was replaced with hydrogen three times, and the reaction was complete after 2 hours at 25°C. The solid was then filtered, and the filtrate was distilled under reduced pressure to obtain a residue that was separated and purified using HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 44. LC-MS: m / z: 460.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.76(s,1H),7.34(d,J=8.3Hz,2H),7.23(d,J=8.3Hz,2H),6.54(s,1H),5. 05(q,J=6.1Hz,1H),4.92(d,J=6.4Hz,1H),4.69(t,J=5.7Hz,1H),4.62(t,J=5.1Hz,1H),4.29(t,J=4 .9Hz,1H),4.16-4.08(m,1H),3.99-3.94(m,1H),3.81-3.72(m,2H),3.54(d,J=5.7Hz,2H),3.40(t, J=8.5Hz,1H),3.05-2.97(m,1H),1.12(dd,J=6.8,1.8Hz,6H),0.86-0.80(m,2H),0.80-0.74(m,2H).

[0584] Example 45: Synthesis of Compound 45

[0585] Step 1: To a 250 mL single-necked flask, add dichloromethane (110 mL), 1e (5.0 g, 18.24 mmol), and imidazole (2.48 g, 36.47 mmol). Tert-butyldimethylsilyl chloride (3.83 g, 25.53 mmol) was added with stirring. The reaction was complete after 16 h at 25°C. The reaction solution was washed three times with water (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified using a normal phase column to obtain compound 45a as a yellow solid. LC-MS: m / z: 411.2 (M+23) + .

[0586] Step 2: Under nitrogen protection, dioxane (10 mL), water (2 mL), 45a (1.032 g, 2.66 mmol), 45b (0.5 g, 2.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.206 g, 0.25 mmol), and potassium carbonate (0.875 g, 6.33 mmol) were added to a 50 mL single-necked flask. The reaction was completed after 16 h at 90°C. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified on a silica gel column to obtain intermediate 45c. LC-MS: m / z: 379.2 (M+1) + .

[0587] Step 3: To a 50 mL single-necked flask, add acetonitrile (15 mL), 45c (790 mg, 2.08 mmol), and N-bromosuccinimide (371 mg, 2.08 mmol). The reaction is complete after 16 hours at 25°C. The reaction solution is filtered and the filtrate is concentrated under reduced pressure to obtain the crude product, which is then purified on a silica gel column to obtain intermediate 45d. LC-MS: m / z: 325.2 (M-17) + . 1 H NMR (400MHz, DMSO-d6) δ7.57-7.47(m,2H),7.40(d,J=8.3Hz,3H),4.73(t,J=5.6Hz,1H),3.55(d,J=5.0Hz,2H),0.91-0.84(m,2H),0.81-0.76(m,2H).

[0588] Step 4: Under nitrogen, dioxane (3 mL), 45d (50 mg, 0.15 mmol), 45e (24.75 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (13.32 mg, 0.01 mmol), 1,1'-binaphthyl-2,2'-diphenylamine (BINAP) (18.12 mg, 0.03 mmol), and potassium phosphate (92.65 mg, 0.44 mmol) were added to a 10 mL microwave tube. The reaction was complete after 2.5 hours of microwave reaction at 110°C. The solid was then filtered, and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 45. LC-MS: m / z: 348.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ7.64-7.57(m,2H),7.53(s,1H),7.48-7.38(m,4H),4.7 5(t,J=5.6Hz,1H),3.57(d,J=5.5Hz,2H),0.92-0.86(m,2H),0.85-0.78(m,2H).

[0589] Example 46: Synthesis of Compound 46

[0590] Step 1: Under nitrogen protection, dichloromethane (10 mL), water (2 mL), 45b (500 mg, 2.53 mmol), 46a (501.42 mg, 2.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (207.28 mg, 0.25 mmol), and potassium carbonate (874.82 mg, 6.33 mmol) were added to a 50 mL single-necked flask. The reaction was completed after 16 h at 90°C. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified on a silica gel column to obtain intermediate 46b. LC-MS: m / z: 271.0 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.89-7.78(m,2H),7.77-7.69(m,5H),7.53-7.46(m,2H),7.43-7.35(m,1H),7.22(dd,J=12.0,5.4Hz,1H).

[0591] Step 2: To a 50 mL single-necked vial was added acetonitrile (10 mL), 46b (325 mg, 1.05 mmol), and N-bromosuccinimide (NBS) (213.65 mg, 1.20 mmol) at room temperature. The reaction was allowed to proceed at 25°C for 16 hours until complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield the crude product, which was then purified on a silica gel column to afford intermediate 46c. 1 H NMR (400MHz, DMSO-d6) δ7.84-7.78(m,2H),7.72(td,J=6.5,3.4Hz,4H),7.53-7.47(m,2H),7.46-7.37(m,2H).

[0592] Step 3: Under nitrogen, dioxane (2.5 mL), 46c (50 mg, 0.14 mmol), 45e (24.33 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (13.09 mg, 0.01 mmol), 1,1'-binaphthyl-2,2'-diphenylamine (BINAP) (17.44 mg, 0.03 mmol), and potassium phosphate (89.15 mg, 0.42 mmol) were added to a 10 mL microwave tube. The reaction was complete after 1 hour of microwave reaction at 110°C. The solid was then filtered, and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 46. LC-MS: m / z: 354.2 (M+1). + . 1H NMR (400MHz, DMSO-d6) δ7.88-7.79(m,4H),7.78-7.71(m,2H),7.57(s,1H),7.51(t,J=7.6Hz,2H),7.47-7.38(m,3H).

