Compound acting as PARP7 inhibitor

Abstract

The present invention relates to a biaromatic compound acting as a PARP7 inhibitor. Specifically, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof. The present invention also relates to a use of the compound for treating or preventing PARP7-mediated diseases, such as cancer, immune diseases, inflammation or viral infections.

Description

Compounds that act as PARP7 inhibitors

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202311406408.4 filed on October 26, 2023 and Chinese patent application CN202410735258.X filed on June 6, 2024, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present invention relates to the field of medicinal chemistry, and in particular to a compound serving as a PARP7 inhibitor. Background Art

[0004] Epigenetics is a key mechanism linking environmental stress to gene expression. It is a general term for heritable or inheritable mechanisms that regulate gene expression without altering the gene's DNA sequence, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA. Epigenetics is involved in the regulation of numerous biological processes, including cell differentiation, individual development, and tumorigenesis and progression. ADP-ribosylation (ADPr) is an epigenetic mechanism mediated by the PARP family. PARPs use NAD+ as a substrate to perform reversible post-translational modifications on proteins, altering their function. ADPr modification participates in a variety of cellular processes: 1) Under non-stressful conditions, ADPr is required for cell division, transcription, and chromatin structure regulation, making it crucial for cellular physiology. 2) ADPr regulation is also required under cellular stress conditions, such as DNA damage, apoptosis, heat shock, cytoplasmic stress, and the unfolded protein response. 3) ADPr also plays a crucial role in immune cell signaling and activation, regulating cellular responses to cytokines and the expression and secretion of cytokines.

[0005] The PARP family currently has 17 members, all of which contain a conserved catalytic domain but have limited sequence similarity. The functions of PARP family members are not fully understood. With the exception of a few special PARPs (such as PARP13, which lacks enzymatic activity), other PARPs can be divided into monoPARPs and polyPARPs, which transfer single or multiple ADP-ribosyl groups to complete MARylation (Mono-ADP-ribosylation) or PARylation (Poly-ADP-ribosylation), respectively. PARP1 is a polyPARP that has been widely studied. PARP7 is a monoPARP that cleaves an NAD+ molecule into an ADP-ribose and nicotinamide, catalyzing the transfer of a single ADP-ribose unit to a protein to alter its function and release nicotinamide. PARP7 is typically localized in the nucleus but can translocate to the cytoplasm in response to viral infection, reactive oxygen species (ROS), and mitochondrial damage.

[0006] When cells are stimulated by environmental toxins such as cigarette smoke toxins, viral infection, and steroid hormones, the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR) is activated, which upregulates PARP7. During viral infection, AHR-induced PARP7 inactivates the kinase TBK1 through mono-ADP ribosylation, preventing TBK1 from phosphorylating IRF3 and thereby suppressing the type I IFN immune response. TBK1 is a major kinase activated when the pathogen-associated molecular pattern pathway is activated, activating type I IFN responses and antiviral immunity. Similar mechanisms also exist in tumors. Due to genomic instability, tumor cells often carry abnormal cytoplasmic nucleic acids, which can activate the cGAS / STING and RIG-I sensing mechanisms. These pattern recognition receptors (PRRs) pathways activate TBK1 and phosphorylate IRF3, thereby activating the type I IFN-induced innate immune response. Tumor cells can evade the host immune system by overexpressing or activating PARP7 and inhibiting the activation of TBK1, thereby suppressing the type I IFN response and CD8+ T cell-mediated anti-tumor immunity. Inhibiting PARP7 can directly inhibit cancer cell proliferation by restoring the response of type I IFN signaling to abnormal nucleic acids, while inducing tumor-specific adaptive immune memory, leading to tumor regression and lasting immunity. In some tumor types, the copy number of the PARP7 gene on chromosome 3 (3q25) is amplified, especially in squamous tissue of primary tumors (SCCL, HNSC) and some ovarian cancers, and the corresponding PARP7 mRNA levels are also increased. Tumor types with high expression of PARP7 mRNA also express higher levels of baseline IFN-stimulated genes (ISGs), and these cancer cell lines are more sensitive to PARP7 inhibition / knockout.

[0007] Therefore, there is a need to develop small molecule inhibitors against PARP7 to provide more potential treatments for PARP7-mediated diseases (such as related sensitive cancer types).

[0008] Summary of the Invention

[0009] The main purpose of the present invention is to provide a compound that acts as a PARP7 inhibitor, and to develop small molecule inhibitors targeting PARP7, thereby providing more possibilities for the treatment of PARP7-mediated diseases (such as related sensitive cancer types). The above-mentioned purpose of the present invention is achieved through the following specific scheme.

[0010] In a first aspect of the present invention, there is provided a compound of formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs:

[0011] in,

[0012] Ring A is selected from C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl;

[0013] Ring B is selected from C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, C6-10 aryl and 5-6 membered heterocycloalkyl, C6-10 aryl and C5-6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and C5-6 cycloalkyl; $L5 represents the site of attachment to L5, and #L represents the site of attachment to L;

[0014] Ring C is selected from:

[0015] The end is connected to L;

[0016] L is a linking group between ring B and ring C, and the number of main chain atoms of the linking group is between 2 and 7, preferably between 4 and 7;

[0017] L5 is selected from a bond, $B-(CH2)sO-#A, $BO-(CH2)s-#A, $B-(CH2)s-NRd-#A, $B-NRd-(CH2)s-#A, wherein s is 0, 1 or 2, and the $B-(CH2)sO-#A, $BO-(CH2)s-#A, $B-(CH2)s-NRd-#A, $B-NRd-(CH2)s-#A are optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, $B represents the site of connection to ring B, and #A represents the site of connection to ring A;

[0018] Each R1, R2, and R3 is independently selected from H, D, halogen, hydroxy, -CN, -NReRf, -NReC(=O)Rf, -C(=O)-NReRf, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6 membered heteroaryl, -C1-6 alkylene-5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, -C1-6 alkylene-4-6 membered heteroaryl, -7-membered heterocycloalkyl, wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6-membered heteroaryl, -C1-6 alkylene-5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, -C1-6 alkylene-4-7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; optionally, two R1 or R2 attached to the same carbon atom form C=O with the carbon atom;

[0019] Rd is selected from H, C1-6 alkyl, halogenated C1-6 alkyl;

[0020] Re and Rf are each independently selected from H, C1-6 alkyl, halo-substituted C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, halo-substituted C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkoxy;

[0021] m1, m2 and m3 each independently represent an integer of 0-4.

[0022] In the second aspect of the present invention, a pharmaceutical composition is provided, which comprises the compound described in the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, and a pharmaceutically acceptable carrier.

[0023] In the third aspect of the present invention, provided is the use of the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition of the second aspect in the preparation of a medicament for inhibiting PARP7 in a subject in need thereof, or for treating a PARP7-mediated disease; preferably, the PARP7-mediated disease is selected from cancer, immune disease, inflammation or viral infection.

[0024] In the fourth aspect of the present invention, a method for treating a PARP7-mediated disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition of the second aspect, wherein the PARP7-mediated disease is selected from cancer, immune disease, inflammation or viral infection.

[0025] In the fifth aspect of the present invention, provided is the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition of the second aspect for inhibiting PARP7 in a subject in need thereof, or for treating a PARP7-mediated disease; preferably, the PARP7-mediated disease is selected from cancer, immune disease, inflammation or viral infection. Beneficial effects

[0026] The compounds of the present invention have a good active inhibitory effect on PARP7, can inhibit the binding of PARP7 to RBN011147, and have a good active inhibitory effect on the proliferation of NCI-H1373 cells, providing more possibilities for the development of small molecule inhibitors against PARP7 and the treatment of PARP7-mediated diseases (such as related sensitive cancer types). DETAILED DESCRIPTION

[0027] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0028] definition

[0029] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0030] As used herein, the expression "about" is understood by one of ordinary skill in the art and varies within certain limits depending on the context in which it is used. If the use of the term is not understood by one of ordinary skill in the art based on the context in which it is used, "about" will mean up to plus or minus 10% of the specified value.

[0031] The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain saturated hydrocarbon radical having the specified number of carbon atoms (i.e., C1-6 refers to a straight or branched chain hydrocarbon radical having from one to six carbon atoms). Preferably, the alkyl radical generally contains from 1 to 6 carbon atoms, i.e., a C1-6 alkyl radical. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0032] As used herein, the term "haloalkyl" refers to a group including branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl" groups including branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0033] The term "fluoroalkyl" or "fluoroalkyl group" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by fluorine atoms.

[0034] The term "alkoxy" refers to a straight or branched chain alkyl group connected through an ether oxygen, with its free valence bond coming from the ether oxygen. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-3 alkoxy group.

[0035] The term "haloalkoxy" refers to -O-haloalkyl, including straight-chain or branched haloalkoxy groups. Representative examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0036] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic alkyl group, such as a C3-8 or C3-12 cycloalkyl group. A C3-8 cycloalkyl group refers to a C3, C4, C5, C6, C7, or C8 cycloalkyl group. Cycloalkyl groups may also include cycloalkyl groups with structures such as spirocyclic, bridged, and parallel rings. Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. C5-12 fused bicyclic groups include, but are not limited to, C5, C6, C7, C8, C9, C10, C11, and C12 bicyclic alkyl groups, including, but not limited to: Etc. C5-12 spiro bicyclic refers to C5, C6, C7, C8, C9, C10, C11, C12 bicycloalkyl, including but not limited to: In the present invention, the cycloalkyl group is preferably a monocyclic cycloalkyl group containing 3 to 6 carbon atoms (ie, C3-6), such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0037] The term "aryl", alone or as part of a group such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system (preferably a 6-10 membered aromatic ring) having a total of 6 to 15 ring members (or ring atoms), wherein all rings in the system are aromatic and wherein each ring in the system contains 3 to 7 ring members; when not all rings in the system are aromatic, they are considered cycloalkyl. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, 1-naphthyl, 2-naphthyl, anthracenyl.

[0038] A connecting line drawn from a ring system indicates that one end of the bond can be connected to any suitable ring atom in the ring system that the bond passes through. If it passes through one ring, it indicates that it can be connected to any optional position on the ring. If it passes through multiple rings, it indicates that it can be connected to any optional position on the multiple rings. For example, the structure shown in formula (E) below includes any possible connection method shown in formulas (E1)-(E3):

[0039] However, in the present application, when ring C is a structure as shown in (F), only possible connection modes as shown in formula (F1) or (F2) are included:

[0040] Alternatively, in the structure shown in the following formula (G), the connecting line passes through the two rings, which includes the structure shown in the following formula (G1):

[0041] (G5) Any possible connection shown:

[0042] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic ring system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C. Preferred heteroaryl groups are monocyclic rings containing 5 to 10, particularly 5 to 8, and more particularly 5 or 6, ring atoms, or multiple fused rings containing 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0043] The term "heterocycloalkyl" refers to a fully saturated or partially unsaturated cyclic group that can exist as a monocyclic, bridged or spirocyclic ring. The heterocycloalkyl group is generally a cycloalkyl group containing 1 to 5, preferably 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from N, O and S. The ring atoms of the heterocycloalkyl group are optionally substituted with oxo (=O). Non-limiting examples of heterocycloalkyl groups include oxiranyl, oxiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, tetrahydropyrazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, azepanyl, oxepanyl, thiepanyl. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0044] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that provide stable or chemically feasible compounds. Typical substitutions include, but are not limited to, one or more (e.g., 1 to 3) of the following groups: hydrogen, deuterium, halogen, hydroxyl (-OH), nitrile, nitro, oxo (e.g., =O, where two H on a carbon atom are replaced by it to form a carbonyl), alkyl (C1-6 alkyl), cycloalkyl (e.g., C3-6 cycloalkyl), alkenyl, alkynyl, heterocycloalkyl (e.g., 4-10 membered heterocycloalkyl), aryl, heteroaryl (e.g., 5-6 membered heteroaryl), alkoxy (e.g., C1-6 alkoxy, such as methoxy, ethoxy), C1-6 haloalkyl (e.g., monohalogen substituted or polyhalogen substituted, the latter such as trifluoromethyl), C1-6 haloalkoxy (e.g., monohalogen substituted or polyhalogen substituted, the latter such as trifluoromethoxy), -OC(=O)NR ii R iii , OR i SR i 、S(=O)R v 、S(=O)2R v 、P(=O)2R v 、S(=O)2OR v , P(=O)2OR v NR ii R iii NR ii S(=O)2R v NR ii P(=O)R v 、S(=O)2NR ii R iii 、P(=O)2NR ii R iii 、C(=O)OR iv 、C(=O)R i 、C(=O)NR ii R iii 、OC(=O)R i 、OC(=O)NR ii R iii NR ii C(=O)OR v NR iv C(=O)NR ii R iii NRiv S(=O)2NR ii R iii NR iv P(=O)2NR ii R iii NR ii C(=O)R i , or NR ii P(=O)2R v , where R i R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic rings. ii 、R iii and R iv R may independently represent hydrogen, deuterium, alkyl (e.g., C1-6 alkyl), cycloalkyl (e.g., C3-6 cycloalkyl), heterocycloalkyl, or aryl, or ii and R iii Together with the atoms to which it is attached, it can form a heterocycloalkyl group (e.g., a C4-10 heterocycloalkyl group), wherein the heterocycloalkyl group is optionally substituted with 1-3 substituents selected from halogen, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; R v " may independently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocycle, or an aromatic ring. The above-mentioned typical substituents, such as an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocycle, or an aromatic ring, may be optionally substituted. Such substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-6 alkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C3-8 cycloalkyl groups, 3-12 membered heterocyclyl groups, aryl groups, heteroaryl groups, C1-8 aldehyde groups, C2-10 acyl groups, C2-10 ester groups, amino groups, C1-6 alkoxy groups, C1-10 sulfonyl groups, and C1-6 urea groups.

[0045] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients, including but not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

[0046] The pharmaceutical composition of the present invention can be prepared into various forms according to different routes of administration. For example, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectally, nasally, buccally, vaginally, topically, parenterally, such as by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or via an explanted reservoir. Oral and intravenous administration are preferred.

[0047] Compound of the present invention optionally also can be used in conjunction with other one or more active components, and its respective consumption and ratio can be adjusted by those skilled in the art according to concrete disease and patient specific condition and clinical need etc.Use in conjunction does not mean that therapy or therapeutic agent must be used simultaneously and / or be prepared for sending together, although these delivery methods are within the scope of the present invention.The therapeutic agent used in conjunction can be used simultaneously with one or more other other therapies or therapeutic agent, before or after it.Therapeutic agent or treatment regimen can be used in any order.

[0048] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs become active compounds only through this reaction under biological conditions, or they have no or only low activity in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0049] Unless otherwise specified, when a substituent is described by a conventional chemical formula written from left to right, the substituent only includes its form written from left to right, connected to the structures on the left and right sides of the corresponding group in the general formula compound structure.

[0050] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0051] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0052] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0053] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0054] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0055] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0056] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0057] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0058] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0059] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0060] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0061] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0062] The compounds described herein include all possible isotopically labeled compounds of all compounds described herein. The term "isotopically labeled compound" refers to a compound wherein any atom in the compound is replaced by an isotope thereof. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0063] "Solvate" or "solvate" are used interchangeably to refer to a compound that exists in combination with certain solvent molecules. The combination may include a stoichiometric amount of a certain solvent, for example, when the solvent is water, a "hydrate" such as a monohydrate or dihydrate is formed, or it may include any amount of water; for example, when the solvent is an alcohol such as methanol or ethanol, an "alcoholate" may be formed, which may also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a solid form, i.e., a compound in solution in a solvent, although it may be solvated, it is not a solvate as the term is used herein.

[0064] As used herein, the term "metabolite" refers to a derivative of a compound formed when the compound is metabolized. The term "metabolism" refers to the sum of processes by which a particular substance is changed by an organism (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions).

[0065] As used herein, the term "ester" refers to an ester formed between the -COOH group present in the compounds provided herein and a suitable alcohol, or an ester formed between the -OH group present in the compounds provided herein and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, stearic acid esters, or palmitates. Esters can undergo hydrolysis in the presence of an acid or base to produce the corresponding acid or alcohol.

[0066] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt formed by an acidic functional group (e.g., -COOH) present in the compounds provided herein with a suitable inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts. and (ii) salts formed by basic functional groups (e.g., -NH2) present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), including but not limited to hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkanesulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[0067] As used herein, the term "crystalline form" refers to the crystal structure of a substance. During crystallization, various factors may alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms within the crystal lattice space, forming different crystal structures. The compounds of the present invention may exist in a single crystal structure or in multiple crystal structures, i.e., they may exhibit "polymorphism." The compounds of the present invention may exist in different crystalline forms.

[0068] As described herein, the term "treat" refers to reducing or ameliorating a condition, such as the progression, severity, and / or duration of a proliferative condition, or improving one or more symptoms (preferably, one or more discernible symptoms) of a condition caused by the administration of one or more therapies. In a specific embodiment, the term "treat" refers to an improvement in at least one measurable physical parameter of a proliferative condition that is not necessarily discernible to the patient, such as the growth of a tumor. In other embodiments, the term "treat" refers to physically or physiologically inhibiting the progression of a proliferative condition, such as by stabilizing discernible symptoms or stabilizing physical parameters or both. In other embodiments, the term "treat" refers to a reduction or stabilization of tumor size or cancer cell count.

[0069] The term "subject" or "patient" refers to a warm-blooded animal, such as a mammal, especially guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans, that has a particular disease, disorder, or condition.