[0593] Example 47: Synthesis of Compound 47

[0594] Step 1: Under nitrogen protection, dichloromethane (15 mL), water (3 mL), 47a (870 mg, 2.78 mmol), 46a (606.23 mg, 3.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (227.83 mg, 0.28 mmol), and potassium carbonate (961.53 mg, 6.96 mmol) were added to a 50 mL single-necked flask. The reaction was completed after 16 hours at 100°C. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was purified on a silica gel column to obtain intermediate 47b. LC-MS: m / z: 408.1 (M+23) + .

[0595] Step 2: Add 47b (540 mg, 1.40 mmol) and dichloromethane (5 mL) to a 50 mL single-necked flask. Add hydrochloric acid in ethyl acetate (5 mL) with stirring. The reaction is complete after 16 hours at 25°C. The reaction solution is concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 47c. LC-MS: m / z: 286.0 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ7.73-7.66(m,4H),7.66-7.58(m,2H),7.47(t,J=7.7Hz,2H),7.40-7.33(m,1H),5.90(s,1H),5.53-5.30(m,2H).

[0596] Step 3: Under nitrogen, dioxane (3 mL), 47c (50 mg, 0.17 mmol), 47d (56.10 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium (15.57 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-diphenylamine (BINAP) (21.17 mg, 0.03 mmol), and potassium phosphate (108.25 mg, 0.51 mmol) were added to a 10 mL microwave tube. The reaction was complete after 1 hour of microwave reaction at 110°C. The solid was then filtered, and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 47. LC-MS: m / z: 370.2 (M+1). + . 1 H NMR (400MHz, DMSO-d6) δ14.21 (s, 1H), 9.12 (d, J = 1.0Hz, 1H), 7.85-7.80 (m, 2H), 7.78-7.73(m,4H),7.71(s,1H),7.51(dd,J=8.4,6.9Hz,2H),7.44-7.38(m,1H).

[0597] Example 48: Synthesis of Compound 48

[0598] Under nitrogen, a 10 mL microwave tube was charged with dioxane (3 mL), 47c (50 mg, 0.17 mmol), 48a (57.02 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium (16.02 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-diphenylamine (BINAP) (21.79 mg, 0.03 mmol), and potassium phosphate (111.41 mg, 0.52 mmol). The reaction was complete after microwave reaction at 110°C for 1 hour. The solid was then filtered, and the filtrate was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to give compound 48. LC-MS: m / z: 368.0 (M+1). + . 1 H NMR (400MHz, DMSO-d6) δ12.15-10.80 (m, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.74-7.6 9(m,4H),7.49(t,J=7.7Hz,2H),7.40-7.37(m,1H),6.79(s,1H),2.42(s,3H).

[0599] Example 49: Synthesis of Compound 49

[0600] Step 1: At room temperature, dioxane (20 mL), water (4 mL), 47a (1.0 g, 3.20 mmol), 1e (1.32 g, 4.80 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.26 g, 0.32 mmol), and potassium carbonate (1.33 g, 9.60 mmol) were added to a 50 mL single-necked tube. Under nitrogen protection, the reaction was completed after 16 hours at 90°C. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate 49a. LC-MS: m / z: 324.0 (M-55) + . 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),7.48(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),6.43(s,1H), 4.72(t,J=5.6Hz,1H),3.54(d,J=5.6Hz,2H),1.48(s,9H),0.87-0.81(m,2H),0.81-0.74(m,2H).

[0601] Step 2: To a 100 mL single-necked flask, add 49a (200 mg, 0.53 mmol) and ethyl acetate (7 mL). Add 4N hydrogen chloride in ethyl acetate (7 mL) dropwise to the reaction mixture. After 16 hours at 25°C, the reaction is complete. The reaction mixture is then concentrated under reduced pressure to yield intermediate 49b. LC-MS: m / z: 279.9 (M+H). + .

[0602] Step 3: To a 10 mL single-necked vial, N,N-dimethylformamide (4 mL), 49c (39 mg, 0.29 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (66 mg, 0.34 mmol) were added. After reacting at 25°C for 5 minutes, 49b (80 mg, 0.29 mmol) and N,N-diisopropylethylamine (148 mg, 1.14 mmol) were added. The reaction was continued for 16 hours until the reaction was complete. The reaction solution was filtered, and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2OB:ACN, column: Waters-Xbridge-C 18-10μm-19*250mm) was analyzed and purified to obtain compound 49. LC-MS: m / z: 380.0 (M-17) + . 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),7.52–7.48(m,2H),7.36–7.24(m,7H), 6.63(s,1H),4.18(s,2H),3.70(s,2H),1.00–0.96(m,2H),0.95–0.91(m,2H).

[0603] Example 50: Synthesis of Compound 50

[0604] Step 1: To a 250 mL reaction flask, 50a (4 g, 28.14 mmol) and dichloromethane (50 mL) were added sequentially, followed by sodium borohydride (1.28 g, 33.77 mmol) at 0°C. The mixture was stirred for 2 hours. After completion of the reaction, a small amount of water was added to quench the reaction mixture, which was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield intermediate 50b. LC-MS: m / z: 145.2 (M+H) + .