[0070] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or spread to other parts of the body through the bloodstream and lymphatic system. The terms "tumor" and "cancer" are used interchangeably herein, for example, both terms cover solid tumors and liquid tumors, for example, diffuse or circulating tumors. As used herein, the terms "cancer" or "tumor" include pre-malignant and malignant cancers and tumors. As used herein, the term "cancer" is meant to include all types of cancerous growth or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of the invasive histopathological type or stage. Examples of cancerous conditions include, but are not limited to, breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (upper respiratory tract cancer), urinary tract cancer, colon cancer, cancer with amplified PARP7 expression, etc. In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies, such as leukemias and lymphomas. Exemplary lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Examples of leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0071] Examples of autoimmune diseases that may be treated or prevented by administering the compounds of the present invention include, but are not limited to, rheumatoid arthritis, insulin-dependent diabetes mellitus, certain hemolytic anemias, rheumatic fever, thyroiditis, ulcerative colitis, myasthenia gravis, glomerulonephritis, allergic encephalomyelitis, viral hepatitis with subsequent nerve and liver damage, multiple sclerosis, systemic lupus erythematosus, juvenile diabetes, autoimmune hemolytic anemia, psoriasis, idiopathic thrombocytopenic purpura, active chronic hepatitis, idiopathic leukopenia, primary Biliary cirrhosis, thyrotoxicosis, dermatomyositis, discoid lupus erythematosus, psoriatic arthritis, regional enteritis, nephrotic syndrome, lupus nephritis, lupus hepatitis, Sjögren's syndrome, Goodpasture's syndrome, Wegener's granulomatosis, scleroderma, seborrheic dermatitis, uveitis and mumps mastitis, ulcerative colitis, Crohn's disease, multiple sclerosis, autoimmune liver disease, type 1 diabetes mellitus, bronchial asthma, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriasis, polymyositis and dermatomyositis.

[0072] Viruses and viral infections that can be treated or prevented by administering the compounds of the present invention include, but are not limited to, DNA viruses such as hepatitis B and hepatitis C viruses; parvoviruses such as adeno-associated virus and cytomegalovirus; papillomaviruses such as papillomavirus, polyomavirus, and SV40; adenovirus; herpes viruses such as herpes simplex type 1 (HSV-I), herpes simplex type II (HSV-II), and Epstein-Barr virus; poxviruses, for example, smallpox and vaccinia virus; and RNA viruses such as human immunodeficiency virus type 1 (HIV-I), human immunodeficiency virus type II (HIV-II), human T-cell lymphotropic virus type 1 (HTLV-I), human T-cell lymphotropic virus type II (HTLV-II), influenza virus, measles virus, rabies virus, Sendai virus, polioviruses such as poliovirus, coxsackievirus, rhinovirus, reovirus, togaviruses such as rubella virus (German measles) and Selici Forest virus, dendroviruses, and hepatitis A virus.

[0073] Unless otherwise stated, substituents or group combinations contemplated herein for Markush structures are those that are stable or chemically feasible.

[0074] Those skilled in the art will understand that when referring to a ring or substituent that is obviously divalent according to the general formula, even if it is not explicitly stated that it can be or is selected from a divalent candidate, it is selected from a divalent ring or group. A divalent group refers to a group formed after the corresponding group, such as an aryl group such as a phenyl group, further loses a hydrogen atom. For example, ring B is selected from phenyl and ring B is selected from It has the same meaning. For example, L3 is selected from C3-10 cycloalkyl, which means that L3 is selected from the group of C3-10 cycloalkyl that has lost a hydrogen atom.

[0075] At the same time, those skilled in the art will understand that when a single group connecting two groups is a bond, it indicates that the two groups connected thereby are directly connected; when multiple consecutive groups connecting two groups are all bonds, it indicates that the two groups connected thereby are directly connected.

[0076] Compound

[0077] In one aspect, the present invention provides a compound of Formula I or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug:

[0078] in,

[0079] Ring A is selected from C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl;

[0080] Ring B is selected from C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, C6-10 aryl and 5-6 membered heterocycloalkyl, C6-10 aryl and C5-6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and C5-6 cycloalkyl; $L5 represents the site of attachment to L5, and #L represents the site of attachment to L;

[0081] Ring C is selected from:

[0082] The end is connected to L;

[0083] L is a linking group between ring B and ring C, and the number of main chain atoms of the linking group is between 2 and 7, preferably between 4 and 7;

[0084] L5 is selected from a bond, $B-(CH2)sO-#A, $BO-(CH2)s-#A, $B-(CH2)s-NRd-#A, $B-NRd-(CH2)s-#A, wherein s is 0, 1 or 2, and the $B-(CH2)sO-#A, $BO-(CH2)s-#A, $B-(CH2)s-NRd-#A, $B-NRd-(CH2)s-#A are optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, $B represents the site of connection to ring B, and #A represents the site of connection to ring A;

[0085] Each R1, R2, and R3 is independently selected from H, D, halogen, hydroxy, -CN, -NReRf, -NReC(=O)Rf, -C(=O)-NReRf, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6 membered heteroaryl, -C1-6 alkylene-5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, -C1-6 alkylene-4-6 membered heteroaryl, -7-membered heterocycloalkyl, wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6-membered heteroaryl, -C1-6 alkylene-5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, -C1-6 alkylene-4-7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; optionally, two R1 or R2 attached to the same carbon atom form C=O with the carbon atom;

[0086] Rd is selected from H, C1-6 alkyl, halogenated C1-6 alkyl;

[0087] Re and Rf are each independently selected from H, C1-6 alkyl, halo-substituted C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, halo-substituted C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkoxy;

[0088] m1, m2 and m3 each independently represent an integer of 0-4.

[0089] In some embodiments, ring B is selected from C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, C6-10 aryl and 5-6 membered heterocycloalkyl, C6-10 aryl and C5-6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and C5-6 cycloalkyl;

[0090] Ring C is selected from:

[0091] The end is connected to L;

[0092] m1, m2 and m3 each independently represent an integer of 0-3.

[0093] In some embodiments, ring B is selected from C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, C6-10 aryl and 5-6 membered heterocycloalkyl, C6-10 aryl and C5-6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and C5-6 cycloalkyl; any of the above heteroaryl groups has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, and any of the above heterocycloalkyl groups has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S.

[0094] In some embodiments, Ring A is selected from C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl; the 5-10 membered heteroaryl has 1, 2, 3 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S, and the 4-10 membered heterocycloalkyl has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0095] In some embodiments, ring A is selected from 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl; preferably, ring A is selected from 5-6 membered heteroaryl, 6 membered heterocycloalkyl, 7-10 membered spiroheterocycloalkyl; further preferably, ring A is selected from 5-6 membered heteroaryl.

[0096] In some embodiments, ring A is selected from 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl; preferably, ring A is selected from 5-6 membered heteroaryl, 6 membered heterocycloalkyl, 7-10 membered spiroheterocycloalkyl; further preferably, ring A is selected from 5-6 membered heteroaryl; the heteroaryl has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, and the heterocycloalkyl has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S. In some embodiments, ring A is selected from 5-6 membered heteroaryl, 6 membered monocyclic partially unsaturated heterocycloalkyl, 6 membered monocyclic saturated heterocycloalkyl and 7-9 membered saturated spiro bicyclic heterocycloalkyl; the 5-6 membered heteroaryl has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, the 6 membered monocyclic partially unsaturated heterocycloalkyl has 1 or 2 (preferably 2) nitrogen heteroatoms, the 6 membered monocyclic saturated heterocycloalkyl has 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms, and the 7-9 membered saturated spiro bicyclic heterocycloalkyl has 1 or 2 (preferably 2) nitrogen heteroatoms.

[0097] In some embodiments, Ring A is selected from a 5-6 membered heteroaryl group having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 or 2 nitrogen heteroatoms and 0 or 1 sulfur heteroatom.

[0098] In some embodiments, ring A is selected from pyrimidinyl, pyridinyl, Piperazinyl, morpholinyl, Thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (e.g., 1,2,4-triazolyl, 1,3,4-triazolyl), oxazolyl, isoxazolyl, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole; The end is connected to L5.

[0099] In some embodiments, ring A is selected from pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl; further preferably, ring A is selected from pyrimidinyl (e.g. ), pyridyl (e.g. ), Piperazinyl (e.g. ), morpholinyl (e.g. ), Thiazolyl (e.g. ), isothiazolyl (e.g. ), imidazolyl (e.g. ), pyrazolyl (e.g. ), 1,2,4-triazolyl (e.g. ), 1,3,4-triazolyl (e.g. ), oxazolyl (e.g. ), isoxazolyl (e.g. ), 1,2,4-oxadiazole (e.g. ), 1,3,4-thiadiazole 1,2,4-thiadiazole (e.g. ); The end is connected to L5.

[0100] In some embodiments, Ring A is selected from The end is connected to L5.

[0101] In some embodiments, R1 is independently selected from halogen, hydroxyl, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C1-6 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf, -C(=O)-NReRf, wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl , -C1-6 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl; optionally, two R1 attached to the same carbon atom form C=O with the carbon atom; Re and Rf are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, or Re and Rf are linked together with the atoms to which they are attached to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl.

[0102] In some embodiments, R1 is independently selected from halogen, hydroxyl, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf; wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -6 membered heteroaryl is optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl; optionally, two R1 attached to the same carbon atom form C=O with the carbon atom; Re and Rf are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl.

[0103] In some embodiments, R1 is independently selected from halogen, hydroxyl, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 saturated cycloalkyl, -C1-6 alkylene-C3-6 saturated cycloalkyl, 4-7 membered saturated heterocycloalkyl, -C1-6 alkylene-4-7 membered saturated heterocycloalkyl, 5-6 membered heteroaryl, -NReRf; wherein the C3-6 saturated cycloalkyl, -C1-6 alkylene-C3-6 saturated cycloalkyl, 4-7 membered saturated heterocycloalkyl R e and R f are each independently selected from H, C1-6 alkyl, C3-6 saturated cycloalkyl, or R e and R f together with the atoms to which they are attached are linked to form a 4-7 membered saturated heterocycloalkyl, and the 4-7 membered saturated heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl. Optionally, two R 1s attached to the same carbon atom form C=O with the carbon atom. R e and R f are each independently selected from H, C1-6 alkyl, C3-6 saturated cycloalkyl, or R e and R f together with the atoms to which they are attached are linked to form a 4-7 membered saturated heterocycloalkyl, and the 4-7 membered saturated heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl.

[0104] In some embodiments, R1 is independently selected from halogen, hydroxy, -CN, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf, -C(=O)-NReRf; Re and Rf are independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl.

[0105] In some embodiments, R1 is independently selected from halogen, hydroxyl, -CN, C1-3 alkyl, C2-6 alkynyl, C1-3 alkoxy, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C1-3 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf, wherein the C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl , -C1-3 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl; optionally, two R1 attached to the same carbon atom form C=O with the carbon atom; Re and Rf are each independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, or Re and Rf are linked together with the atoms to which they are attached to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 halogen.

[0106] In some embodiments, R1 is independently selected from halogen, hydroxyl, -CN, C1-3 alkyl, C2-6 alkynyl, C1-3 alkoxy, halo-C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, -NReRf; wherein the C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl are optionally substituted with 1 to 3 substituents selected from halogen and C1-3 alkyl; optionally, two R1 attached to the same carbon atom form C=O with the carbon atom; Re and Rf are independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7-membered heterocycloalkyl, and the 4-7-membered heterocycloalkyl is optionally substituted with 1 to 3 halogen.

[0107] In some embodiments, R1 is independently selected from halogen, hydroxyl, -CN, C1-3 alkyl, C2-6 alkynyl, C1-3 alkoxy, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C1-3 alkylene-4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.

[0108] In some embodiments, R1 is independently selected from F, Cl, -CN, methyl, -CH2CH2CH3, -CHF2, -CF3, methoxy, ethoxy, cyclopropyl, Piperidinyl (e.g. ), morpholinyl (e.g. ), Oxazolyl (e.g. ), pyridyl (e.g. )、-N(CH3)2、 Optionally, two R1s attached to the same carbon atom form a C=O group with the carbon atom; The end is connected to ring A.

[0109] In some embodiments, R1 is independently selected from halogen, -CN, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, pyridyl (e.g. ), -NReRf; Re and Rf are each independently selected from C1-3 alkyl, C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted with 1 to 3 substituents selected from halogen, C1-3 alkyl; The end is connected to ring A.

[0110] In some embodiments, R1 is independently selected from halogen, -CN, C1-3 alkyl, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, pyridyl (e.g. ), -NReRf; Re and Rf are each independently selected from C1-3 alkyl; The end is connected to ring A.

[0111] In some embodiments, R1 is selected from F, -CN, methyl, -CH2CH2CH3, -CF3, cyclopropyl, Pyridyl (e.g. ), -N(CH3)2; The end is connected to ring A.

[0112] In some embodiments, R1 is selected from F, -CN, methyl, -CHF2, -CF3, methoxy, cyclopropyl, Pyridyl (e.g. )、-N(CH3)2、 The end is connected to ring A;

[0113] In some embodiments, R1 is selected from -CF3, -N(CH3)2; The end is connected to ring A.

[0114] In some embodiments, any 4-7 membered heterocycloalkyl group in R1 is a 4-7 membered saturated heterocycloalkyl group.

[0115] In some embodiments, the 4-7 membered heterocycloalkyl group in the -C1-6 alkylene-4-7 membered heterocycloalkyl group or the -C1-3 alkylene-4-7 membered heterocycloalkyl group in R1 is a 4-7 membered saturated heterocycloalkyl group.

[0116] In some embodiments, any C3-6 cycloalkyl group in R1 is a C3-6 saturated cycloalkyl group.

[0117] In some embodiments, the C3-6 cycloalkyl group in the -C1-6 alkylene-C3-6 cycloalkyl group or -C1-3 alkylene-C3-6 cycloalkyl group in R1 is a C3-6 saturated cycloalkyl group.

[0118] In some embodiments, the 4-7 membered heterocycloalkyl, 4-7 membered saturated heterocycloalkyl, and 5-6 membered heteroaryl groups in R1 have 0, 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0119] In some embodiments, the 5-6 membered heteroaryl group in R1 has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom and 0 or 1 heteroatoms selected from O and S, and more preferably has 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom.

[0120] In some embodiments, the 4-7 membered heterocycloalkyl group in R1 has 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 0 or 1 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, and more preferably has 0 or 1 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms.

[0121] In some embodiments, the 4-7 membered saturated heterocycloalkyl group in R1 has 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 0 or 1 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, and more preferably has 0 or 1 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms.

[0122] In some embodiments, m1 is 0, 1, or 2.

[0123] In some embodiments, m1 is 1 or 2.

[0124] In some embodiments, m1 is 0 or 1.

[0125] In some embodiments, m1 is 1.

[0126] In some embodiments, Selected from

[0127] The end is connected to L5.

[0128] In some embodiments, Selected from The end is connected to L5.

[0129] In some embodiments, Selected from The end is connected to L5.

[0130] In some embodiments, Selected from The end is connected to L5.

[0131] In some embodiments, Selected from The end is connected to L5.

[0132] In some embodiments, Selected from The end is connected to L5.

[0133] In some embodiments, the conditions are:

[0134] is not a group E, the group E is selected from:

[0135] Among them, $L5 represents the point connected to L5, and #L represents the point connected to L.

[0136] In some embodiments, the conditions are:

[0137] is not a group E, the group E is selected from:

[0138] Among them, R E is selected from C1-6 alkyl (preferably methyl), halogen (preferably fluorine, chlorine), m4 is selected from an integer of 0 to 5, $L5 represents the point of connection with L5, and #L represents the point of connection with L.

[0139] In some embodiments, the conditions are:

[0140] is not a group E, the group E is selected from:

[0141] X 1Selected from N, C=O, CR F1 、C-(R F1 )2;

[0142] X 2 Selected from N, NR F2 , CR F3 、C-(R F3 )2;

[0143] X 3 Selected from N, CR F4 ;

[0144] X 4 Selected from N, CR F4 ;

[0145] X 5 Selected from N, CR F4 ;

[0146] where R F1 Selected from H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR F5 、C(O)-R F5 、C(O)-N(R F6 )(R F7 )、N(R F6 )(R F7 )、N(R F6 )C(O)-R F5 、N(R F6 )C(O)OR F5 、N(R F6 )S(O)2(R F5 )、-N(R F6 )C(O)-N(R F7 )(R F7 )、S(O)2R F5 、-SF5、S(O)2N(R F6 )(R F7 )、S(O)(NH)R F6 、S(O)(NR F6 )NR F7 , C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-10 membered heterocycloalkyl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heterocycloalkyl is optionally replaced by one or more R F5 replace;

[0147] R F2is selected from H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 6-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace;

[0148] R F3 Selected from H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR F5 、C(O)-R F5 、C(O)-N(R F6 )(R F7 )、N(R F6 )(R F7 )、N(R F6 )C(O)-R F5 、N(R F6 )C(O)OR F5 、N(R F6 )S(O)2(R F5 )、-N(R F6 )C(O)-N(R F7 )(R F7 )、S(O)2R F5 、S(O)2N(R F6 )(R F7 )、S(O)(NH)R F6 、S(O)(NR F6 )NR F7 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace;

[0149] R F4 Selected from H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR F5 、C(O)-R F5 、C(O)-N(R F6 )(R F7 )、N(R F6 )(R F7 )、N(R F6 )C(O)-R F5 、N(R F6 )C(O)OR F5、N(R F6 )S(O)2(R F5 )、-N(R F6 )C(O)-N(R F7 )(R F7 )、-SF5、S(O)2R F5 、S(O)2N(R F6 )(R F7 )、S(O)(NH)R F6 、S(O)(NR F6 )NR F7 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace

[0150] R F5independently selected from the group consisting of: H, C=O, halogen, -NO2, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocycloalkyl, -OH, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocycloalkyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH( C6-10 aryl), -NH (5-12 membered heterocyclic aryl), -NH (4-12 membered heterocyclic alkyl), -N (C1-9 alkyl) 2, -N (C3-15 cycloalkyl), -N (C2-6 alkenyl), -N (C2-6 alkynyl), -N (C3-15 cycloalkyl), -N (C1-8 haloalkyl), -N (C6-10 aryl), -N (5-12 membered heterocyclic aryl), -N (4-12 membered heterocyclic alkyl), -N (C1-9 alkyl) (C3-15 cycloalkyl), -N (C1-9 alkyl) (C2-6 alkenyl), -N (C1-9 alkyl) (C2-6 alkynyl), -N (C1-9 alkyl) (C3-15 cycloalkyl), -N (C1-9 alkyl) (C1-8 haloalkyl), -N (C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-12 membered heterocyclic aryl), -N(C1-9 alkyl)(4-12 membered heterocyclic alkyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(C6-10 aryl), -C(O)(5-12 membered heterocyclic aryl), -C(O)(4-12 membered heterocyclic alkyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O )O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heterocyclic aryl), -C(O)O(4-12 membered heterocyclic alkyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heterocyclic aryl), -C(O)NH(4-12 membered heterocyclic alkyl),-C(O)N(C1-9 alkyl)2、-C(O)N(C3-15 cycloalkyl)2、-C(O)N(C2-6 alkenyl)2、-C(O)N(C2-6 alkynyl)2、-C(O)N(C3-15 cycloalkyl)2、-C(O)N(C1-8 haloalkyl)2、-C(O)N(C6-10 aryl)2、-C(O)N(5-12 membered heterocyclic aryl)2、-C(O)N(4-12 membered heterocyclic alkyl)2、-NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5-12 membered heterocyclic aryl), -NHC(O) (4-12 membered heterocyclic alkyl), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 alkenyl), -NHC(O)O (C2-6 alkynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (C6-10 aryl), -NHC(O)O (5-12 membered heterocyclic aryl), -NHC(O)O (4-12 membered heterocyclic alkyl), -NHC(O)NH (C1-9 alkyl), -NHC(O)NH (C2-6 alkenyl), -NHC(O)NH (C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heterocyclic aryl), -NHC(O)NH(4-12 membered heterocyclic alkyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heterocyclic aryl), -S(4-12 membered heterocyclic alkyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O) N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(NH)(C3-9 cycloalkyl), -S(O)(NC1-9 alkyl)(C1-9 alkyl), -S(O)(NH)(C6-10 aryl), -S(O)(NH)(5-12 membered heterocyclic aryl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)(C6-10 aryl), -S(O)(5-12 membered heterocyclic aryl), -S(O)(4-12 membered heterocyclic alkyl), -S(O)2(C1-9 alkyl),-S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocycloalkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more of halogen, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heterocyclic aryl), -NH(4-12 membered heterocyclic alkyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-12 membered heterocyclic aryl), - NHC(O)(4-12 membered heterocycloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heterocycloaryl), -NHC(O)O(4-12 membered heterocycloalkyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2(C1-9 alkyl), - S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heterocyclic aryl), -S(O)2(4-12 membered heterocyclic alkyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heterocyclic aryl), -O(4-12 membered heterocyclic alkyl), or -O(C1-9 alkyl); and,

[0151] R F6 and R F7 independently selected from: H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally replaced by one or more R F5 replace;

[0152] Among them, $L5 represents the point connected to L5, and #L represents the point connected to L.