[0605] Step 2: To a 250 mL reaction flask, dioxane (120 mL), 50b (4.5 g, 31.07 mmol), 3a (1.5 g, 6.21 mmol), diphenylphosphoryl azide (2.05 g, 7.45 mmol), and triethylamine (1.29 mL, 9.32 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified on a silica gel column to yield intermediate 50c. LC-MS: m / z: 382.0 (M+H). + .

[0606] Step 3: To a 50 mL single-necked tube, add dioxane (8 mL), water (2 mL), 50c (1.0 g, 2.61 mmol), 1e (0.79 g, 2.87 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.21 g, 0.26 mmol), and potassium carbonate (0.90 g, 6.35 mmol). Under nitrogen protection, the reaction was completed after 16 hours at 90°C. The reaction solution was poured into 50 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate 50d. LC-MS: m / z: 450.2 (M+1) + .

[0607] Step 4: Under nitrogen protection, 50d (100 mg, 0.22 mmol) and tetrahydrofuran (5 mL) were added to a 10 mL reaction flask. A solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 N, 0.1 mL) was added dropwise to the reaction flask at 0°C, and the reaction was completed after 2 hours at 25°C. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was analyzed and purified to obtain compound 50. LC-MS: m / z: 422.2 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ10.90(s,1H),7.48(d,J=8.2Hz,2H),7.36(d,J=8.3Hz,2H),6. 46(d,J=3.5Hz,1H),5.09(d,J=23.2Hz,1H),4.70(t,J=5.6Hz,1H),4.54(t,J=5.3Hz,1H ),3.55(d,J=5.6Hz,2H),3.35(t,J=5.9Hz,2H),2.15–1.91(m,2H),1.86–1.78(m,1H),1 .76–1.58(m,2H),1.57–1.24(m,2H),0.85(q,J=4.1Hz,2H),0.76(q,J=4.6,4.1Hz,2H).

[0608] Example 51: Synthesis of Compound 51

[0609] Step 1: To a 100 mL single-necked flask, add dioxane (20 mL), water (5 mL), 51a (1 g, 3.53 mmol), 51b (0.75 g, 3.18 mmol), tetrakistriphenylphosphine palladium (0.20 g, 0.18 mmol), and potassium carbonate (1.22 g, 8.84 mmol). The reaction was allowed to proceed at 85°C for 16 hours under nitrogen protection until the reaction was complete. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 51c. LC-MS: m / z: 264.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.48 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.70-7.63 (m, 2H), 7.56-7.51 (m, 2H), 7.36 (d, J = 4.8 Hz, 1H), 3.90 (s, 3H).

[0610] Step 2: To a 25 mL single-necked flask, 51c (60 mg, 0.23 mmol) dissolved in dichloromethane (3 mL) was added. Boron tribromide (1 mL, 0.68 mmol) was added at 0°C and the reaction was allowed to proceed at 25°C for 16 h until complete. The reaction mixture was slowly quenched by the addition of 30 mL of sodium bicarbonate solution at 0°C. The mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield intermediate 51d. LC-MS: m / z: 250.0 (M+H). + .

[0611] Step 3: Under nitrogen, dioxane (3 mL), 51d (50 mg, 0.20 mmol), pinacol diboron (60.92 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14.83 mg, 0.02 mmol), and potassium acetate (58.86 mg, 0.60 mmol) were added to a 25 mL single-necked flask. The reaction was completed after 16 hours at 85°C. The reaction solution was filtered and concentrated under reduced pressure to obtain intermediate 51e. LC-MS: m / z: 298.2 (M+H) + .

[0612] Step 4: To a 25 mL single-necked vial was added dioxane (3 mL), 51e (50 mg, 0.17 mmol), 3b (64.72 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13.77 mg, 0.02 mmol), and potassium carbonate (69.76 mg, 0.50 mmol). The atmosphere was replaced with nitrogen and the reaction was completed by microwave at 100°C for 2 hours. The crude product was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 51. LC-MS: m / z: 475.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.17(s,1H),8.28(s,1H),8.11(d,J=4.9Hz ,1H),7.79-7.71(m,2H),7.71-7.63(m,2H),7.36(d,J=4.9Hz,1H),6.54(s,1H),5. 10(q,J=6.0Hz,1H),4.95(d,J=6.6Hz,1H),4.65(t,J=5.1Hz,1H),4.30(t,J=4.9Hz ,1H),4.13(s,1H),3.97(dd,J=9.5,6.2Hz,1H),3.79(m,2H),3.39(d,J=8.5Hz,1H).

[0613] Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications, if necessary).

[0614] Biological tests:

[0615] Test Example 1: In vitro test of AMPK (α1β1γ1) enzyme activating activity

[0616] The test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted to the desired assay concentration using kinase buffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, 0.01% Brij-35, pH = 7.5). 5 μL of AMPKα1β1γ1 (CARNA, 02-113), 2.5 μL of the diluted test compound solution, and 2.5 μL of a mixture of Ulight-CRBN and ATP were added to a 384-well plate to achieve the following final concentrations: 1.6 mg / L AMPKα1β1γ1, 5 nM Ulight-CRBN, and 0.1 mM ATP. Mix the components and incubate at room temperature for 1 hour. Then, add 5 μL of LANCE Detection Buffer (CR97-100, PerkinElmer) containing 40 mM EDTA. After incubation for 5 minutes, add 5 μL of 4× Eu-anti-phospho-CREB Antibody (TRF0200-M, PerkinElmer) and incubate at room temperature for 1 hour. Read the values ​​of each well using a microplate reader in TR-FRET mode (excitation wavelength: 320 nm, emission wavelengths: 665 nm and 615 nm). The relative activity of AMPKα1β1γ1 at each test compound concentration (4.57 nM, 13.72 nM, 41.15 nM, 123.46 nM, 370.37 nM, 1111.11 nM, 3333.33 nM, and 10000 nM) was calculated by comparing the values ​​with those of the blank control (1% DMSO) and the positive control (1 μM A769662). The activity of AMPKα1β1γ1 at each test compound concentration (4.57 nM, 13.72 nM, 41.15 nM, 123.46 nM, 370.37 nM, 1111.11 nM, 3333.33 nM, and 10000 nM) was calculated (with the activity of 1 μM A769662 as 100%). The data were subjected to a dose-response-stimulation four-parameter regression analysis in GraphPad Prism 9 to obtain the top value and EC value of the test compound. 50 Some test results are shown in Table 2.

[0617] The structure of A769662 is:

[0618] Table 2

[0619] Note: In Table 2,

[0620] A stands for EC 50 ≤200nM; B indicates 200nM <EC 50 ≤500nM; C represents 500nM <EC 50 ≤1000nM; D represents EC 50 >1000nM; and

[0621] Taking the AMPK (α1β1γ1) enzyme agonist activity value of 1 μM A769662 as 100%, A indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is ≥300%; B indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is 200%≤<300%; C indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is 150%≤<200%; D indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is 100%≤<150%; E indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is 70%≤<100%.

[0622] The test results show that the compounds of the present invention have good AMPK agonist activity, and some compounds show even better AMPK agonist activity.

[0623] Experimental Example 2: Experimental method for detecting phosphorylated AMPK at the cellular level

[0624] HepG2 (ATCC, HB-8065) ​​cells were cultured in complete DMEM (Gibco, 11965-092) supplemented with 10% fetal bovine serum (Gibco, 10099-141C), 100 U penicillin, and 100 μg / mL streptomycin (Gibco, 15140-122). This method was tested using the Perkin Elmer HTRF phospho-AMPK (Thr172) detection kits (Perkin Elmer, 64MPKPEG).

[0625] HepG2 cells were cultured in T75 cell culture flasks (Corning, 430641) in a 37°C, 5% CO2 incubator. When the cell density reached 70-80%, passage was performed approximately twice a week. When conducting the experiment, 20,000 cells / well were seeded into a 384-well plate (Corning, 3765) and the cells were cultured overnight. The test compound (10mM stock solution of the test compound dissolved in DMSO) was then added to the cell test 384-well plate at a set concentration (69nM-50μM) using ECHO. After incubating HepG2 cells with different concentrations of compounds for 40 minutes, the cell culture medium was removed. 16μL of cell lysate in the detection kit was then added and incubated at room temperature with shaking for 30 minutes. Subsequently, 4μL of a mixture of the diluted pAMPK Eu Cryptate antibody and pAMPK d2 antibody in the kit was added to make the final concentration of the detection antibody 1X. After centrifugation at 1500 rpm for 2 minutes to mix, the mixture was incubated at room temperature for 4 hours. The values ​​of each well sample were read at 620 nm and 665 nm using a microplate reader in TR-FRET mode. The pAMPK levels of the test compound at each concentration were calculated by comparing with the values ​​of the blank control group (medium only) and the positive control group (0.5% DMSO) (with 0.5% DMSO activity as 100%). The data were subjected to a dose-response-stimulation four-parameter regression analysis in GraphPad Prism 9 to obtain the compound's Top value and EC 50 The curve of the change of intracellular pAMPK (%) with the increase of compound concentration is shown in Figure 1.

[0626] The structure of MK-8722 is:

[0627] The test results show that the compounds of the present invention have good AMPK agonist activity at the cellular level, and some compounds show even better AMPK agonist activity at the cellular level.

[0628] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. Compounds of formula (I): or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: X 1 is selected from -C(=O)-, -C(=S)- and -CH2-; L 1 Selected from -O-, -S-, -NR c -and-CR a R b -; L 2 selected from -O-, -S-, -NR c -, -CR a R b -, -O-CR a R b - and -S-CR a R b -; Alternatively, -L 1 -X 1 -L 2 - as a whole is -NH-; R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace; R 1a independently selected from halogen, -OH, -CN, oxo, -COOR c ,-C(=O)NHR c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 1-6 Alkylene -OH, -OC 1-6 Alkylene -OH, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-COOR c , -C 1-6 Alkylene-C(=O)NHR c 、-S(=O)2-C 1-6 Alkyl and R a and R b is independently selected at each occurrence from H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 3-6 Cycloalkyl; R c independently selected at each occurrence from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; Ring A is selected from a benzene ring and a 5-6 membered aromatic heterocyclic ring, wherein the benzene ring and the 5-6 membered aromatic heterocyclic ring are each optionally substituted by 1, 2 or 3 R A Substituted, wherein R A independently selected from H, D, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 4-6 Carbocyclyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl; L 3 Selected from bond, -O-, -S-, -NR L3 -, -C(=O)-NR L3 -、-C(=O)-O-、-C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR L3 -、-C 1-6 Alkylene-S-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-; R L3 Selected from H, D and C 1-6 alkyl; R 2 Selected from C 6-10 Aryl, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group and 5-10 membered heteroaryl group, the C 6-10 Aryl, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon groups, 4-10 membered heterocyclic groups and 5-10 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected from H, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Saturated or partially unsaturated cyclic hydrocarbon group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2 or more R; and R is independently selected from: H, halogen, -OH, -CN, -NH2, oxo, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, -C substituted with 1 or 2 OH 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyleneoxy-C 1-6 Alkoxy, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-10 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -N=S(=O)R s1 R s2 、-NH-S(=O)2C 1-6 Alkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-4-10 membered heterocyclic group, -S(=O)2NH-C 1-6 Alkyl, -S(=O)2NH-C 3-10 Cycloalkyl, -C 3-10 Cycloalkylene-COOH, -C(=O)-4-10 membered heterocyclic group, 4-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2 or more independently selected from C 1-6 Alkyl, -NH2, =NH and oxo are substituted, the C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2 or more independently selected from halogen, -OH, -CN, -NH2, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN and -C 1-6 Alkylene-NH2 is substituted with a substituent, and R s1 and R s2 Each is C 1-6 Alkyl, or R s1 and R s2 Together with the S atom to which they are attached, they form a 4-6 membered heterocycloalkyl group; provided that: (1) The compound of formula (I) is not the following compound: (include ), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; b; and (2) When ring A is a thiazole ring, L 3 For-NR L3 -, and R 2 When L is a substituted or unsubstituted phenyl group, 1 No -CR a R b -; (3) When -L 1 -X 1 -L 2 When - as a whole is -NH-, for And R 2 C 6-10 Aryl, wherein the bond designated by "a" is attached to L 3 and the bond marked with "b" is connected to L 1 .

2. The compound according to claim 1, or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, wherein: When ring A is a thiazole ring and L 3 If R does not exist, 2 Not unsubstituted biphenyl.

3. The compound according to claim 1 or 2, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a benzene ring and a 5-6 membered aromatic heterocyclic ring, wherein the benzene ring and the 5-6 membered aromatic heterocyclic ring are each optionally substituted by 1, 2 or 3 R A replace; Preferably, ring A is selected from phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl and pyridinyl, wherein each of the phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl and pyridinyl groups is optionally substituted by 1 or 2 R A replace; Preferably, ring A is selected from phenyl, thienyl, imidazolyl, thiazolyl, and each of the phenyl, thienyl, imidazolyl, thiazolyl groups is optionally substituted with 1 or 2 R A replace; Preferably, ring A is selected from thienyl, which is optionally substituted by 1 or 2 R A replace; Preferably, ring A is selected from: wherein any of the above groups is optionally substituted with 1, 2 or 3 (preferably 1 or 2, more preferably 1) R A substituted, and wherein the bond identified by "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, ring A is selected from: Any of the above groups is optionally substituted with 1 or 2 R A replace; Preferably, ring A is selected from: Any of the above groups is optionally replaced by 1 R A replace; Preferably, ring A is selected from It is optionally replaced by 1 R A replace; Preferably, ring A is selected from: The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, ring A is selected from: More preferably, Ring A is selected from: Most preferably, Ring A is selected from 4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The R A are independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Halogenated alkenyl, C 2-6 Haloalkynyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 Carbocyclyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Preferably, the R A are independently selected from H, D, halogen, -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclyl, phenyl; or, where applicable, two adjacent R A Together with the ring atoms to which they are attached, they can form C 5-6 Carbocyclic group; Preferably, the R A are independently selected from H, D, halogen (e.g., F, Cl), -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Halogenated alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, phenyl; Preferably, the R A are independently selected from H, halogen (such as Cl), C 1-4 Alkyl, C 3-4 Cycloalkyl, phenyl; Preferably, the R A are independently selected from H, halogen (such as Cl), C 1-4 alkyl; Preferably, the R A Each is independently selected from H, D, F, Cl, -CN, methyl, ethyl, isopropyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, methoxy, ethoxy, isopropoxy, tert-butoxy, -CF3, -OCF3, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, phenyl; Preferably, the R A Each is independently selected from H, F, Cl, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl; More preferably, the R A Each is independently selected from Cl or methyl.

5. A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The ring A is selected from: The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, the ring A is selected from: More preferably, the ring A is selected from: Most preferably, the ring A is selected from Further preferably, the ring A is selected from 6. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in one of the following formulas: Preferably, Partially selected Preferably More preferred Further optimization The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Partially selected Preferably More preferably The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, for The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of Preferably The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 ; or Preferably, Part of The bond marked with "a" is connected to L 3 and the bond marked with "b" is connected to L 1 .