[0153] In some embodiments, particularly preferred embodiments, the conditions are:

[0154] is not a group E, the group E is selected from:

[0155] X 1 Selected from N, C=O, CR F1 、C-(R F1 )2;

[0156] X 2 Selected from N, NR F2 , CR F3 、C-(R F3 )2;

[0157] X 3 Selected from N, CR F4 ;

[0158] X 4 Selected from N, CR F4 ;

[0159] X 5 Selected from N, CR F4 ;

[0160] where R F1 、R F3 、R F4 Each independently selected from H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR F5 、C(O)-R F5 、C(O)-N(R F6 )(R F7 )、N(R F6 )(R F7 )、N(R F6 )C(O)-R F5 、N(R F6 )C(O)OR F5 、N(R F6 )S(O)2(R F5 )、-N(R F6 )C(O)-N(R F7 )(R F7 )、S(O)2R F5 、-SF5、S(O)2N(R F6 )(R F7 )、S(O)(NH)RF6 、S(O)(NR F6 )NR F7 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace;

[0161] R F2 、R F6 、R F7 Each is independently selected from H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace;

[0162] R F5independently selected from the group consisting of: H, C=O, halogen, -NO2, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocycloalkyl, -OH, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocycloalkyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl) , -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocycloalkyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl), -N(C2-6 alkenyl), -N(C2-6 alkynyl), -N(C3-15 cycloalkyl), -N(C1-8 haloalkyl), -N(C6-10 aryl), -N(5-12 membered heteroaryl), -N(4-12 membered heterocycloalkyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)( C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-12 membered heteroaryl), -N(C1-9 alkyl)(4-12 membered heterocycloalkyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocycloalkyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocycloalkyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocycloalkyl),-C(O)N(C1-9 alkyl)2、-C(O)N(C3-15 cycloalkyl)2、-C(O)N(C2-6 alkenyl)2、-C(O)N(C2-6 alkynyl)2、-C(O)N(C3-15 cycloalkyl)2、-C(O)N(C1-8 haloalkyl)2、-C(O)N(C6-10 aryl)2、-C(O)N(5-12 membered heteroaryl)2、-C(O)N(4-12 membered heterocycloalkyl)2、-NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O) (C6-10 aryl), -NHC(O) (5-12 membered heteroaryl), -NHC(O) (4-12 membered heterocycloalkyl), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 alkenyl), -NHC(O)O (C2-6 alkynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (C6-10 aryl), -NHC(O)O (5-12 membered heteroaryl), -NHC(O)O (4-12 membered heterocycloalkyl), -NHC(O)NH (C1-9 alkyl), -NHC(O)NH (C2-6 alkenyl), -NHC(O)NH (C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), -NHC(O)NH(4-12 membered heterocycloalkyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocycloalkyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O) N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(NH)(C3-9 cycloalkyl), -S(O)(NC1-9 alkyl)(C1-9 alkyl), -S(O)(NH)(C6-10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)(C6-10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocycloalkyl), -S(O)2(C1-9 alkyl),-S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocycloalkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more of: halogen, C1-9 alkyl , C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocycloalkyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocycloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocycloalkyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2(C1-9 alkyl) , -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocycloalkyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocycloalkyl), or -O(C1-9 alkyl);

[0163] Among them, $L5 represents the point connected to L5, and #L represents the point connected to L.

[0164] In some embodiments, ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl.

[0165] In some embodiments, ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; wherein each of the heteroaryl groups has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, and each of the heterocycloalkyl groups has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 or 2 nitrogen heteroatoms. In some embodiments, ring B is selected from phenyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl, benzo 5-6 membered saturated heterocycloalkyl, benzo 5-6 membered partially unsaturated heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered saturated heterocycloalkyl; wherein each of the heteroaryl groups has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, and each of the heterocycloalkyl groups has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 or 2 nitrogen heteroatoms.

[0166] In some embodiments, ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl.

[0167] In some embodiments, ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; the heteroaryl has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, and the heterocycloalkyl has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 or 2 nitrogen heteroatoms.

[0168] In some embodiments, Ring B is selected from phenyl, pyridyl, pyrazolyl, pyrazinyl, oxazolyl, isoxazolyl, benzopyrazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiadiazolyl, indolyl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, isoindolyl, pyridopyridinyl, pyrrolopyrimidinyl.

[0169] In some embodiments, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,3-triazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), 5-membered nitrogen-containing heterocycloalkyl and phenyl, phenyl and pyrazolyl, phenyl and 5-membered nitrogen-containing heterocycloalkyl (e.g., phenyl and tetrahydropyrrole), pyrimidinyl and 5-membered nitrogen-containing heterocycloalkyl, 6-membered nitrogen-containing heterocycloalkyl and 5-membered nitrogen-containing heterocycloalkyl, 6-membered nitrogen-containing heterocycloalkyl and pyrazolyl.

[0170] In some embodiments, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,3-triazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), 5-membered nitrogen-containing heterocycloalkyl and phenyl, phenyl and 5-membered nitrogen-containing heterocycloalkyl, pyrimidinyl and 5-membered nitrogen-containing heterocycloalkyl, 6-membered nitrogen-containing heterocycloalkyl and 5-membered nitrogen-containing heterocycloalkyl.

[0171] In some embodiments, ring B is phenyl, 5-6 membered heteroaryl, or benzo 5-6 membered heteroaryl.

[0172] In some embodiments, ring B is phenyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl, the heteroaryl having 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, more preferably having 1 or 2 nitrogen heteroatoms.

[0173] In some embodiments, Ring B is selected from phenyl, 5-6 membered heteroaryl.

[0174] In some embodiments, ring B is selected from phenyl, a 5-6 membered heteroaryl group having 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, and more preferably having 1 or 2 nitrogen heteroatoms.

[0175] In some embodiments, Ring B is selected from phenyl and 6-membered heteroaryl.

[0176] In some embodiments, ring B is selected from phenyl, a 6-membered heteroaryl group having 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, and more preferably having 1 or 2 nitrogen heteroatoms.

[0177] In some embodiments, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,3-triazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl).

[0178] In some embodiments, Ring B is selected from phenyl, pyridyl, pyrazinyl, isoxazolyl.

[0179] In some embodiments, Ring B is selected from phenyl, pyridinyl, and pyrazinyl.

[0180] In some embodiments, Ring B is selected from the following groups:

[0181] The end is connected to the L end or L5.

[0182] In some embodiments, Ring B is selected from the following groups:

[0183] The end is connected to the L end or L5.

[0184] In some embodiments, Ring B is selected from The end is connected to the L end or L5.

[0185] In some embodiments, Ring B is selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0186] In some embodiments, Ring B is selected from $L5 represents

[0187] The site where L5 is connected, #L represents the site 0 where L is connected.

[0188] In some embodiments, Ring B is selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0189] In some embodiments, Ring B is selected from

[0190] In some embodiments, Ring B is selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0191] In some embodiments, R2 is selected from halogen, hydroxyl, C1-3 alkyl, halo-substituted C1-3 alkyl, C1-3 alkoxy, halo-substituted C1-3 alkoxy, C3-4 cycloalkyl, -C1-2 alkylene-C3-4 cycloalkyl, -NReRf; Re and Rf are each independently selected from H and C1-3 alkyl; optionally, two R2 attached to the same carbon atom form C=O with the carbon atom.

[0192] In some embodiments, R2 is selected from F, Cl, hydroxyl, amino, and methyl; optionally, two R2 attached to the same carbon atom form C=O with the carbon atom; preferably, R2 is F.

[0193] In some embodiments, R2 is selected from F or hydroxy.

[0194] In some embodiments, m2 is an integer from 0 to 2; preferably, m2 is 0 or 1; preferably, m2 is 0.

[0195] In some embodiments, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0196] In some embodiments, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0197] In some embodiments, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0198] In some embodiments, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0199] In some embodiments, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0200] In some embodiments, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

[0201] In some embodiments, L is a linker group represented by formula L: $B-L1-L2-X1-L3-L4-#C(L);

[0202] Among them, $B represents the site of connection to loop B, and #C represents the site of connection to loop C;

[0203] wherein L1 is selected from a bond, -C(=O)-, $BC(=O)-NRa-#L2, -NRb-, $B-NRb-C(=O)-#L2, t is 1, 2 or 3, Optionally substituted by a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy; preferably, L1 is selected from a bond, -C(=O)-, $BC(=O)NH-#L2, $BC(=O)N(CH3)-#L2, $B-NH(C=O)-#L2, -NH-, (For example ); further preferably, L1 is selected from -C(=O)-, $BC(=O)NH-#L2, $B-NH(C=O)-#L2; more preferably, L1 is selected from $BC(=O)NH-#L2, $B-NH(C=O)-#L2;

[0204] Ra and Rb are each independently selected from H, D, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl; $B represents the site of attachment to ring B, #L2 represents the site of attachment to L2; preferably, Ra and Rb are each independently selected from H, C1-6 alkyl; preferably, Ra and Rb are each independently selected from H, C1-3 alkyl;

[0205] L2 is selected from a bond, C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2 substituents; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy;

[0206] Preferably, L2 is selected from a bond, C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by 1 to 3 groups selected from halogen, oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl, -C(=O)N(R L2)2 substituents; C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl as C1-6 alkylene substituents are optionally substituted by one or more substituents selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, halo C1-3 alkyl, halo C1-3 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0207] Preferably, L2 is selected from a bond, C2-5 alkylene; wherein C2-5 alkylene is optionally substituted by 1 or 2 oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)N(R L2 )2, as a C2-5 alkylene substituent, a 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl is optionally substituted by a substituent selected from halogen, cyano, and C1-3 alkyl; R L2 Each is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and the C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0208] Preferably, L2 is selected from a bond, C1-6 alkylene; wherein the C1-6 alkylene is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a substituent of the C1-6 alkylene is optionally substituted by one or more substituents selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy;

[0209] Preferably, L2 is selected from a bond, C1-6 alkylene; wherein the C1-6 alkylene is optionally substituted with 1 to 3 substituents selected from halogen, oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl; C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl as a C1-6 alkylene substituent is optionally substituted with 1 or more substituents selected from halogen, C1-3 alkyl, C1-3 alkoxy, halo-C1-3 alkyl, halo-C1-3 alkoxy;

[0210] Further preferably, L2 is selected from a bond, C1-5 alkylene; wherein the C1-5 alkylene is optionally substituted by 1 or 2 substituents selected from oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl, and the 4-7 membered nitrogen-containing saturated heterocycloalkyl and -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl as C1-5 alkylene substituents are optionally substituted by substituents selected from C1-3 alkyl;

[0211] Further preferably, L2 is selected from a bond, C2-5 alkylene; wherein C2-5 alkylene is optionally selected from C1-3 alkyl, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl), 4-7 membered heterocycloalkyl (e.g. oxetanyl, oxetanyl, ), -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 5-6 membered heteroaryl (e.g., pyridyl), and the C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0212] More preferably, L2 is selected from C2-5 alkylene, said C2-5 alkylene being optionally selected from C1-3 alkyl, cyclopropyl, -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (such as azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen (such as F, Cl), C1-3 alkyl (such as methyl, isopropyl), q is selected from 0, 1; RL2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 6 membered heteroaryl (e.g., pyridyl), and the 4-7 membered heterocycloalkyl and 6 membered heteroaryl are optionally substituted with a substituent selected from C1-3 alkyl;

[0213] X1 is selected from a bond, O, S; preferably, X1 is selected from a bond, O; further preferably, X1 is selected from a bond;

[0214] L3 is selected from a bond, C1-6 alkylene, C3-10 cycloalkyl-(CH2) k -#L4, 4-10 membered heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4; wherein, C1-6 alkylene, C3-10 cycloalkyl-(CH2) k -#L4, 4-10 membered heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted with one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; k is selected from 0, 1, 2, 3; #L4 represents the site of attachment of L4;

[0215] Preferably, L3 is selected from a bond, C1-6 alkylene, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl; wherein C1-6 alkylene, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl;

[0216] Preferably, L3 is selected from a bond, C1-3 alkylene, C3-6 cycloalkyl-(CH2) k -#L4, 4-6 membered monocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered bridged heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k-#L4; wherein the C1-3 alkylene, C3-6 cycloalkyl-(CH2) k -#L4, 4-6 membered monocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered bridged heterocycloalkyl-(CH2) k -#L4 or 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted by a substituent selected from halogen, hydroxy, C1-3 alkyl, halo-C1-3 alkyl, C1-3 alkoxy, halo-C1-3 alkoxy, -O-C3-6 cycloalkyl;

[0217] Preferably, L3 is selected from a bond, C1-3 alkylene, C3-6 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, 6-10 membered spirocyclic heterocycloalkyl, 6-10 membered bridged heterocycloalkyl, 5-6 membered heteroaryl; wherein the C1-3 alkylene, C3-6 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, 6-10 membered spirocyclic heterocycloalkyl or 6-10 membered bridged heterocycloalkyl, 5-6 membered heteroaryl is optionally substituted with a substituent selected from halogen, hydroxy, C1-3 alkyl, halo-substituted C1-3 oxy, C1-3 alkoxy, halo-substituted C1-3 alkoxy, -O-C3-6 cycloalkyl;

[0218] Preferably, L3 is selected from a bond, a C1-3 alkylene group, a C3-6 cycloalkyl group, a 4-6-membered monocyclic heterocycloalkyl group, a 6-10-membered spirocyclic heterocycloalkyl group, and a pyrrolyl group; wherein the C1-3 alkylene group, the C3-6 cycloalkyl group, the 4-6-membered monocyclic heterocycloalkyl group, the 6-10-membered spirocyclic heterocycloalkyl group, and the pyrrolyl group are optionally substituted with a substituent selected from a C1-3 alkyl group, a C1-3 alkoxy group, and an -O-C3-6 cycloalkyl group;

[0219] More preferably, L3 is selected from a bond, a C1-3 alkylene group, a 4-6 membered monocyclic heterocycloalkyl group -(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, pyrrolyl-(CH2) k -#L4; wherein the C1-3 alkylene, 4-6 membered monocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, pyrrolyl-(CH2) k -#L4 is optionally substituted by a substituent selected from C1-3 alkyl, C1-3 alkoxy, -O-C3-6 cycloalkyl;

[0220] More preferably, L3 is selected from a bond, a C1-3 alkylene group;

[0221] L4 is selected from a bond, O, S, -NRc-; Rc is selected from H, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl;

[0222] Preferably, L4 is selected from a bond, O, -NRc-; Rc is selected from H, C1-3 alkyl;

[0223] More preferably, L4 is selected from -NH-.

[0224] In some embodiments, when L1 is selected from $BC(=O)-NRa-#L2, any of the following conditions is met:

[0225] (1) L2 is selected from C1-6 alkylene; wherein the C1-6 alkylene is optionally substituted by one or more groups selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl, the 4-10 membered saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 oxygen heteroatom), -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl (preferably -C(=O)-4-10 membered saturated heterocycloalkyl, the 4-10 membered saturated heterocycloalkyl having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom), -C(=O)N(R L2 )2 substituents; C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl), -C(=O)-4-10 membered heterocycloalkyl (preferably -C(=O)-4-10 membered saturated heterocycloalkyl) as a C1-6 alkylene substituent is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkyl, halo-substituted C1-6 alkoxy; R L2each independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl, the 4-10 membered saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 oxygen heteroatom), C6-10 aryl, 5-10 membered heteroaryl (preferably 5-10 membered heteroaryl, the 5-10 membered heteroaryl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 oxygen heteroatom 1 heteroatom selected from O and S, preferably with 1 nitrogen heteroatom), and C1-6 alkyl, C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl), C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond, O, -NRc-, Rc is selected from H, C1-3 alkyl;

[0226] Preferably, L2 is selected from C2-6 alkylene; wherein the C2-6 alkylene is optionally replaced by C1-3 alkyl, C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl), 4-7 membered heterocycloalkyl (preferably 4-7 membered saturated heterocycloalkyl, the 4-7 membered saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 oxygen heteroatom), -C(=O)N(R L2 )2 substituents; wherein, ring G is a 4-10 membered nitrogen-containing saturated heterocycloalkyl group (preferably a 4-10 membered nitrogen-containing saturated heterocycloalkyl group, the 4-10 membered nitrogen-containing saturated heterocycloalkyl group having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably having 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom), R' is selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxacyclohexyl, pyridyl, and the oxacyclohexyl group is optionally substituted with a substituent selected from C1-3 alkyl;

[0227] Preferably, L2 is selected from C2-6 alkylene; wherein C2-6 alkylene is optionally replaced by C1-3 alkyl, C3-6 saturated cycloalkyl, 4-6 membered monocyclic saturated heterocycloalkyl, 7 membered saturated spiroheterocycloalkyl, -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-6 membered monocyclic nitrogen-containing saturated heterocyclic alkyl group, a 7-membered nitrogen-containing saturated spiro heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, q is selected from 0, 1 or 2; R L2Each is independently selected from H, C1-4 alkyl, C3-6 saturated cycloalkyl, 4-6-membered monocyclic saturated heterocycloalkyl, 5-6-membered heteroaryl (preferably 6-membered heteroaryl), and the 4-6-membered monocyclic saturated heterocycloalkyl and the 5-6-membered heteroaryl (preferably 6-membered heteroaryl) are optionally substituted with substituents selected from C1-3 alkyl; wherein the 4-6-membered monocyclic saturated heterocycloalkyl and the 7-membered saturated spiro heterocycloalkyl have 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably have 1 oxygen heteroatom, the 4-6-membered monocyclic nitrogen-containing saturated heterocycloalkyl and the 7-membered nitrogen-containing saturated spiro heterocycloalkyl have 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably have 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom, the 5-6-membered heteroaryl (preferably 6-membered heteroaryl) have 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably have 1 nitrogen heteroatom.

[0228] (2) L2 is selected from a bond, C1-6 alkylene; X1 is selected from a bond; L3 is selected from C3-10 cycloalkyl-(CH2) k -#L4 (preferably C3-10 saturated cycloalkyl-(CH2) k -#L4), 4-10 membered heterocycloalkyl-(CH2) k -#L4 (preferably 4-10 membered saturated heterocyclic alkyl-(CH2) k -#L4, the 4-10 membered saturated heterocycloalkyl group has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom), 5-6 membered heteroaryl-(CH2) k -#L4 (preferably 5-6 membered heteroaryl-(CH2) k -#L4, the 5-6 membered heteroaryl group has 1, 2 or 3 nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom), wherein C3-10 cycloalkyl-(CH2) k -#L4 (preferably C3-10 saturated cycloalkyl-(CH2) k -#L4), 4-10 membered heterocycloalkyl-(CH2) k -#L4 (preferably 4-10 membered saturated heterocyclic alkyl-(CH2) k -#L4), 5-6 membered heteroaryl-(CH2) k-#L4 is optionally substituted with one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl), -O-C3-6 cycloalkyl (preferably -O-C3-6 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl), -O-4-10 membered heterocycloalkyl (preferably -O-4-10 membered saturated heterocycloalkyl); k is selected from 0, 1, 2, 3; #L4 represents the site of attachment to L4; L4 is selected from a bond or -NRc-;

[0229] Preferably, L2 is selected from a bond, C1-3 alkylene; X1 is selected from a bond; L3 is selected from C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl, the 4-10 membered saturated heterocycloalkyl having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably having 1 nitrogen heteroatom), 5-6 membered heteroaryl -(CH2) k -#L4 (preferably 5-6 membered heteroaryl-(CH2) k -#L4, the 5-6 membered heteroaryl group has 1, 2 or 3 nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom), wherein C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl), 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted by one or more substituents selected from C1-3 alkyl, C1-3 alkoxy, -O-C3-6 cycloalkyl (preferably -O-C3-6 saturated cycloalkyl); k is selected from 0, 1, 2; #L4 represents the site of attachment of L4; L4 is selected from a bond or -NRc-;

[0230] Preferably, L2 is selected from a bond, a C1-3 alkylene group; X1 is selected from a bond; L3 is selected from a C3-6 saturated cycloalkyl group, a 4-6 membered monocyclic saturated heterocycloalkyl group, a 7-9 membered saturated spiro heterocycloalkyl group, an 8-10 membered saturated fused heterocycloalkyl group, a 5 membered heteroaryl group -(CH2) k -#L4, the 4-6 membered monocyclic saturated heterocyclic alkyl, 5 membered heteroaryl-(CH2) k -#L4 is optionally substituted by one substituent selected from C1-3 alkyl, C1-3 alkoxy, -O-C3-6 saturated cycloalkyl; wherein any of the heterocycloalkyl groups has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom, the 5-membered heteroaryl group has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom, k is selected from 0 or 1, #L4 represents the site of connection to L4; L4 is selected from a bond or -NRc-, preferably L4 is selected from a bond.

[0231] In some embodiments, when L1 is selected from $B-NRb-C(=O)-#L2, any of the following conditions is met:

[0232] (1) L2 is selected from C1-6 alkylene, wherein C1-6 alkylene is optionally substituted by one or more of D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2 substituents; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond or O;

[0233] Preferably, L2 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted by one substituent selected from C1-3 alkyl, C3-6 cycloalkyl; X1 is selected from a bond, L3 is selected from a bond, and L4 is selected from a bond or O;

[0234] Preferably, L2 is selected from C1-3 alkylene, wherein C1-3 alkylene is optionally substituted with one substituent selected from C1-3 alkyl, C3-6 saturated cycloalkyl; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond or O; (2) L2 is selected from C1-6 alkylene; X1 is selected from O; L3 is selected from C1-6 alkylene, wherein C1-6 alkylene is optionally substituted with one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; L4 is selected from -NRc-;

[0235] Preferably, L2 is selected from C1-3 alkylene, X1 is selected from O; L3 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted by one substituent selected from C1-3 alkyl; L4 is selected from -NRc-.

[0236] In some embodiments, when L1 is selected from -C(=O)-, any of the following conditions is met:

[0237] (1) L2 is selected from a bond; X1 is selected from a bond; L3 is selected from a 4-10 membered heterocycloalkyl group -(CH2) k -#L4 (preferably 4-10 membered saturated heterocyclic alkyl-(CH2) k -#L4, the 4-10 membered saturated heterocycloalkyl group has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom), wherein the 4-10 membered heterocycloalkyl group -(CH2) k -#L4 (preferably 4-10 membered saturated heterocyclic alkyl-(CH2) k -#L4) is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; k is selected from 0, 1, 2, 3; #L4 represents the site of attachment of L4, L4 is selected from -NRc-;

[0238] Preferably, L3 is selected from 4-10 membered heterocycloalkyl-(CH2) k -#L4 (preferably 4-10 membered saturated heterocyclic alkyl-(CH2) k -#L4, the 4-10 membered saturated heterocycloalkyl group has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom), wherein the 4-10 membered heterocycloalkyl group -(CH2) k -#L4 (preferably 4-10 membered saturated heterocyclic alkyl-(CH2) k -#L4) is optionally substituted by one substituent selected from C1-3 alkyl;

[0239] Preferably, L3 is selected from 4-6 membered monocyclic saturated heterocyclic alkyl-(CH2) k -#L4, 7-9 membered saturated spiroheterocycloalkyl-(CH2) k -#L4, the 4-6 membered monocyclic saturated heterocyclic alkyl-(CH2) k -#L4, 7-9 membered saturated spiroheterocycloalkyl-(CH2) k-#L4 is optionally substituted by 1 substituent selected from C1-3 alkyl, k is selected from 0, 1 or 2; wherein any of the heterocycloalkyl groups has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom;

[0240] (2) L2 is selected from C1-6 alkylene; X1 is selected from O; L3 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; L4 is selected from -NRc-;

[0241] Preferably, L2 is selected from C1-3 alkylene; X1 is selected from O; L3 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted with one substituent selected from C1-3 alkyl; L4 is selected from -NRc-.

[0242] In some embodiments, when L1 is selected from -NRc-, L2 is selected from C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2 substituents; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, and L4 is selected from -NRc-;

[0243] Preferably, L2 is selected from C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by one or more halogen, hydroxy, oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl, -C(=O)N(RL2 )2 substituents; C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl as C1-6 alkylene substituents are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, halogenated C1-3 alkoxy; R L2 Each is independently selected from H, D, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; X1 is selected from a bond, L3 is selected from a bond, and L4 is selected from -NRc-;

[0244] Preferably, L2 is selected from C1-6 alkylene; wherein the C1-6 alkylene is optionally substituted by one substituent selected from C1-3 alkyl.

[0245] In some embodiments, when L1 is selected from a bond, any of the following conditions is met:

[0246] (1) L2 is selected from C1-6 alkylene, wherein C1-6 alkylene is optionally substituted by one or more of D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2 substituents; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond or -NRc-;

[0247] Preferably, L2 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one substituent selected from C1-3 alkyl;

[0248] (2) L2 is selected from C1-6 alkylene, X1 is selected from O, L3 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; L4 is selected from -NRc-;

[0249] Preferably, L2 is selected from C1-3 alkylene, X1 is selected from O, and L3 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted by one substituent selected from C1-3 alkyl.

[0250] In some embodiments, when L1 is selected from When L2 is selected from a bond; X1 is selected from O or S; L3 is selected from a bond, C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted with one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; and L4 is selected from a bond, $B represents the site of attachment to ring B, #L2 represents the site of attachment to L2; t, Ra, Rb, and Rc are as defined in any of the above schemes;

[0251] Preferably, L2 is selected from a bond; X1 is selected from O, L3 is selected from a bond; and L4 is selected from a bond.

[0252] In some embodiments, when L1 is selected from $BC(=O)-NRa-#L2, X1 is selected from O, S, or -NRc-, and L3 and L4 both represent a single bond; or

[0253] When L1 is selected from $B-NRb-C(=O)-#L2, X1 represents a single bond, O or S, L3 represents a single bond or a substituted or unsubstituted C1-6 alkylene group, and L4 represents a single bond or -NRc-; or

[0254] When L1 is selected from a single bond, X1 is selected from O, S, or -NRc-, L3 represents a substituted or unsubstituted C1-6 alkylene group, and L4 represents -NRc-; or

[0255] When L1 is selected from When X1 is selected from O, S, or -NRc-, L3 represents a single bond or a substituted or unsubstituted C1-6 alkylene group, and L4 represents a single bond, $B represents the site of attachment to ring B, and #L2 represents the site of attachment to L2;

[0256] wherein t, Ra, Rb, and Rc are as defined above.

[0257] In some embodiments, when L1 is selected from $BC(=O)-NRa-#L2, L2 is selected from: wherein $L1 represents the site of attachment to L1, #X1 represents the site of attachment to X1, n is an integer selected from 0, 1, 2, 3, 4, or 5, and wherein Rs is selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, -C(=O)NR ii R iii , where R ii and R iii may independently represent hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl or aryl, or R ii and R iii Together with the atoms to which it is attached, it forms a 4-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1-3 substituents selected from halogen, -OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy,

[0258] wherein Ra is as defined in any of the above schemes; or

[0259] When L1 is selected from $BC(=O)-NRa-#L2, L2 is selected from: wherein $L1 represents the site of attachment to L1, #X1 represents the site of attachment to X1, n is an integer selected from 0, 1, 2, 3, 4, or 5, and Rs is selected from H, D, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl, the saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 oxygen heteroatom), -C(=O)N(R L2 )2; wherein, ring G is a 4-10 membered nitrogen-containing saturated heterocycloalkyl group (preferably a 4-10 membered nitrogen-containing saturated heterocycloalkyl group, the 4-10 membered nitrogen-containing saturated heterocycloalkyl group having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably having 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom), R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2each independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl, the saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, preferably having 1 oxygen heteroatom), C6-10 aryl, 5-10 membered heteroaryl (preferably 5-10 membered heteroaryl, the heteroaryl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, preferably having 1 nitrogen heteroatom), and C1-6 alkyl, C3-10 cycloalkyl (preferably C3-10 saturated cycloalkyl), 4-10 membered heterocycloalkyl (preferably 4-10 membered saturated heterocycloalkyl), C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy;

[0260] Preferably, Rs is selected from H, D, halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl), 4-7 membered heterocycloalkyl (preferably 4-7 membered saturated heterocycloalkyl, the saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably having 1 oxygen heteroatom), -C(=O)N(R L2 )2; wherein, ring G is a 4-10 membered nitrogen-containing saturated heterocycloalkyl group (preferably a 4-10 membered nitrogen-containing saturated heterocycloalkyl group, the 4-10 membered nitrogen-containing saturated heterocycloalkyl group having 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably having 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom), R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 each independently selected from H, D, C1-4 alkyl, C3-6 cycloalkyl (preferably C3-6 membered saturated cycloalkyl), 4-7 membered heterocycloalkyl (preferably 4-7 membered saturated heterocycloalkyl, the saturated heterocycloalkyl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, preferably having 1 oxygen heteroatom), phenyl, 5-6 membered heteroaryl (preferably 5-6 membered heteroaryl, the heteroaryl having 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O or S, preferably having 1 nitrogen heteroatom), and C1-4 alkyl, C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl), 4-7 membered heterocycloalkyl (4-7 membered saturated heterocycloalkyl), phenyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0261] Preferably, Rs is selected from H, C1-3 alkyl, C3-6 saturated cycloalkyl, 4-6 membered monocyclic saturated heterocycloalkyl, 7 membered saturated spiro heterocycloalkyl, -C(=O)N(R L2 )2; wherein ring G is a 4-6 membered monocyclic nitrogen-containing saturated heterocyclic alkyl group, a 7 membered nitrogen-containing saturated spiro heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-4 alkyl, C3-6 saturated cycloalkyl, 4-6-membered monocyclic saturated heterocycloalkyl, 5-6-membered heteroaryl (preferably 6-membered heteroaryl), and the 4-6-membered monocyclic saturated heterocycloalkyl and the 5-6-membered heteroaryl (preferably 6-membered heteroaryl) are optionally substituted with substituents selected from C1-3 alkyl; wherein the 4-6-membered monocyclic saturated heterocycloalkyl and the 7-membered saturated spiro heterocycloalkyl have 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably have 1 oxygen heteroatom, the 4-6-membered monocyclic nitrogen-containing saturated heterocycloalkyl and the 7-membered nitrogen-containing saturated spiro heterocycloalkyl have 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably have 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom, the 5-6-membered heteroaryl (preferably 6-membered heteroaryl) have 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably have 1 nitrogen heteroatom.

[0262] In some embodiments, when L1 is selected from $BC(=O)-NRa-#L2, L2 is selected from: wherein $L1 represents the site of attachment to L1, #X1 represents the site of attachment to X1, n is an integer selected from 0, 1, 2, 3, 4, or 5, and wherein

[0263] Rs is selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 cycloalkyl, -OC(=O)NR ii R iii , where R ii and R iii may independently represent hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl or aryl, or R ii and R iii Together with the atoms to which it is attached, it forms a 4-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1-3 substituents selected from halogen, -OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy,

[0264] wherein Ra is as defined above.

[0265] In some embodiments, n is selected from 3, and Rs is selected from the following groups, which are substituted or unsubstituted: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0266] In some embodiments, n is selected from 3, Rs is selected from: methyl, cyclopropyl, cyclobutyl, cyclohexyl,

[0267] Preferably, Rs is selected from methyl,

[0268] In some embodiments, when L1 is selected from $B-NRb-C(=O)-#L2, X1, L3 and L4 all represent a single bond, and L2 is selected from substituted or unsubstituted C1-4 alkylene, preferably substituted or unsubstituted methyl, ethyl or propyl; or

[0269] When L1 is selected from $B-NRb-C(=O)-#L2, X1 is selected from O or S, L2 and L3 are each independently selected from substituted or unsubstituted C1-4 alkylene, preferably substituted or unsubstituted methyl, ethyl or propyl, and L4 is selected from -NRc-,

[0270] wherein Rb and Rc are as defined above.

[0271] In some embodiments, when L1 is selected from a single bond, X1 is selected from O, S or -NRc-, L2 and L3 are each independently selected from substituted or unsubstituted C1-4 alkylene, and L4 is selected from -NRc-, wherein Rb and Rc are as defined above.

[0272] In some embodiments, when L1 is selected from a single bond, X1 is selected from O or S, L2 and L3 are each independently selected from substituted or unsubstituted C1-4 alkylene, and L4 is selected from -NRc-, wherein Rb and Rc are as defined above.

[0273] Preferably, the carbon atom where L2 is attached to ring B is substituted with =O to form a carbonyl group.

[0274] In some embodiments, when L1 is selected from When X1 is selected from O, L2, L3 and L4 all represent single bonds, and t is selected from 1; $B represents the site for connecting ring B, and #L2 represents the site for connecting L2.

[0275] In some embodiments, L is selected from:

[0276] wherein $B represents the connection site with ring B, #C represents the connection site with ring C, Ra, Rb and Rc are as defined in any of the foregoing schemes, Rs is as defined in any of the foregoing schemes, and R" is selected from C1-6 alkoxy, -O-C3-6 cycloalkyl, preferably, R" is selected from C1-6 alkoxy, -O-C3-6 saturated cycloalkyl.