7. A compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-6 Alkylene-O-*, #-C 1-6 Alkylene-NR L3 -*,#-C 1-6 Alkylene-S-*, -C 2-6 Alkenylene- and -C 2-6 Alkyne-, where the bond marked with "#" is connected to R 2 Connection, the bond marked with "*" is connected to ring A; Preferably, L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-4 Alkylene-O-*, #-C 1-4 Alkylene-NR L3 -*,#-C 1-4 Alkylene-S-*, -C 2-4 Alkenylene- and -C 2-4 Alkyne-, where the bond marked with "#" is connected to R 2 are connected, and the bond marked with "*" is connected to ring A; Preferably, L 3 Selected from bond, -S-, -O-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-(CH2) n -O-*, #-(CH2) n -NR L3 -*、#-(CH2) n -S-*, vinylene, propenylene, ethynylene and propynylene, where "#" is used to mark The key to identify 2 Connected, the bond marked with "*" is connected to ring A, and n is selected from 1 and 2; Preferably, L 3 Selected from bond, -O-, -S-, -NR L3 -、#-C(=O)-NR L3 -*、#-C(=O)-O-*、#-C 1-4 Alkylene-NR L3 -* and -C 2-4 Alkyne-, where the bond marked with "#" is connected to R 2 are connected, and the bond marked with "*" is connected to ring A; Preferably, L 3 Select from bonds, -C 2-4 Alkyne- (e.g., ethynylene and propynylene); Preferably, L 3 is selected from a bond, an ethynylene group; More preferably, L 3 Select from keys.

8. A compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R L3 Selected from H, D and C 1-4 alkyl; Preferably, R L3 is selected from the group consisting of H, D, -CH3, -CH2CH3 and -CH(CH3)2; More preferably, R L3 For H.

9. A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: L 3 is selected from the group consisting of a bond, -O-, -S-, -NH-, #-C(=O)-NH-*, #-CH2-NH-*, #-CH2-O-*, #-CH2-S-* and -C≡C-, wherein the bond marked with "#" is 2 Connection, the bond marked with "*" is connected to ring A; Preferably, L 3 is selected from the group consisting of a bond, -O-, -S-, -NH-, #-C(=O)-NH-*, #-CH2-NH-* and -C≡C-, wherein the bond marked with "#" is 2 The bond marked with "*" is connected to ring A.

10. A compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R 2 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group and C 9-10 Partially unsaturated cyclic hydrocarbon group, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group or C 9-10 The partially unsaturated cyclic hydrocarbon group is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl are optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 Selected from C 3-6 Cycloalkyl, phenyl, 9-membered heteroaryl, the C 3-6 Cycloalkyl, phenyl, 9-membered heteroaryl, optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 phenyl, 9-membered heteroaryl, wherein the phenyl, 9-membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindole, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindanyl and 1,2,3,4-tetrahydronaphthyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindole, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindanyl and 1,2,3,4-tetrahydronaphthyl. pentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindole, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindanyl and 1,2,3,4-tetrahydronaphthyl are each optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 is selected from cyclopropyl, cyclobutyl, phenyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, indolyl, dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl, wherein the cyclopropyl, cyclobutyl, phenyl, thienyl, thiazolyl, oxazolyl, pyridinyl, indolyl, dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl are each optionally substituted by 1, 2, 3, 4, 5 groups independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 is selected from cyclopropyl, cyclobutyl, phenyl, thienyl, pyridyl, indolyl, dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl, wherein the cyclopropyl, cyclobutyl, phenyl, thienyl, pyridyl, indolyl, dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydroindenyl and 1,2,3,4-tetrahydronaphthyl are each optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 is selected from cyclopropyl, cyclobutyl, phenyl, and indolyl, wherein the cyclopropyl, cyclobutyl, phenyl, and indolyl are each optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 is selected from phenyl and indolyl, wherein the phenyl and indolyl are each optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R 2 Selected from Preferably, R 2 Selected from Preferably, R 2 Selected from More preferably, R 2 Selected from 11. A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered monocyclic heterocyclic group, 8-10 membered bicyclic heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered monocyclic heterocyclyl, 8-10 membered bicyclic heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2 or 3 R; preferably, R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclic group, phenyl and 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, F, Cl, Br, -OH, -CN, methyl, ethyl alkyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydrotriazolyl, phenyl, imidazolyl, pyrazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl, the methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydrotriazolyl, phenyl, imidazolyl, pyrazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl are each optionally substituted with 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e Each of the following is independently selected from H, F, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, Phenyl and pyridyl, the -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, Phenyl and pyridyl are each optionally substituted with 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e They are each independently selected from H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, cyclopropyl, cyclobutyl, phenyl, pyridinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, and piperidinyl, and the -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, cyclopropyl, cyclobutyl, phenyl, pyridinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, and piperidinyl are each optionally substituted by 1, 2 or 3 R.

12. A compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R is selected from the group listed in groups (1) to (3): (1)H, halogen, -OH, -CN, -NH2, oxo, -COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, -C substituted with 1 or 2 OH 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyleneoxy-C 1-4 Alkoxy, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N=S(=O)R s1 R s2 、-NH-S(=O)2C 1-4 Alkyl, -S(=O)2-C 1-4 alkyl, -S(=O)2-4-6 membered heterocyclic group, -S(=O)2NH-C 1-4 Alkyl, -S(=O)2NH-C 3-6 Cycloalkyl, -C 3-6 Cycloalkylene-COOH and -C(=O)-4-6 membered heterocyclic group, wherein R s1 and R s2 Each is C 1-4 Alkyl, or R s1 and R s2 Together with the S atom to which they are attached, they form a 4-6 membered heterocycloalkyl group; (2) 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or more independently selected from C 1-4 Alkyl, -NH2, =NH and oxo substituents; and (3) phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2 or more independently selected from halogen, -OH, -CN, -NH2, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -CN and -C 1-4 Preferably, R is selected from: H, -NH2, -OH, -C substituted with 1 OH 1-4 Alkyl, C 1-4 Alkyl, -S(=O)2-C 1-4 Alkyl, 4-6 membered heterocyclic group; Preferably, R is selected from the group listed in groups (1) to (3): (1) H, halogen, -OH, -CN, -NH2, oxo, -COOH, methyl, ethyl, propyl, butyl, halomethyl, Halogenated ethyl, halogenated propyl, halogenated butyl, -CH2OH, -ethylene-OH, methoxy, ethoxy, propoxy, butoxy, -methyleneoxy-methoxy, -methyleneoxy-ethoxy, -methyleneoxy-propoxy, -ethyleneoxy-methoxy, -ethyleneoxy-ethoxy, -ethyleneoxy-propoxy, -C(=O)-NH-methyl, -C(=O)-NH-ethyl, -C(=O)-NH-propyl, -C(=O)-NH-butyl, -N=S(=O)(methyl)2, -N=S(=O)(methyl)(ethyl), -N=S(=O)(methyl)(propyl), -N=S(=O)(methyl)(butyl), -N=S(=O)(ethyl)2, -N=S(=O)(ethyl)(propyl), -(NH) p -W-methyl, -(NH) p -W-ethyl, -(NH) p -W-propyl, -(NH) p -W-butyl, -W-NH-cyclopropyl, -W-oxetanyl, -W-azetidinyl, -W-tetrahydrofuranyl, -W-pyrrolidinyl, -W-tetrahydropyranyl, -W-piperidinyl, -W-morpholinyl, -cyclopropylene-COOH and wherein each W is independently C(=O) or S(=O)2, and each p is independently 0 or 1; (2) oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyrazolyl, dihydroimidazolyl and dihydrotriazolyl, wherein the oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyrazolyl, dihydroimidazolyl and dihydrotriazolyl are each optionally substituted with 1, 2 or more substituents independently selected from methyl, ethyl, propyl, tert-butyl, -NH2, =NH and oxo; and (3) phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl, wherein each of the phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl groups is optionally substituted by 1, 2 or more groups independently selected from halogen, -OH, -CN, -NH2, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -CN and -C 1-4 Alkylene -NH2 is substituted by a substituent; Preferably, R is selected from: H, F, -OH, -CN, -NH2, oxo, -COOH, -CH3, -CH2OH、 -OCH3、-OCH2CH2OCH3、-C(=O)CH3、-C(=O)NHCH3、-NHC(=O)CH3、-N=S(=O)(CH3)2、 -NH-S(=O)2CH3、-S(=O)2CH3、 Preferably, R is H, -NH2, -OH, -CH2OH, -CH3, -S(=O)2CH3, More preferably, R is H, -OH, -CH2OH, -CH3, -S(=O)2CH3, 13. A compound according to any one of claims 1 to 12, wherein R 2 Selected from: Preferably, R 2 Selected from More preferably, R 2 Selected from 14. A compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound has a structure represented by any one of the following formulas (II-1) to (II-9): Preferably, the compound has a structure represented by any one of formulas (I-24) to (I-33):

15. A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: X 1 is selected from -C(=O)-, -C(=S)-; preferably, X 1 Selected from -C(=O)-.

16. A compound according to any one of claims 1 to 15, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R a and R b Each occurrence is independently selected from H, D, F, Cl, Br, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 3-4 Cycloalkyl; Preferably, R a and R b Each occurrence is independently H.

17. A compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R c independently selected at each occurrence from H, D, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-4 Cycloalkyl; preferably, R c H and C independently at each occurrence 1-4 The alkyl group is preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and more preferably H and methyl.

18. A compound according to any one of claims 1 to 17, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: L 1 Selected from -O-, -NR c -and-CR a R b -; Preferably, L 1 Selected from -NR c -; Preferably, L 1 is selected from -O-, -S-, -NH-, -N(CH3)- and -CH2-; more preferably, L 1 Selected from -NH-.

19. A compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: L 2 Selected from -O-, -S-, -NR c -、-CR a R b -、#-O-CR a R b -* and #-S-CR a R b -*, where the key marked with "#" is the same as X 1 Connect, the key marked with "*" and R 1 connect; Preferably, L 2 Selected from -O-, -CR a R b -; Preferably, L 2 Selected from -O-; Preferably, L 2 is selected from -O-, -S-, -NH-, -N(CH3)-, -CH2-, #-O-CH2-* and #-S-CH2-*, wherein the bond marked with "#" is 1 Connect, the key marked with "*" and R 1 connect; Preferably, L 2 is selected from -O-, -S-, -NH-, -N(CH3)-, -CH2- and #-O-CH2-*, wherein the bond marked with "#" is 1 Connect, the key marked with "*" and R 1 connect; More preferably, L 2 Selected from -O-, -CH2-.

20. A compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: -L 1 -X 1 -L 2 - Partially selected from: -NH-, preferably -NH-, more preferably The bond marked with "c" is connected to ring A, and the bond marked with "d" is connected to R 1 connect.