[0277] Preferably, Ra, Rb and Rc are each independently selected from H or methyl;

[0278] Preferably, Rs is selected from H, methyl, cyclopropyl, cyclobutyl, cyclohexyl,

[0279] In some embodiments, L is selected from:

[0280] wherein $B represents the attachment site to ring B, #C represents the attachment site to ring C, Ra, Rb, and Rc are as defined above, and Rs is as defined above;

[0281] Preferably, Ra, Rb and Rc are each independently selected from H or methyl;

[0282] Preferably, Rs is selected from H or substituted or unsubstituted groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0283] In some embodiments, L is selected from:

[0284] wherein $B represents the attachment site to ring B, #C represents the attachment site to ring C, Ra, Rb, and Rc are as defined in any of the aforementioned schemes, and Rs is as defined in any of the aforementioned schemes;

[0285] Preferably, L is selected from:

[0286] More preferably, L is selected from:

[0287] Preferably, Ra, Rb and Rc are each independently selected from H or methyl;

[0288] Preferably, Rs is selected from H, D, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)N(R L2)2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, D, C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0289] Preferably, Rs is selected from H, D, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 saturated cycloalkyl, 4-7 membered saturated heterocycloalkyl, -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 each independently selected from H, D, C1-4 alkyl, C3-6 saturated cycloalkyl, 4-7 membered saturated heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-4 alkyl, C3-6 saturated cycloalkyl, 4-7 membered saturated heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; the 4-7 membered saturated heterocycloalkyl has 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 oxygen atom, the 4-10 membered nitrogen-containing saturated heterocycloalkyl has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom, the 5-6 membered heteroaryl has 1, 2 or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably 1 nitrogen heteroatom;

[0290] More preferably, Rs is selected from C1-3 alkyl, C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl, such as cyclopropyl, cyclobutyl, cyclohexyl), -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (e.g., azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen (such as F, Cl), C1-3 alkyl (such as methyl, isopropyl), q is selected from 0, 1; R L2Each is independently selected from H, C1-3 alkyl (such as methyl, ethyl, isopropyl), C3-6 cycloalkyl (preferably C3-6 saturated cycloalkyl, such as cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (preferably 4-7 membered saturated heterocycloalkyl, such as oxacyclohexyl), 6 membered heteroaryl (such as pyridyl), and the 4-7 membered heterocycloalkyl (preferably 4-7 membered saturated heterocycloalkyl) and 6 membered heteroaryl are optionally substituted with a substituent selected from C1-3 alkyl; preferably, Rs is selected from H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0291] In some embodiments, L is selected from:

[0292] wherein $B represents the attachment site to ring B, #C represents the attachment site to ring C, Ra, Rb, and Rc are as defined above, and Rs is as defined above;

[0293] Preferably, Ra, Rb and Rc are each independently selected from H or methyl;

[0294] Preferably, Rs is selected from H or substituted or unsubstituted groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0295] In some embodiments, L is selected from $B-CH2-CH2-#C, $B-CH2-CH2-CH2-#C, $B indicates the site of ligation to loop B, and #C indicates the site of ligation to loop C;

[0296] Preferably, L is selected from

[0297] Preferably, L is selected from

[0298] Preferably, L is selected from

[0299] In some embodiments, L is selected from $B-CH2-CH2-#C; $B represents the site for connecting ring B, and #C represents the site for connecting ring C.

[0300] In some embodiments, L is selected from

[0301] In some embodiments, Ring C is selected from the following groups:

[0302] In some embodiments, Ring C is selected from the following groups:

[0303] In some embodiments, Ring C is selected from:

[0304] In some embodiments, Ring C is

[0305] In some embodiments, Selected from:

[0306] In some embodiments, Selected from:

[0307] In some embodiments, Selected from:

[0308] In some embodiments, Selected from: In some embodiments, Selected from:

[0309] In some embodiments, Selected from:

[0310] In some embodiments, R3 is selected from halogen, -CN, C1-3 alkyl, halo-C1-3 alkyl, -NReRf, -NReC(=O)Rf, -C(=O)-NReRf, wherein Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl (e.g., a 7-membered nitrogen-containing spiroheterocycloalkyl);

[0311] Preferably, R3 is selected from halogen, -CN, C1-3 alkyl, halo-C1-3 alkyl, -NReRf, -NReC(=O)Rf, -C(=O)-NReRf, wherein Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered saturated heterocycloalkyl (e.g., a 7-membered saturated nitrogen-containing spiroheterocycloalkyl); the 4-7 membered saturated heterocycloalkyl or the 7-membered saturated nitrogen-containing spiroheterocycloalkyl has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from O and S, preferably has 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom. Preferably, R3 is selected from halogen, -CN, C1-3 alkyl, halo C1-3 alkyl, -NReC(=O)Rf, -C(=O)-NReRf, wherein Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl; preferably, when R3 is selected from -NReRf, said Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered saturated heterocycloalkyl, preferably Re and Rf together with the atoms to which they are attached are linked to form a 7 membered saturated spiroheterocycloalkyl; wherein any of said heterocycloalkyls has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from O and S, preferably has 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom;

[0312] Preferably, when R3 is selected from -NReC(=O)Rf or -C(=O)-NReRf, said Re and Rf are each independently selected from H, C1-3 alkyl;

[0313] More preferably, R3 is selected from Cl, methyl, -CF3, -CN, -NHC(=O)CH3, -C(=O)NH2,

[0314] More preferably, R3 is selected from -CF3, -CN,

[0315] Further preferably, R3 is selected from -CF3,

[0316] Further preferably, R3 is selected from -CF3, methyl,

[0317] Preferably, m3 is selected from 1, 2, and 3; more preferably, m1 is selected from 1 or 2.

[0318] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in any one of Formulas I-1 to I-4, I-7 to I-10:

[0319] wherein, Ring A, Ring C, R1, R2, R3, L, L5, m1, m2 and m3 are as defined above.

[0320] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in any one of Formulas I-1 to I-4.

[0321] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in Formula I-5 or I-6:

[0322] in,

[0323] In formula I-5, ring B is selected from phenyl or 6-membered heteroaryl, Z1, Z2, Z3, and Z4 are each independently selected from N or CH, and ring A, ring C, R1, R2, R3, L, m1, m2, and m3 are as defined above;

[0324] Preferably, at most 2 of Z1, Z2, Z3, and Z4 are N;

[0325] Preferably, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl;

[0326] Preferably, ring B is selected from phenyl, pyridyl, pyrazinyl;

[0327] Preferably, ring B is selected from the following groups 1) to 5):

[0328] 1) Z1, Z2, Z3, and Z4 are all CH;

[0329] 2) Z1 and Z2 are both CH, and Z3 and Z4 are both N;

[0330] 3) Z1 and Z4 are both CH, and Z2 and Z3 are both N;

[0331] 4) Only one of Z1, Z2, Z3, and Z4 is N;

[0332] 5) Z1 and Z3 are both CH, one of Z2 and Z4 is N and the other is CH;

[0333] In formula I-6, Ring B is selected from a 5-membered heteroaryl group, U1, U2, and U3 are each independently selected from N, O, S, and CH, and at most one of U1, U2, and U3 is S, and at most one of U1, U2, and U3 is O, W1 and W2 are each independently selected from N and CH, and Ring A, Ring C, R1, R2, R3, L, m1, m2, and m3 are as defined above;

[0334] Preferably, ring B is selected from the following groups 1) to 5):

[0335] 1) Z1, Z2, Z3, and Z4 are all CH;

[0336] 2) Z1 and Z2 are both CH, and Z3 and Z4 are both N;

[0337] 3) Z3 and Z4 are both CH, and Z1 and Z2 are both N;

[0338] 4) Only one of Z1, Z2, Z3, and Z4 is N;

[0339] 5) Z1 and Z3 are both CH, one of Z2 and Z4 is N and the other is CH;

[0340] In formula I-6, Ring B is selected from a 5-membered heteroaryl group, U1, U2, and U3 are each independently selected from N, O, S, and CH, and at most one of U1, U2, and U3 is S, W1 and W2 are each independently selected from N and CH, and Ring A, Ring C, R1, R2, R3, L, m1, m2, and m3 are as defined above;

[0341] Preferably, ring B contains 2 or 3 heteroatoms each independently selected from N, O, and S;

[0342] Preferably, ring B is selected from pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (eg 1,2,3-triazolyl), thiadiazolyl (eg 1,3,4-thiadiazolyl);

[0343] Preferably, at least one of U1, U2, and U3 is N; at most one of W1 and W2 is N;

[0344] Preferably, at most two of U1, U2, and U3 are heteroatoms;

[0345] Preferably, U1, U2, and U3 are each independently selected from N, O, and CH;

[0346] Preferably, U1 and W2 are CH; U3 and W1 are CH and N; U2 is O and N;

[0347] Preferably, ring B is selected from isoxazolyl, pyrazolyl;

[0348] Preferably, ring B is selected from isoxazolyl;

[0349] Preferably, U1 is CH, U2 is O, U3 is N, W1 is CH, and W2 is CH; or W1 and U2 are N, and U1, W2, and U3 are CH;

[0350] Preferably, U1 is CH, U2 is O, U3 is N, W1 is CH, and W2 is CH.

[0351] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in either Formula II-1 or II-2:

[0352] wherein L1 is selected from $BC(=O)-NRa-#L2, $B-NRb-C(=O)-#L2; Ra and Rb are as defined above;

[0353] L2 is selected from C1-6 alkylene, wherein C1-6 alkylene is optionally substituted by 1 or 2 oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)N(R L2 )2, the 4-7 membered nitrogen-containing saturated heterocycloalkyl and -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl as C1-6 alkylene substituents are optionally substituted by a substituent selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, and halogenated C1-3 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy;

[0354] Preferably, L2 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by 1 or 2 substituents selected from oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl, and the 4-7 membered nitrogen-containing saturated heterocycloalkyl and -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl as C1-6 alkylene substituents are optionally substituted by substituents selected from C1-3 alkyl;

[0355] Preferably, L2 is selected from C2-5 alkylene; wherein C2-5 alkylene is optionally selected from C1-3 alkyl, C3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclohexyl), 4-7 membered heterocycloalkyl (such as oxetanyl, oxetanyl, ), -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (such as azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 5-6 membered heteroaryl (e.g., pyridyl), and the C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0356] L4 is selected from a bond, O, -NRc-, wherein Rc is selected from H, C1-3 alkyl.

[0357] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in any one of Formulas III-1 to III-6:

[0358] wherein, Z1, Z2, Z3, Z4, U1, U2, U3, W1, and W2 are as defined above; L1, L2, L3, L4, Ra, and Rb are as defined above; and ring A, R1, R2, R3, m1, m2, and m3 are as defined above.

[0359] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in any one of Formulas IV-1 to IV-4:

[0360] wherein V1 and V2 are each independently selected from N and CH, Y1 is N or CH, Y2, Y3, and Y4 are each independently selected from N, CH, and S, ring A is a 5-membered heteroaromatic ring, and ring B, ring C, L, R1, R2, R3, m1, m2, and m3 are as defined above; and L1, L2, and L4 are as defined above.

[0361] Preferably, at least one of V1 and V2 is N; more preferably, both V1 and V2 are N;

[0362] Preferably, only two of Y1, Y2, Y3, and Y4 are heteroatoms;

[0363] Preferably, Y2 is N, and one of Y1, Y3, and Y4 is a heteroatom;

[0364] Preferably, Y1 and Y2 are N, and Y3 and Y4 are CH; or Y1 and Y3 are CH, and Y2 and Y4 are S and N respectively; or Y1 and Y4 are CH, Y2 is N, and Y3 is S.

[0365] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in any one of Formulas V-1 to V-4:

[0366] wherein, Ring A, Ring B, Ring C, L, R1, R2, R3, m1, m2 and m3 are as defined above; and L1, L2 and L4 are as defined above.

[0367] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in any one of Formulas VI-1 to VI-6:

[0368] Wherein, L1, L2, L3, L4, Ra, and Rb are as defined above; Z1, Z2, Z3, Z4, U1, U2, U3, W1, and W2 are as defined above; and ring A, V1, V2, Y1, Y2, Y3, and Y4 are as defined above.

[0369] In some embodiments, Selected from and / or Selected from:

[0370] and / or

[0371] Selected from

[0372] wherein R1 is selected from halogen, -OH, -CN, -NReRf, -CF3, -CHF2, substituted or unsubstituted C3-6 cycloalkyl, Re and Rf are each independently selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or Re and Rf, together with the atoms to which they are attached, are linked to form a 4-7 membered heterocycloalkyl;

[0373] Each R2 is independently selected from halogen, -OH, -CN, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-6 cycloalkyl;

[0374] each R3 is independently selected from halogen, -OH, -CN, -NReRf, -CF3, -CHF2, substituted or unsubstituted C3-6 cycloalkyl, Re and Rf are each independently selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or Re and Rf, together with the atoms to which they are attached, are joined to form a 4-7 membered heterocycloalkyl; and / or

[0375] m2 and m3 are each independently selected from 0, 1, 2 or 3.

[0376] In some embodiments, ring A is selected from phenyl, pyrimidinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, oxazolyl, isoxazolyl,

[0377] Ring B is selected from phenyl, pyridyl, pyrazolyl, pyrazinyl, oxazolyl, isoxazolyl, benzopyrazolyl, thiazolyl, isothiazole, pyridazinyl, pyrimidinyl, triazolyl, thiadiazole, indolinyl, benzimidazolyl, dihydrobenzimidazolyl, indolinyl, indazolyl, isoindolinyl, pyridopyridinyl, pyrrolopyrimidinyl;

[0378] Ring C is selected from the following groups:

[0379] L5 is selected from a bond; and

[0380] L is selected from:

[0381] in,

[0382] $B represents the attachment site to ring B, #C represents the attachment site to ring C, Ra, Rb and Rc are as defined above, and Rs is as defined above;

[0383] Preferably, Ra, Rb and Rc are each independently selected from H or methyl;

[0384] Preferably, Rs is selected from H, methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0385] Preferably, Rs is selected from H or substituted or unsubstituted groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0386] In some embodiments, Ring A is selected from pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl;

[0387] Ring B is selected from:

[0388] The end is connected to the L end or L5;

[0389] Ring C is selected from:

[0390] L5 is a key;

[0391] L is selected from: $B indicates the attachment site to ring B, and #C indicates the attachment site to ring C;

[0392] Ra, Rb and Rc are as defined above, and Rs is as defined above;

[0393] Preferably, Ra, Rb and Rc are each independently selected from H or methyl;

[0394] Preferably, Rs is selected from H, methyl, cyclopropyl, cyclobutyl, cyclohexyl,

[0395] Preferably, Rs is selected from H or substituted or unsubstituted groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, In some embodiments, m1 is selected from 1, 2 or 3, and each R1 is independently selected from halogen, -OH, -CN, -NReRf, -C(=O)-NReRf, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, wherein the C3- 6-membered cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl are optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl; wherein, Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7-membered heterocycloalkyl; preferably, R1 are each independently selected from halogenated C1-3 alkyl (e.g., -CF3), cyclopropyl, -N(CH3)2; and / or

[0396] m2 is selected from 0 or 1, and each R2 is independently selected from -OH, halogen, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, preferably -F, hydroxyl; and / or

[0397] m3 is selected from 1, 2 or 3, and each R3 is independently selected from -CN, C1-3 alkyl, halogenated C1-3 alkyl (e.g., -CF3), -NReRf, -C(=O)-NReRf; wherein, Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl (e.g., a 7-membered nitrogen-containing spiroheterocycloalkyl).

[0398] In some embodiments, m1 is selected from 1, 2 or 3, and each R1 is independently selected from halogen, -OH, -CN, -NReRf, -C(=O)-NReRf, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, preferably halogenated C1-3 alkyl, cyclopropane; and / or

[0399] m2 is selected from 0 or 1, and each R2 is independently selected from -OH, halogen, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, preferably -F, cyclopropane; and / or

[0400] m3 is selected from 1, 2 or 3, and each R3 is independently selected from -CN, C1-3 alkyl, halogenated C1-3 alkyl, -C(=O)-NReRf, -NReC(=O)Rf;

[0401] wherein Re and Rf are each independently selected from H, C1-6 alkyl, halo-substituted C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, C1-6 alkyl, halo-substituted C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkoxy;

[0402] Preferably, Re is selected from H or C1-3 alkyl, and / or Rf is selected from H, C1-3 alkyl, halogenated C1-3 alkyl.

[0403] In some embodiments, at least one of the R1s is selected from a halogenated C1-6 alkyl group, and / or at least one of the R3s is selected from a halogenated C1-6 alkyl group;

[0404] Preferably, at least one of the R1s is selected from a halogenated C1-3 alkyl group, and / or at least one of the R3s is selected from a halogenated C1-3 alkyl group;

[0405] Preferably, at least one of the R1s is a trifluoromethyl group, and / or at least one of the R3s is a trifluoromethyl group.

[0406] In some embodiments, the compound of the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug has a structure as shown in Formula VII-1 or VII-2:

[0407] in,

[0408] Selected from

[0409] V1 and V2 are each independently selected from CH and N; preferably, at least one of V1 and V2 is N;

[0410] Ring A' is a 5-membered heteroaromatic ring, Y1 is N or CH, and Y2, Y3, and Y4 are each independently selected from N, CH, and S; preferably, Y1 and Y2 are N, and Y3 and Y4 are CH; or Y1 is CH, Y2 is N, and one of Y3 and Y4 is S and the other is CH; more preferably, Y1 and Y3 are CH, Y2 is N, and Y4 is S;

[0411] R1 is as defined in any of the above schemes; preferably, R1 is selected from halogenated C1-3 alkyl, -C1-3 alkylene-C3-6 cycloalkyl, -NReRf; Re and Rf are each independently selected from H, C1-3 alkyl; more preferably, R1 is -CF3;

[0412] Ring B is phenyl or a 6-membered heteroaromatic ring, and Z1, Z2, Z3, and Z4 are each independently selected from N or CH; preferably, Ring B is phenyl, or only one of Z1, Z2, Z3, and Z4 is N, or both Z1 and Z4 are CH, and both Z2 and Z3 are N;

[0413] R2 is as defined in any of the above schemes; preferably, R2 is selected from H, halogen, hydroxyl, C1-3 alkyl; more preferably, R2 is selected from H or F; more preferably, the condition is that: when Z1 and Z4 are both CH, and Z2 and Z3 are both N, R2 is H; when ring B is phenyl, or one N in Z2 or Z4, and Z1 and Z3 are both CH, R2 is H or F, and F is ortho to -CONRa- in formula VII-1; more preferably, R2 is H;

[0414] Ra and Rb are each independently selected from H or methyl; preferably, Ra is H; preferably, Rb is H;

[0415] Rs is as defined in any of the above schemes, preferably, Rs is selected from C1-3 alkyl, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl), 4-7 membered heterocycloalkyl (e.g., oxetanyl, oxetanyl, ), -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (e.g., azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen (e.g., F, Cl), cyano, C1-3 alkyl (e.g., methyl, isopropyl), C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 5-6 membered heteroaryl (e.g., pyridyl), and the C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy;

[0416] L4 is selected from NH or O, preferably NH;

[0417] R3 is defined in any of the above schemes, preferably, R3 is selected from halogenated C1-3 alkyl; more preferably, R3 is selected from -CF3;

[0418] R3' and R3" are each independently R3; preferably, R3' is selected from a halogenated C1-3 alkyl group, R3" is selected from -NReRf, and Re and Rf together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl group (e.g., a 7-membered nitrogen-containing spiroheterocycloalkyl group); more preferably, R3' is -CF3, and R3" is

[0419] It should be noted that the compounds in this embodiment have a better inhibitory effect on PARP7 activity; the compounds whose ring A is a 6-membered heteroaromatic ring tend to have better selectivity for PARP7 than the compounds whose ring A is a 5-membered heteroaromatic ring; Rs is -C(=O)N(R L2 )2 compound with Rs Compared with the compounds with Among the compounds, those with a larger number of G ring atoms tend to have better selectivity for PARP7.

[0420] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug is selected from the compounds listed in Table 1.

[0421] Table 1 Exemplary compounds of the present invention

[0422] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug is selected from compounds 1-219 listed in Table 1.

[0423] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0424] Pharmaceutical compositions and uses

[0425] In some embodiments, the present invention also provides a pharmaceutical composition comprising a compound of Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, and a pharmaceutically acceptable carrier.

[0426] Pharmaceutically acceptable carriers can be liquids, such as water and oils, including petroleum, animal oils, vegetable oils or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical carriers can be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants, etc. can be used. When administered to a subject, the compound of Formula I and the pharmaceutically acceptable carrier are preferably sterile. When the composition is used for intravenous administration, water is a preferred carrier. Saline solutions and dextrose and glycerol aqueous solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients, such as starch, glucose, lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk, glycerol, propylene glycol, water, ethanol, etc. If necessary, the composition of the present invention can also contain a small amount of wetting agent or emulsifier, or pH buffer.

[0427] The compositions of the present invention can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, aerosols, sprays, or any other form suitable for use. In one embodiment, the pharmaceutically acceptable carrier is a capsule. Other examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0428] In some embodiments, appropriate co-drugs or excipients may be selected based on actual needs to form a drug combination with combined efficacy or that can improve certain aspects of drug performance (such as stability).

[0429] In some embodiments, the present invention also provides pharmaceutical packaging or kits comprising one or more containers filled with one or more compounds of the present invention. Optionally, associated with such containers is a notice in the form prescribed by a government agency that manages and controls the manufacture, use or sale of pharmaceuticals, indicating that permission is obtained for use or sale for human medication. In certain preferred embodiments, for example, when administered to treat or prevent cancer, the kit may also include one or more chemotherapeutic agents for treating cancer or tumor diseases co-administered with the compounds of the present invention. In certain preferred embodiments, for example, when administered to treat or prevent viruses or autoimmune diseases, the kit may include one or more compounds of the present invention and one or more antiviral or immunosuppressive agents.

[0430] In some embodiments, the compound of Formula I or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug can selectively inhibit the enzymatic activity of PARP7 and can therefore be used to inhibit PARP7 in a subject in need thereof, or to treat a PARP7-mediated disease; preferably, the PARP7-mediated disease is selected from cancer, immune disease, inflammation or viral infection.

[0431] In some embodiments, PARP7 is inhibited, or used to treat a PARP7-mediated disease is a hyperproliferative disease, particularly cancer, including but not limited to breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (upper respiratory tract cancer), urinary tract cancer, colon cancer, cancer with amplified PARP7 expression, etc. In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies, such as leukemias and lymphomas. Exemplary lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Examples of leukemia include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AMIL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0432] In some embodiments, PARP7 is inhibited, or used to treat a PARP7-mediated disease, such as an autoimmune or inflammatory disease, including but not limited to rheumatoid arthritis, insulin-dependent diabetes mellitus, certain hemolytic anemias, rheumatic fever, thyroiditis, ulcerative colitis, myasthenia gravis, glomerulonephritis, allergic encephalomyelitis, viral hepatitis with subsequent nerve and liver damage, multiple sclerosis, systemic lupus erythematosus, juvenile diabetes, autoimmune hemolytic anemia, psoriasis, idiopathic thrombocytopenic purpura, active chronic hepatitis, idiopathic leukocytopenia, Cytopenia, primary biliary cirrhosis, thyrotoxicosis, dermatomyositis, discoid lupus erythematosus, psoriatic arthritis, regional enteritis, nephrotic syndrome, lupus nephritis, lupus hepatitis, Sjögren's syndrome, Goodpasture's syndrome, Wegener's granulomatosis, scleroderma, sebaceous dermatosis, uveitis and mumps mastitis, ulcerative colitis, Crohn's disease, multiple sclerosis, autoimmune liver disease, type 1 diabetes mellitus, bronchial asthma, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriasis, polymyositis, and dermatomyositis.

[0433] In some embodiments, PARP7 is inhibited, or a PARP7-mediated disease is treated, for viral infections, including but not limited to DNA viruses such as hepatitis B and C viruses; parvoviruses such as adeno-associated virus and cytomegalovirus; papillomaviruses such as papillomavirus, polyomavirus, and SV40; adenovirus; herpes viruses such as herpes simplex type 1 (HSV-I), herpes simplex type 2 (HSV-II), and Epstein-Barr virus; poxviruses such as smallpox and vaccinia virus; and RNA viruses. viruses such as human immunodeficiency virus type 1 (HIV-I), human immunodeficiency virus type 2 (HIV-II), human T-cell lymphotropic virus type 1 (HTLV-I), human T-cell lymphotropic virus type 2 (HTLV-II), influenza virus, measles virus, rabies virus, Sendai virus, polioviruses such as poliovirus, coxsackievirus, rhinovirus, reovirus, togaviruses such as rubella virus (German measles) and Selic Forest virus, dendriviruses and hepatitis A virus.

[0434] Example

[0435] The following examples are provided to assist in understanding the present invention. However, it should be understood that these examples are intended to illustrate the present invention only and do not constitute any limitation. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and variations can be made without departing from the spirit of the present invention. Where specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used where the manufacturer is not specified are conventional products that can be obtained commercially.

[0436] The abbreviations and their corresponding names involved in the following examples are shown in Table 2

[0437] Table 2

[0438] 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).

[0439] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0440] High-performance liquid chromatography (HPLC) assay conditions: Gilson high-pressure liquid chromatograph (Gilson GX-281), C18 column (10 μM, 19 mm × 250 mm), UV detection at 220 and 254 nm, and elution with a gradient of 5–95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate) for 15 min unless otherwise specified.

[0441] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0442] Thin layer chromatography separation and purification was performed using thin layer chromatography silica gel plates (aluminum plates (20 cm×20 cm×1 mm) produced by Meck, or GF 254 produced in Yantai).

[0443] Microwave reaction was carried out using a Biotage Initiator+ (400 W, RT 300° C.) microwave reactor.

[0444] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include DCM / methanol, n-hexane / EA, and PE / EA. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0445] The silica gel used for column chromatography is generally 100-200 mesh. Common eluent systems include DCM / methanol and PE / EA. 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.

[0446] 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.

[0447] Synthesis Example

[0448] Intermediate Preparation Example 1

[0449] Step 1: Dissolve 4,5-dibromopyridazin-3-one (50 g, 196.94 mmol), potassium carbonate (40.83 g, 295.42 mmol), and 4-methoxybenzyl chloride (34.87 mL, 256.03 mmol, Titanium) in acetonitrile (500 mL). React at 80°C for 16 hours. Filter the reaction mixture through celite, and concentrate the filtrate under reduced pressure. Add 300 mL of methanol and slurry for 1 hour. Filter the mixture and wash with methanol (50 mL x 2). The resulting solid was dried under nitrogen at room temperature to yield Intermediate 1-2. MS m / z (ESI): 375.0 [M+1].

[0450] Step 2: Dissolve Intermediate 1-2 (48 g, 128.33 mmol) in methanol (480 mL) and add potassium hydroxide (28.80 g, 513.33 mmol). Reaction at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was slurried in 300 mL of water for 1 hour, filtered, and washed with water (100 mL x 2). The resulting solid was dissolved in DCM (500 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield Intermediate 1-3. MS m / z (ESI): 327.0 [M+1].

[0451] Step 3: Add Intermediate 1-3 (39 g, 119.94 mmol), CuI (6.50 mL, 191.91 mmol), and methyl fluorosulfonyldifluoroacetate (51.12 mL, 401.80 mmol) to NMP (400 mL) and stir at 110°C for another 4 hours under nitrogen. Pour the reaction mixture into EA (3000 mL) / water (1000 mL) and stir. The two phases are separated, and the aqueous phase is extracted with EA (100 mL x 2). The combined organic phases are washed with saturated NaCl solution (30 mL x 4). Dry over anhydrous sodium sulfate and filter through a short silica gel column (100 g silica gel) eluting with EA (100 mL x 2). The filtrate is concentrated under reduced pressure to yield Intermediate 1-4. MS m / z (ESI): 315.2 [M+1].

[0452] Step 4: Intermediate 1-4 (17 g, 54.10 mmol) and iodotrimethylsilane (13.92 mL, 97.37 mmol) were added to NMP (400 mL) and stirred at 85°C for 3 hours. The mixture was diluted with water (400 mL) and then extracted with EA (300 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Intermediate 1-5 was obtained by silica gel chromatography eluting with DCM / MeOH = 5:1.

[0453] Step 5: Intermediate 1-5 (15 g, 49.96 mmol) was added to DMF (120 mL) and cooled to 0-5°C. 2-Chloro-2-oxoacetyl chloride (25 mL, 291.52 mmol) was added dropwise. Stir at 20°C for an additional hour. The mixture was allowed to react at 20°C for 6 hours. 200 mL of saturated sodium bicarbonate solution was added to the reaction solution, and EA was extracted (150 mL x 3). The organic phases were combined and washed with semi-saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield Intermediate 1. MS m / z (ESI): 341.0 [M+Na].

[0454] Intermediate Preparation Example 2

[0455] Step 1: Dissolve tert-butyl (S)-(1-hydroxypropyl-2-yl)carbamate (100 g, 570.68 mmol, Bid) in DCM (2000 mL). Cool to 0°C and add Dess-Martin periodinane (290.46 g, 684.81 mmol) portionwise. Return to room temperature and allow to react for 18 hours. Add 1000 mL of methyl tert-butyl ether (MTBE). Filter the solid and wash with MTBE (200 mL x 2). The filtrate is washed twice with aqueous sodium bicarbonate and saturated brine, respectively. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield Intermediate 2-1. 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 5.11 (s, 1H), 4.37–4.06 (m, 1H), 1.44 (s, 9H), 1.38–1.23 (m, 3H).

[0456] Step 2: Dissolve Intermediate 2-1 (70.2 g, 405.29 mmol) in THF (700 mL) and add ethoxycarbonylmethylenetriphenylphosphine (141.19 g, 405.29 mmol). Reaction was allowed to proceed at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was added with 500 mL of DCM. The mixture was filtered through a short silica gel column and washed with DCM (100 mL x 2). The combined filtrates were concentrated and purified by silica gel column chromatography using an eluent system (DCM:MeOH = 100 / 0 -> 10 / 1) to afford Intermediate 2-2. MS m / z (ESI): 188.3 [M-56+H].

[0457] Step 3: Dissolve Intermediate 2-2 (20 g, 82.20 mmol) in ethanol (400 mL) and add sodium borohydride (18.66 g, 493.22 mmol). Heat to 75°C and react for 8 hours. Concentrate to dryness under reduced pressure, add DCM (500 mL), filter, and concentrate the filtrate under reduced pressure. Purify by silica gel column chromatography using an eluent system (DCM:MeOH = 100 / 0 -> 10 / 1) to obtain Intermediate 2-3. MS m / z (ESI): 148.3 [M-56+H].

[0458] Step 4: Dissolve Intermediate 2-3 (14.45 g, 71.08 mmol) and triethylamine (29.56 mL, 213.25 mmol) in DCM (75 mL), cool to 0-5°C, and add methanesulfonyl chloride (8.25 mL, 106.63 mmol) dropwise. Allow to react at room temperature for 18 hours. Pour the reaction mixture into ice water (150 mL) and extract with DCM (100 mL x 3). The combined organic phases are washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to yield Intermediate 2-4. MS m / z (ESI): 226.0 [M-56+H].

[0459] Step 5: Intermediate 2-4 (18.1 g, 64.33 mmol) was dissolved in N,N-dimethylformamide (200 mL) and potassium phthalimide (15.9 g, 85.83 mmol) was added. The mixture was reacted at 50°C for 18 hours. The reaction solution was poured into water (300 mL) and extracted with EA (150 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography using an eluent system (PE:EtOAc = 1 / 1) to afford Intermediate 2-5. MS m / z (ESI): 233.1 [M-100+H].

[0460] Step 6: Dissolve intermediate 2-5 (18.3 g, 55.05 mmol) in 4 mol / L 1,4-dioxane, react at room temperature for 18 hours, and concentrate the reaction solution under reduced pressure to obtain intermediate 2. MS m / z (ESI): 233.1 [M+1].

[0461] Intermediate Preparation Example 3

[0462] Step 1: Intermediate 1 (10.08 g, 31.64 mmol) was dissolved in acetonitrile (100 mL). Intermediate 2 (7, 30.14 mmol) and triethylamine (12.53 mL, 90.42 mmol) were added and reacted at 85°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the remaining solution was added with water (40 mL). The mixture was extracted with EA (20 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered to remove the filtrate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE:EA = 3 / 1) to obtain Intermediate 3-1. MS m / z (ESI): 515.2 [M+1].

[0463] Step 2: Dissolve intermediate 3-1 (11.2 g, 21.77 mmol) in ethanol (125 mL), add hydrazine hydrate (21.12 mL, 435.37 mmol), and react at 20°C for 3 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure, add acetonitrile (100 mL), stir, filter, and concentrate the filtrate under reduced pressure. Repeat this process four times, and concentrate the filtrate under reduced pressure to obtain intermediate 3. MS m / z (ESI): 385.2 [M+1].

[0464] Intermediate Preparation Example 4

[0465] Intermediate 4-1 (500 mg, 3.63 mmol, Bid), compound 6-2 (661.68 mg, 3.63 mmol, Bid), and cesium carbonate (2362.21 mg, 7.25 mmol) were added to a solution of 1,4-dioxane (6 mL) and water (1.5 mL). Bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (592.07 mg, 0.73 mmol) was also added. The mixture was purged with nitrogen three times and reacted at 100°C for 18 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluent: PE:EA = 10:1 to 1:1) to provide Intermediate 4. MS m / z (ESI): 241.0 [M+1].

[0466] Intermediate Preparation Example 5

[0467] Step 1: Dissolve diisopropylamine (22.40 mL, 141.14 mmol) in THF (150 mL) at room temperature under nitrogen. Lower the reaction temperature to -78°C and add 2.6 M n-butyllithium solution (65.40 mL, 169.37 mmol) dropwise to the reaction mixture. Stir at this temperature for 10 minutes. After 10 minutes, add intermediate 5-0 (25 g, 141.14 mmol) dropwise to the reaction mixture. After two hours of reaction, add a solution of elemental iodine (53.77 g, 211.7 mmol) in THF dropwise to the reaction mixture at this temperature and allow to react at room temperature for 18 hours. After completion of the reaction, add water (300 mL) and EA (300 mL) to the reaction mixture. The organic phase is washed with saturated brine (300 mL x 3), dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column (eluent: EA:PE = 0%-5%) to obtain intermediate 5-1. 1 H NMR (400MHz, DMSO-d6) δ 8.01 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H).

[0468] Step 2: Intermediate 5-1 (0.5 g, 1.65 mmol) and Intermediate 2 (0.38 g, 1.65 mmol) were dissolved in 1,4-dioxane (6 mL) at room temperature. Cesium carbonate (1.075 g, 3.30 mmol), tris(dibenzylideneacetone)dipalladium (0.151 g, 0.17 mmol), and 1,1-binaphthyl-2,2-bisdiphenylphosphine (0.121 g, 0.17 mmol) were added to the reaction solution. The reaction was allowed to proceed at 110°C for 18 hours until completion. After completion, the reaction was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluent: EA:PE = 25%-33%) to obtain Intermediate 5-3. MS m / z (ESI): 408.1 [M+1].

[0469] Step 3: At room temperature, intermediate 5-3 (0.180 g, 0.44 mmol) was dissolved in ethanol (2 mL), and hydrazine hydrate (0.221 g, 4.42 mmol) was added. The reaction mixture was stirred at 25°C for 18 hours to complete the reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with acetonitrile, then filtered, and the filtrate was concentrated to obtain intermediate 5. MS m / z (ESI): 278.1 [M+1].

[0470] Intermediate Preparation Example 6

[0471] Intermediate 2-4 (1 g, 3.55 mmol) was added to a 30-33 wt% ethanolic solution of methylamine (10 mL). The mixture was reacted at 75°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure to obtain Intermediate 6. MS m / z (ESI): 217.1 [M+1].