21. A compound according to any one of claims 1 to 20, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in the following formula (III'): Wherein, X is selected from O or S; preferably, X is selected from O; Preferably, the compound has a structure shown in formula (III): Preferably, the compound has a structure shown in formula (III-1): Preferably, the compound has a structure represented by any one of formulas (III-A) to (III-F):

22. A compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in the following formula (III-2) or (III-3): Preferably, the compound has a structure shown in formula (III-G) or (III-H): More preferably, the compound has a structure shown in formula (III-I) or (III-J):

23. A compound according to any one of claims 1 to 22, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclic group, 8-10 membered fused bicyclic heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclyl, 8-10 membered fused bicyclic heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic nitrogen-containing heterocyclic group, 4-6 membered monocyclic oxygen-containing heterocyclic group, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered monocyclic nitrogen-containing heterocyclic group, 4-6 membered monocyclic oxygen-containing heterocyclic group, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, phenyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, phenyl and 5-6 membered heteroaryl, wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from C 3-6 Cycloalkyl, 8-10 membered fused bicyclic oxygen-containing heterocyclic group, wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, phenyl and (Preferred ), wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 is selected from n-propyl, cyclopentyl, cyclohexyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, phenyl and (Preferred ), wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from n-propyl, cyclopentyl, cyclohexyl and (Preferred ), wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from cyclopentyl and (Preferred ), wherein any of the above groups is optionally substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from (Preferred ), which is optionally replaced by 1, 2 or 3 R 1a replace; Preferably, R 1 A group selected from Groups (1)-(2): (1) methyl, ethyl and n-propyl, each of which is optionally substituted with 1, 2 or 3 R 1a replace; (2) (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred More preferred )、 (Preferred )、 Preferably, R 1 Selected from: (Preferred )、 (Preferred More preferred ), wherein s is selected from 0, 1 or 2, preferably s is selected from 2; Preferably, R 1 Selected from: (Preferred More preferred )； More preferably, R 1 Selected from (Preferred More preferred )。 24. A compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: Each R 1a independently selected from halogen, -OH, -CN, oxo, -COOR c , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 Alkylene -OH, -OC 1-4 Alkylene -OH, -C 1-4 Alkylene-COOH, -S(=O)2-C 1-4 Alkyl and Preferably, each R 1a Independently selected from -OH, -COOR c , -C 1-4 Alkylene-OH, Preferably, each R 1a Independently selected from -OH, -C 1-2 Alkylene-OH; Preferably, each R 1a independently selected from F, Cl, Br, -OH, oxo, -COOH, methyl, ethyl, isopropyl, tert-butyl, -CH2-OH, -CH2CH2-OH, -C(CH3)2-OH, -CH2-COOH, -CH2CH2-COOH, -C(CH3)2-COOH, -S(=O)2-CH3 and Preferably, each R 1a independently selected from Cl, -OH, -CN, oxo, -COOH, -COOEt, methyl, ethyl, -CH2-OH, -CH2CH2-OH, -OCH2CH2-OH, -C(CH3)2-OH, -CH2-COOH, -CH2CH2-COOH, -C(CH3)2-COOH, -S(=O)2-CH3 and Preferably, each R 1a Independently selected from -OH, -CH2-OH, -COOH, -COOEt; Preferably, each R 1a Independently selected from -OH, -CH2-OH, -COOH; Preferably, each R 1a Independently selected from -OH, -CH2-OH; More preferably, each R 1a are independently selected from -OH.

25. A compound according to any one of claims 1 to 24, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from: Preferably, R 1 Selected from: Preferably, R 1 Selected from: Preferably, R 1 Selected from: Preferably, R 1 Selected from: More preferably, R 1 Selected from:

26. A compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: -L 1 -X 1 -L 2 -R 1 Some selected from: (Preferred ), (Preferred ); Preferably, -L 1 -X 1 -L 2 -R 1 Some selected from: More preferably, -L 1 -X 1 -L 2 -R 1 Some selected from:

27. A compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: -L 1 -X 1 -L 2 -R 1 Some selected from: Preferably, -L 1 -X 1 -L 2 -R 1 Some selected from: Preferably, -L 1 -X 1 -L 2 -R 1 Some selected from: Preferably, -L 1 -X 1 -L 2 -R 1 Some selected from: More preferably, -L 1 -X 1 -L 2 -R 1 Some selected from:

28. A compound according to any one of claims 1 to 27, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound has a structure represented by any one of formulas (IV-1) to (IV-4): (Preferred )、 (Preferred )； Preferably, the compound has a structure represented by any one of formulas (IV-5) to (IV-8): (Preferred )、 (Preferred )； Preferably, the compound has a structure represented by any one of formulas (V-1) to (V-9): (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )； More preferably, the compound has a structure represented by any one of formulas (VI-1) to (VI-14): (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 29. A compound according to any one of claims 1 to 28, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound has a structure represented by any one of formulas (I-3) and (X-1) to (X-5): (Preferred More preferred )、 (Preferred More preferred )、 (Preferred More preferred )、 (Preferred )。 30. A compound according to any one of claims 1 to 29, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.

32. Use of a compound according to any one of claims 1 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31 in the preparation of a medicament as an AMPK agonist.

33. Use of a compound according to any one of claims 1 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31 in the preparation of a medicament for treating and / or preventing a disease, disorder or condition associated with AMPK kinase, the disease, disorder or condition preferably being selected from type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease and alopecia.

34. Use of a compound according to any one of claims 1 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31 in the preparation of a medicament for treating and / or preventing a disease, disorder or condition that can be treated and / or prevented by activating AMPK, the disease, disorder or condition preferably being selected from type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease and alopecia.

35. A method for treating and / or preventing a disease, disorder or condition that can be treated and / or prevented by activating AMPK, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 30, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition according to claim 31, wherein the disease, disorder or condition is preferably selected from type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease and alopecia.

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