[0472] Intermediate Preparation Example 7

[0473] Step 1: Dissolve 4,5-dibromopyridazin-3-one (25 g, 98.47 mmol) and DIPEA (51.33 mL, 295.4 mmol) in acetonitrile (500 mL). Add 2-(trimethylsilyl)ethoxymethyl chloride (18.26 g, 108.32 mmol) dropwise to the solution. React at 70°C for 3 hours. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, and elute on silica gel with PE:EA = 10:1 to obtain Intermediate 7-1. MS m / z (ESI): 357.0 [M-27].

[0474] Step 2: Dissolve Intermediate 7-1 (22 g, 57.27 mmol) in NMP (66 mL) and add lithium chloride (2.42 g, 57.27 mmol). Reaction at 95°C for 4 hours. Pour the reaction solution into 200 mL of water with stirring. The aqueous phase is then extracted with PE:EA = 5:1 (500 mL x 2). The combined organic phases are washed with saturated NaCl solution (100 mL x 4). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to yield Intermediate 7-2. MS m / z (ESI): 311.0 [M-27].

[0475] Step 3: Add intermediate 7-2 (2 g, 5.89 mmol), CuI (110 mg, 0.59 mmol) and methyl 2,2-difluoro-2-(fluorodioxy-λ6-thio)acetate (2.25 mL, 17.66 mmol) to NMP (10 mL) and stir at 110 ° C for another 4 hours under nitrogen protection. The reaction mixture was poured into water (20 mL) and stirred. The two phases were separated and the aqueous phase was extracted with PE:EA=5:1 (50 mL×2). The combined organic phases were washed with saturated NaCl solution (30 mL×4). Drying with anhydrous sodium sulfate and eluting with PE:DCM=2:1 silica gel chromatography to obtain intermediate 7-3. MS m / z (ESI): 301.0 [M-27]

[0476] Step 4: Intermediate 7-3 (10.0 g, 30.48 mmol) was dissolved in acetonitrile (100 mL), and Intermediate 2 (7 g, 30.14 mmol) and triethylamine (12.53 mL, 90.42 mmol) were added. The mixture was reacted at 85°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the remaining solution was added with water (40 mL). The mixture was extracted with EA (20 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE:EA = 3 / 1) to obtain Intermediate 7-4. MS m / z (ESI): 497.0 [M-27].

[0477] Step 5: Dissolve intermediate 7-4 (10.0 g, 25.3 mmol) in ethanol (125 mL), add hydrazine hydrate (21.12 mL, 435.37 mmol), and react at 20°C for 3 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure, add acetonitrile (100 mL), stir, filter, and concentrate the filtrate under reduced pressure. Repeat this process four times, and concentrate the filtrate under reduced pressure to obtain intermediate 7. MS m / z (ESI): 367.2 [M-27].

[0478] Intermediate Preparation Example 8

[0479] To a solution of Intermediate 7 (3.0 g, 7.61 mmol) in EA (10 mL) was added a 4 M hydrochloric acid solution in EA (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to yield Intermediate 8. MS m / z (ESI): 265.1 [M+1].

[0480] Intermediate Preparation Example 9

[0481] Step 1: Intermediate 9-1 (10.00 g, 52.08 mmol, Bis(II)) was dissolved in DCM (100 mL) at room temperature under nitrogen. The reaction temperature was lowered to -0°C, and bis(2-methoxyethyl)aminosulfur trifluoride (19.20 mL, 104.1 mmol) was added dropwise to the reaction mixture, which was stirred at this temperature for 30 minutes. After 30 minutes, the reaction mixture was warmed to room temperature and allowed to react for two hours. TLC monitored the reaction for completion. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: EA:PE = 0% to 5%) to obtain Intermediate 9-2. 1H NMR (400 MHz, CDCl3) δ 7.75 (t, J = 2.2 Hz, 1H), 6.85 (t, J = 54.8 Hz, 1H).

[0482] Step 2: At room temperature, Intermediate 9-2 (1.30 g, 6.08 mmol) and 6-(methoxycarbonyl)pyridin-3-ylboronic acid (1.00 g, 5.33 mmol, Bis(R)) were dissolved in 1,4-dioxane (6 mL). Sodium carbonate (1.17 g, 11.0 mmol), palladium acetate (0.12 g, 0.55 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.32 g, 0.55 mmol) were added to the reaction solution. The reaction was allowed to proceed at 120°C for 18 hours until completion. After completion, the reaction was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluent: EA:PE = 25% to 33%) to afford Intermediate 9. MS m / z (ESI): 271.0 [M+1].

[0483] Intermediate Preparation Example 10

[0484] Step 1: Intermediate 9-2 (300 mg, 1.40 mmol) and compound 4-2 (420 mg, 1.40 mmol) were dissolved in 1,4-dioxane (6 mL) at room temperature. Pd(PPh3)4 (162 mg, 0.14 mmol) and cuprous iodide (26.7 mg, 0.14 mmol) were added to the reaction solution. The reaction was allowed to proceed at 120°C for 18 hours until completion. After completion, the reaction was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluent: EA:PE = 25% to 33%) to obtain intermediate 10-2. MS m / z (ESI): 272.0 [M+1].

[0485] Step 2: Intermediate 10-2 (170 mg, 0.63 mmol) was dissolved in methanol (1 mL), THF (1 mL), and water (1 mL). LiOH (50.3 mg, 1.26 mmol) was added and the mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was added with 50 mL of water. The mixture was extracted with EA (5 mL × 3). The aqueous phase was adjusted to pH = 5 by adding hydrochloric acid (1 M). The mixture was extracted with DCM / methanol (10 / 1, 5 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Intermediate 10. MS m / z (ESI): 258.0 [M+H]

[0486] Intermediate Preparation Example 11

[0487] Intermediate 4-1 (300 mg, 2.18 mmol, Bid), compound 17-0 (504 mg, 2.18 mmol, Bid), and cesium carbonate (1.41 g, 4.35 mmol) were added to 1,4-dioxane (6 mL) and water (1 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (355 mg, 0.44 mmol) was added. The mixture was purged with nitrogen three times and reacted at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (eluent: PE:EA = 2:1 to 1:1) to obtain Intermediate 11. MS m / z (ESI): 246.0 [M+1].

[0488] Intermediate Preparation Example 12

[0489] Step 1: Compound 4-2 (500 mg, 1.66 mmol) and compound 17-0 (385 mg, 1.66 mmol, Bid) were dissolved in toluene (5 mL). Pd(PPh3)4 (192 mg, 0.17 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction was carried out at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 10 / 1 to 5 / 1) to obtain intermediate 12-1. MS m / z (ESI): 290.0 [M+1].

[0490] Step 2: Dissolve Intermediate 12-1 (160 mg, 0.55 mmol) in methanol (3 mL) and water (3 mL), and add LiOH (40 mg, 1.55 mmol). Reaction was allowed to proceed at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was added with 10 mL of water and adjusted to pH 6 with 1 M hydrochloric acid solution. The mixture was filtered, washed with water (5 mL), and the filter cake was dried to obtain Intermediate 12. MS m / z (ESI): 276.0 [M+1]

[0491] Intermediate Preparation Example 13

[0492] Step 1: To a solution of 4-chloro-3-iodopyridin-2-ylamine (4.50 g, 17.68 mmol) and zinc cyanide (1.04 g, 8.84 mmol) in NMP (50 mL) was added Pd(PPh3)4 (2.04 g, 1.77 mmol). Under nitrogen, the mixture was heated at 95°C and stirred for 24 hours. The reaction mixture was poured into water (100 mL), stirred for 5 minutes, and filtered. The crude product was washed with water (50 mL x 3) and filtered to obtain Intermediate 13-1. MS m / z (ESI): 154.0 [M+H].

[0493] Step 2: To a solution of Intermediate 13-1 (2.5 g, 16.28 mmol) in hydrochloric acid (30 mL, 6 M) at 0°C were added sodium nitrite (1.24 g, 17.91 mmol) and copper sulfate pentahydrate (4.06 g, 16.28 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water (30 mL) and stirred. The mixture was extracted with EA (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a solvent system (DCM:methanol = 20:1) to afford Intermediate 13-2. MS m / z (ESI): 155.0 [M+H].

[0494] Step 3: To a solution of Intermediate 13-2 (550 mg, 3.56 mmol) in acetonitrile (20 mL) was added Intermediate 2 (413.31 mg, 1.78 mmol) and triethylamine (1.48 mL, 10.68 mmol). The mixture was heated to reflux at 85°C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure and eluted with silica gel chromatography using a 10:1 ratio of DCM:CH3OH to afford Intermediate 13-3. MS m / z (ESI): 351.38 [M+H].

[0495] Step 4: Intermediate 13-3 (425 mg, 1.21 mmol) and ethanol (15 mL) were added to an 8 mL reactor. 20 equivalents of aqueous ammonia were added, and the mixture was stirred at 20°C under nitrogen for 3 hours. The mixture was filtered and washed with MeCN (20 mL x 2). The filtrate was concentrated on a rotary evaporator (35-40°C) to yield Intermediate 13. MS m / z (ESI): 221.28 [M+H].

[0496] Intermediate Preparation Example 14

[0497] Step 1: Intermediate 14-0 (1.2 g, 6.48 mmol) and THF (25 mL) were added to a 250 mL reactor. The mixture was cooled to -70°C. Methylmagnesium bromide (3.0 mol / L in diethyl ether) (3.24 mL, 9.72 mmol) was added dropwise. The mixture was stirred at -70°C for another 2 hours. After concentration on a rotary evaporator (35-40°C), a saturated aqueous ammonium chloride solution (50 mL) and EA (20 mL) were added to the residue, and the resulting mixture was stirred for 15 minutes. The two phases were separated and the aqueous phase was back-extracted with EA (10 mL×2). The combined organic phases were washed with half-saturated brine and dried over anhydrous sodium sulfate. The filtered filtrate was concentrated on a rotary evaporator (35-40°C) and purified by flash column chromatography (PE:EA=1 / 1) to obtain intermediate 14-1. MS m / z (ESI): 146.1 [M-56].

[0498] Step 2: Add intermediate 14-1 (900 mg, 4.47 mmol) and methanol (30 mL) to a 100 mL reactor. Add sodium borohydride (338.32 mg, 8.94 mmol). Stir at 20°C for another 3 hours under nitrogen protection. Back-extract the aqueous phase with EA (50 mL × 2). Wash the combined organic phase with half-saturated brine and dry over anhydrous sodium sulfate. The filtered filtrate is concentrated on a rotary evaporator (40-45°C) to obtain intermediate 14-2. MS m / z (ESI): 148.1 [M-56].

[0499] Step 3: Intermediate 14-2 (685 mg, 3.37 mmol), intermediate 1 (1181.25 mg, 3.71 mmol) and DCM (30 mL) were added to a 100 mL reactor. Sodium tert-butoxide (453.36 mg, 4.72 mmol) was added. Under nitrogen protection, the mixture was stirred at 20°C for another 12 hours. The aqueous phase was extracted with DCM (40 mL × 2). The combined organic phase was washed with half-saturated brine and dried over anhydrous sodium sulfate. The filtered filtrate was concentrated by rotary evaporation (35-40°C) and purified by flash column chromatography (PE:EA=1 / 1) to obtain intermediate 14-3. MS m / z (ESI): 430.2 [M-56].

[0500] Step 4: Under nitrogen at 25°C, intermediate 14-3 (300 mg, 0.62 mmol) and DCM (8 mL) were added to a 50 mL reactor. A solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 M) was added. Stirring was continued at 25°C under nitrogen for another hour. The mixture was then concentrated under reduced pressure to yield intermediate 14. MS m / z (ESI): 386.4 [M+1].

[0501] Intermediate Preparation Example 15

[0502] Step 1: Dissolve Intermediate 15-1 (850 mg, 2.27 mmol, Bidex), Intermediate 15-2 (522.63 mg, 2.27 mmol, Bidex), and bis(tri-tert-butylphosphine)palladium (116.10 mg, 0.23 mmol) in 1,4-dioxane (3 mL). The mixture was stirred under nitrogen and heated under reflux at 100°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA as the eluent to afford Intermediate 15-3. MS m / z (ESI): 235.0 [M-56]. 1H NMR (400MHz, DMSO-d6) δ9.29(d,J=2.1Hz,1H),8.51(dd,J=8.2,2.3Hz,1H),8.17(d,J=8.2Hz,1 H), 8.09 (d, J = 3.2Hz, 1H), 8.01 (d, J = 3.2Hz, 1H), 4.38 (q, J = 7.1Hz, 2H), 1.36 (t, J = 7.1Hz, 3H).

[0503] Step 2: Dissolve Intermediate 15-3 (230 mg, 0.98 mmol) and sodium hydroxide (196.35 mg, 4.91 mmol) in methanol (4 mL) and water (0.8 mL). Stir the mixture at room temperature for 3 hours. Add 6 M hydrochloric acid to the reaction solution, adjust the pH to 3-4, and then extract with EA. Dry the organic layer over anhydrous sodium sulfate, remove the desiccant, and concentrate the filtrate under reduced pressure to yield Intermediate 15. MS m / z (ESI): 207.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ13.43 (s, 1H), 9.27 (d, J = 1.8 Hz, 1H), 8.49 (dd, J = 8.2, 2.2 Hz, 1H), 8.12 (dd, J = 30.8, 5.7 Hz, 2H), 8.00 (d, J = 3.2 Hz, 1H).

[0504] Example 1

[0505] Step 1: Dissolve compound 1-1 (575 mg, 2.74 mmol, Bis(II)), compound 6-2 (500 mg, 2.75 mmol), sodium carbonate (871 mg, 8.25 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (80 mg, 0.11 mmol) in a mixture of 6 mL of 1,4-dioxane and 0.6 mL of water. Heat the reaction mixture at 90°C with stirring for 16 hours. Add 10 mL of water to the reaction mixture, extract with EA (20 mL x 2), and concentrate the organic phase to yield compound 1-2. MS m / z (ESI): 313.0 [M+H].

[0506] Step 2: Compound 1-2 (650 mg, 2.08 mmol) was dissolved in methanol (4 mL) and water (3 mL). Sodium hydroxide (250 mg, 6.24 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 70°C for 3 hours. After the reaction, the reaction mixture was concentrated, and dilute hydrochloric acid was added to adjust the pH to <7. The mixture was extracted with EA (20 mL x 2). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield compound 1-3. MS m / z (ESI): 299.0 [M+H].

[0507] Step 3: Compound 1-3 (330 mg, 1.01 mmol) was dissolved in 5 mL of DMF. HATU (383 mg, 1.01 mmol) and DIPEA (261 mg, 2.02 mmol) were added, and the mixture was stirred at 25°C for 0.5 hour. Intermediate 7 (265 mg, 0.67 mmol) was added, and the mixture was stirred at 25°C for 1 hour. Water (15 mL) was added to the reaction solution, and the mixture was extracted with EA (10 mL x 2). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 1) to obtain compound 1-4. MS m / z (ESI): 647.2 [M-27].

[0508] Step 4: Compound 1-4 (275 mg, 0.41 mmol) was dissolved in anhydrous DCM (10 mL). The reaction mixture was cooled to 0°C and 1 M boron tribromide (1.93 mL, 1.93 mmol) was slowly added under nitrogen. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30% to 60%, flow rate: 30 mL / min) to obtain compound 1. MS m / z (ESI): 531.1 [M+H]. 1H NMR (400MHz, DMSO) δ12.63(s,1H),12.44(s,1H),9.39(d,J=0.9Hz,2H),9.00(s,1H),8.02(d,J=8.2Hz ,1H),7.98–7.91(m,3H),4.00(s,1H),1.73–1.65(m,1H),1.58(d,J=5.0Hz,3H),1.20(d,J=6.3Hz,3H).

[0509] Example 2

[0510] Step 1: Dissolve compound 2-1 (543 mg, 2.75 mmol, Bis(II)), compound 6-2 (500 mg, 2.75 mmol), sodium carbonate (871 mg, 8.25 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (80 mg, 0.11 mmol) in a mixture of 6 mL of 1,4-dioxane and 0.6 mL of water. Heat the reaction mixture at 90°C with stirring for 16 hours. Add 10 mL of water to the reaction mixture, extract with EA (20 mL x 2), and concentrate the organic phase to yield compound 2-2. MS m / z (ESI): 301.0 [M+H].

[0511] Step 2: Compound 2-2 (650 mg, 2.17 mmol) was dissolved in methanol (4 mL) and water (3 mL). Sodium hydroxide (260 mg, 6.50 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 70°C for 3 hours. After the reaction, the reaction mixture was concentrated, and dilute hydrochloric acid was added to adjust the pH to <7. The mixture was extracted with EA (20 mL x 2). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain compound 2-3. MS m / z (ESI): 287.1 [M+H].

[0512] Step 3: Compound 2-3 (112 mg, 0.39 mmol) was dissolved in 5 mL of DMF. HATU (111 mg, 0.29 mmol) and DIPEA (76 mg, 0.59 mmol) were added, and the mixture was stirred at 25°C for 0.5 hour. Intermediate 7 (79 mg, 0.20 mmol) was added, and the mixture was stirred at 25°C for 16 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with EA (10 mL x 2). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 1) to obtain compound 2-4. MS m / z (ESI): 635.2 [M-27].

[0513] Step 4: Compound 2-4 (156 mg, 0.24 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (10 mL). The reaction mixture was stirred at 45°C for 1 hour. The reaction mixture was dried with nitrogen and then dissolved in methanol (4 mL). The resulting mixture was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 2. MS m / z (ESI): 533.2 [M+H]. 1H NMR (400MHz, DMSO) δ12.46(s,1H),9.42(s,2H),8.53(t,J=5.1Hz,1H),8.33(dd,J=8.1,1.5Hz,1H),8.20(dd,J=11.3,1.4Hz,1H),7.94(s,1H),7 .79(t,J=7.7Hz,1H),6.42–6.29(m,1H),4.00(s,1H),3.28(d,J=5.5Hz, 2H), 1.68 (d, J = 7.5Hz, 1H), 1.57 (d, J = 5.7Hz, 3H), 1.20 (d, J = 6.3Hz, 3H).

[0514] Example 3

[0515] Step 1: Dissolve compound 3-1 (500 mg, 2.75 mmol, Bis(II)), compound 6-2 (500 mg, 2.75 mmol), sodium carbonate (871 mg, 8.25 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (80 mg, 0.11 mmol) in a mixture of 6 mL of 1,4-dioxane and 0.6 mL of water. Heat the reaction mixture at 90°C with stirring for 16 hours. Add 10 mL of water to the reaction mixture, extract with EA (20 mL x 2), and concentrate the organic phase to yield compound 3-2. MS m / z (ESI): 283.0 [M+H].

[0516] Step 2: Compound 3-2 (600 mg, 2.13 mmol) was dissolved in methanol (5 mL) and water (5 mL). Sodium hydroxide (256 mg, 6.39 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 70°C for 3 hours. After the reaction, the reaction mixture was concentrated, and dilute hydrochloric acid was added to adjust the pH to <7. The mixture was extracted with EA (20 mL x 2). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain compound 3-3. MS m / z (ESI): 269.1 [M+H].

[0517] Step 3: Compound 3-3 (104 mg, 0.39 mmol) was dissolved in 5 mL of DMF. HATU (148 mg, 0.39 mmol) and DIPEA (101 mg, 0.78 mmol) were added, and the mixture was stirred at 25°C for 0.5 hour. Intermediate 7 (102 mg, 0.26 mmol) was added, and the mixture was stirred at 25°C for 16 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with EA (10 mL x 2). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 1) to obtain compound 3-4. MS m / z (ESI): 617.2 [M-27].

[0518] Step 4: Compound 3-4 (134 mg, 0.21 mmol) was dissolved in 4 M 1,4-dioxane hydrochloride solution (10 mL). The reaction mixture was stirred at 45°C for 1 hour. The reaction mixture was dried under nitrogen and dissolved in methanol (4 mL). The resulting mixture was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 45% to 65%, flow rate: 30 mL / min) to obtain compound 3. MS m / z (ESI): 515.2 [M+H]. 1H NMR (400MHz, DMSO) δ12.45(s,1H),9.40(s,2H),8.67(t,J=5.6Hz,1H),8.52(d,J=8.5Hz,2H),8.03(d,J=8.5Hz,2H),7.94(s ,1H),6.35(d,J=4.9Hz,1H),4.00(s,1H),3.30(d,J=5.5Hz,2H),1.68(d,J=7.9Hz,1H),1.57(s,3H),1.20(d,J=6.3Hz,3H).

[0519] Example 4

[0520] Step 1: Dissolve compound 4-1 (10.0 g, 58 mmol, Bid) in toluene (200 mL). Add hexamethyltin (24.7 g, 75.3 mmol, Bid) and Pd(PPh3)4 (3.35 g, 2.9 mmol, Bid). Heat to 120°C and stir for 2 hours under a nitrogen atmosphere. Filter the reaction mixture through celite and concentrate. The crude product is purified by column chromatography on a neutral alumina column using an eluent system (PE:EtOAc = 5 / 1) to afford compound 4-2. MS m / z (ESI): 303.0 [M+1].

[0521] Step 2: Compound 4-2 (5.5 g, 18.3 mmol) was dissolved in toluene (100 mL). Pd(PPh3)4 (2.1 g, 1.83 mmol, Pd) and compound 6-2 (3.34 g, 18.3 mmol) were added. The mixture was heated to 100°C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered to obtain a crude solid. The crude solid was purified by silica gel column chromatography using an eluent system (PE:EtOAc = 1 / 1) to obtain compound 4-3. MS m / z (ESI): 285.1 [M+1].

[0522] Step 3: Compound 4-3 (1.4 g, 4.93 mmol) was dissolved in methanol (10 mL) and water (10 mL). LiOH (0.83 g, 19.7 mmol) was added and the mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was added with 30 mL of water. The mixture was extracted with EA (25 mL × 3). Hydrochloric acid (1 M) was added to the aqueous phase until pH = 5. The mixture was extracted with DCM / methanol (10 / 1, 40 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain compound 4-4. MS m / z (ESI): 271.0 [M+H].

[0523] Step 4: Compound 4-4 (1.22 g, 4.52 mmol) was dissolved in DMF (15 mL), followed by the addition of intermediate 3 (1.56 g, 4.06 mmol), TCFH (1.52 g, 5.42 mmol, Bidex), and N-methylimidazole (1.11 g, 13.55 mmol, Bidex). The reaction was allowed to react at 20°C for 2 hours. Water (40 mL) was added to the reaction solution, and the mixture was extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (DCM:MeOH = 20 / 1) to afford compound 4-5. MS m / z (ESI): 637.4 [M+1].

[0524] Step 5: Compound 4-5 (1.80 g, 2.83 mmol) was dissolved in TFA (20 mL), and methanesulfonic acid (2 mL) was added. The reaction mixture was reacted at 20°C for 1 hour. Methanol (10 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure. EA (20 mL) was added to the remaining solution, and the solution was neutralized with saturated sodium bicarbonate solution to pH 8. The aqueous phase was extracted with EA (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (DCM:MeOH = 20 / 1) to obtain the crude product. The crude product was then purified by preparative purification to obtain compound 4. MS m / z (ESI): 517.2 [M+1]. 1H NMR (400MHz, DMSO) δ12.41(s,1H),9.60(d,J=1.4Hz,1H),9.52(s,2H),9.37(d,J=1.4Hz,1H),9.16(t,J=6.0Hz,1H),7.9 2(s,1H),6.31(d,J=4.9Hz,1H),3.99(d,J=5.5Hz,1H),3.35(d,J=6.3Hz,2H),1.72–1.50(m,4H),1.18(d,J=6.3Hz,3H).

[0525] Example 5

[0526] Step 1: Dissolve compound 5-0 (2.0 g, 11.42 mmol, Bid) in 100 mL of DCM. Add TFA (17.9 mL, 239.7 mmol) and triethylsilane (5.0 mL, 30.82 mmol). React at room temperature for 16 h. Pour the reaction mixture into 100 mL of water, adjust the pH to 9 with sodium hydroxide, and extract with DCM (50 mL x 2). The organic phases are combined and dried over anhydrous sodium sulfate. The desiccant is filtered and the filtrate is concentrated under reduced pressure to yield compound 5-1. MS m / z (ESI): 178.0 [M+1].

[0527] Step 2: Compound 5-1 (600 mg, 3.38 mmol) and DIPEA (0.88 mL, 5.08 mmol) were dissolved in 12 mL of isopropanol. Compound 6-2 (925 mg, 5.07 mmol) was added at room temperature. The reaction system was reacted at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 3 / 1) to obtain compound 5-2. MS m / z (ESI): 324.1 [M+1].

[0528] Step 3: Compound 5-2 (240 mg, 0.74 mmol) was added to methanol / water (3 mL / 1 mL), followed by the addition of LiOH (71 mg, 2.96 mmol). The reaction system was allowed to react at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 5 by adding 1 M aqueous hydrochloric acid. The mixture was extracted with EA (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield compound 5-3. MS m / z (ESI): 310.0 [M+1].

[0529] Step 4: Compound 5-3 (120 mg, 0.39 mmol) was dissolved in 2 mL of DMF. DIPEA (101 mg, 0.78 mmol) and HATU (148 mg, 0.39 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 h. Intermediate 7 (102 mg, 0.26 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 h. 10 mL of water was added to the reaction mixture, and EA was extracted twice (5 mL). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield compound 5-4. MS m / z (ESI): 658.2 [M-27].

[0530] Step 5: Compound 5-4 (200 mg, 0.26 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (2 mL) and allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 38% to 45%, flow rate: 30 mL / min) to afford compound 5. MS m / z (ESI): 556.2 [M+1]. 1 H NMR (400MHz, DMSO) δ8.97 (s, 2H), 8.48 (d, J = 7.9Hz, 1H), 8.34 (t, J = 5.7Hz, 1 H),7.93(s,1H),7.32(t,J=7.8Hz,1H),7.30–7.21(m,1H),6.38–6.29(m,1H ),4.24(t,J=8.6Hz,2H),3.99(s,1H),3.38(t,J=8.6Hz,2H),3.30(s,2H),3 .24(d,J=7.3Hz,1H),1.75–1.62(m,1H),1.54(s,3H),1.20(d,J=6.3Hz,3H).

[0531] Example 6

[0532] Step 1: Dissolve compound 6-0 (2500 mg, 15.04 mmol, Bid) and N,N'-carbonyldiimidazole (2.25 mL, 18.05 mmol) in 15 mL of 1,2-dichloroethane. Stir the reaction mixture at room temperature for 16 hours. Concentrate the reaction mixture, wash the residue with 20 mL of water, collect the solid by filtration, and dry under reduced pressure to yield compound 6-1. MS m / z (ESI): 193.0 [M+1].

[0533] Step 2: Compound 6-1 (500 mg, 2.60 mmol) and compound 6-2 (712.38 mg, 3.90 mmol) were dissolved in DMF (15 mL). Cesium carbonate (2543.22 mg, 7.81 mmol) was added and stirred at 90°C for 12 hours. After cooling the reaction solution to room temperature, 10 mL of water was added and extracted with EA (10 mL x 3). The organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 1) to obtain compound 6-3. MS m / z (ESI): 339.0 [M+1]. 1 H NMR (400MHz, DMSO) δ 11.32 (s, 1H), 9.35 (s, 2H), 8.08 (d, J = 7.9Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.15 (t, J = 8.0Hz, 1H), 3.85 (s, 3H).

[0534] Step 3: Dissolve compound 6-3 (250 mg, 0.74 mmol) in 2 mL of water, then add 10 mL of hydrogen chloride solution. The reaction mixture is incubated at 60°C for 4 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified using a reverse phase chromatography system (acetonitrile / water = 3 / 1) to obtain compound 6-4. MS m / z (ESI): 323.0 [M-1].

[0535] Step 4: Compound 6-4 (30 mg, 0.09 mmol) and intermediate 8 (27.87 mg, 0.11 mmol) were dissolved in DMF (3 mL). 1-Hydroxybenzotriazole (0.04 mL, 0.23 mmol) and DIPEA (0.04 mL, 0.23 mmol) were then added, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.58 mg, 0.19 mmol). The mixture was allowed to react overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30% to 60%, flow rate: 30 mL / min) to afford compound 6. MS m / z (ESI): 555.1 [M-1]. 1H NMR (400MHz, DMSO) δ12.45(s,1H),10.94(s,1H),9.41(s,2H),8.61(s,1H),8.02(d,J=8.0Hz,1H),7.92(s,1H),7.59(d,J=8.1Hz,1H),7.16 (t,J=8.0Hz,1H),6.42(s,1H),4.07(s,1H),2.52(s,2H),1.94(dd,J=13.9,7.0Hz,1H),1.83(dd,J=13.9,6.1Hz,1H),1.24(d,J=6.3Hz,3H).

[0536] Example 7

[0537] Step 1: Compound 7-0 (2.5 g, 9.8 mmol) was dissolved in 30 mL of DCM. Boc anhydride (2.6 g, 11.9 mmol), triethylamine (2 g, 20 mmol), and DMAP (122 mg, 1 mmol) were added at room temperature. The reaction was stirred and maintained at this temperature for 16 hours. The reaction solution was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 5 / 1) to obtain compound 7-1. MS m / z (ESI): 298.9 [M-56+1].

[0538] Step 2: 1,4-Dioxane (20 mL) was added to compound 7-1 (1.3 g, 3.6 mmol), compound 7-2 (1.1 g, 4.4 mmol), potassium acetate (900 mg, 9.2 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium(II) chloride (140 mg, 0.2 mmol). The atmosphere was purged with nitrogen three times and stirred at 85°C for 16 hours. The reaction solution was cooled to room temperature, diluted with EA, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (DCM / methanol = 50 / 1) to obtain compound 7-3. MS m / z (ESI): 347.1 [M-56+1].

[0539] Step 3: Compound 7-3 (500 mg, 1.2 mmol) was added to a single-necked flask, followed by compound 6-2 (320 mg, 1.8 mmol), sodium carbonate (250 mg, 2.4 mmol), and bis(tri-tert-butylphosphine)palladium (75 mg, 146.1 μmol). The atmosphere was purged with nitrogen three times, and 1,4-dioxane (7 mL) and water (0.7 mL) were added. The mixture was stirred at 85°C for 5 hours. After cooling to room temperature, the reaction solution was diluted with EA and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (DCM / methanol = 50 / 1) to obtain compound 7-5. MS m / z (ESI): 323.0 [M+1].

[0540] Step 4: Compound 7-5 (150 mg, 465.8 μmol) was dissolved in methanol (2.1 mL) and water (0.7 mL). Anhydrous LiOH (67.2 mg, 2.8 mol) was added and stirred at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure and the pH was adjusted to 5 with 2M dilute hydrochloric acid. The solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 7-6. MS m / z (ESI): 309.0 [M+1].

[0541] Step 5: Compound 7-6 (60 mg, 194.8 μmol) was dissolved in DMF (3 mL). DIPEA (82.4 mg, 638.8 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 392.7 μmol), 1-hydroxybenzotriazole (53 mg, 392.5 μmol), and intermediate 8 (30 mg, 120 μmol) were added at room temperature. The mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 28% to 41%, flow rate: 30 mL / min) to obtain compound 7. MS m / z (ESI): 541.2 [M+1]. 1 H NMR (400MHz, DMSO) δ13.83(s,1H),12.44(s,1H),9.40(s,3H),8.71(s,1H),8.61(t,J=5.9Hz,1H),8.33(dt,J=17.6,8 .6Hz,3H),7.90(s,1H),6.39(s,1H),4.15–3.93(m,1H),3.44–3.34(m,3H),2.05–1.74(m,3H),1.24(d,J=6.3Hz,5H).

[0542] Example 8

[0543] Step 1: Compound 8-0 (1 g, 3.7 mmol) was dissolved in 10 mL of DCM. TFA (3 mL, Shanghai Bidex) was added at room temperature. The mixture was stirred and reacted for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain compound 8-1. MS m / z (ESI): 168.2 [M+1].

[0544] Step 2: Compound 8-1 (640 mg, 3.8 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 6-2 (800 mg, 4.2 mmol) and DIPEA (2.451 g, 19 mol) were added. The mixture was stirred at 85°C for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (DCM / methanol = 10 / 1) to obtain compound 8-2. MS m / z (ESI): 314.1 [M+1].

[0545] Step 3: Compound 8-2 (50 mg, 159.7 μmol) was dissolved in DMF (3 mL). DIPEA (82.4 mg, 638.8 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 319.4 μmol), 1-hydroxybenzotriazole (43.1 mg, 319.4 μmol), and intermediate 8 (50 mg, 200 μmol) were added at room temperature. The mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 8. MS m / z (ESI): 546.2 [M+1]. 1 H NMR(400MHz,DMSO)δ13.03(s,1H),12.42(s,1H),8.77(s,2H),8.13(s,1H),7.85(s,1H),6.35(s,1H),4.95(s,2H), 4.09(t,J=5.5Hz,2H),4.01–3.89(m,1H),3.28–3.19(m,2H),2.79(s,2H),1.93–1.67(m,2H),1.20(d,J=6.3Hz,3H).

[0546] Example 9

[0547] Step 1: Compound 9-0 (220 mg, 0.98 mmol, Bid) and intermediate 7 (502 mg, 1.27 mmol) were dissolved in 20 mL of ethanol. The reaction mixture was stirred at room temperature for 16 hours. 10 mL of acetic acid was added, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) to obtain compound 9-1. MS m / z (ESI): 575.0 [M-28].

[0548] Step 2: Compound 9-1 (168 mg, 0.27 mmol) and pinacol diboronate (140 mg, 0.56 mmol) were dissolved in anhydrous 1,4-dioxane (3.5 mL). Potassium acetate (82 mg, 0.83 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (26 mg, 0.06 mmol), and tris(dibenzylideneacetone)dipalladium (25 mg, 0.03 mmol) were added sequentially. The mixture was stirred at 90°C under nitrogen for 4 hours. After cooling to room temperature, the reaction solution was concentrated and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 5 / 1) to obtain compound 9-2. MS m / z (ESI): 623.4 [M-27].

[0549] Step 3: Compound 9-2 (123 mg, 0.19 mmol) was dissolved in a mixture of 7.5 mL of 1,4-dioxane and 1.5 mL of water. Sodium carbonate (60 mg, 0.57 mmol), compound 6-2 (35 mg, 0.19 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (15 mg, 2.02 mmol) were added. The mixture was stirred at 90°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 10 / 1) to yield compound 9-3. MS m / z (ESI): 647.2 [M-27].

[0550] Step 4: Compound 9-3 (31 mg, 0.05 mmol) was dissolved in 4 M 1,4-dioxane hydrochloride solution (4.5 mL) and stirred at 45°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 9. MS m / z (ESI): 541.2 [M+H]. 1H NMR(400MHz,DMSO)δ12.41(s,1H),8.87(d,J=7.9Hz,1H),8.75(s,1H),8.11–7.90(m,2H),6.3 4(s,1H),3.96(s,1H),3.62(t,J=6.3Hz,2H),1.66(s,4H),1.52(s,1H),1.16(d,J=6.3Hz,3H).

[0551] Example 10

[0552] Step 1: Dissolve compound 10-0 (10 g, 53.19 mmol, Bid) and N-iodosuccinimide (19.15 g, 85.10 mmol) in 100 mL of acetonitrile. Stir the reaction mixture at room temperature for 16 hours. Concentrate the reaction mixture to obtain compound 10-1. 1 H NMR (400MHz, DMSO) δ12.07(s,1H),7.72(s,1H),2.51(s,3H).

[0553] Step 2: Compound 10-1 (500 mg, 1.59 mmol) was dissolved in DMF (6 mL). Sodium hydroxide (38.23 mg, 1.59 mmol) was added at 0°C. Half an hour later, 4-methoxybenzyl chloride (0.22 mL, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, 10 mL of water was added and the mixture was extracted with EA (20 mL x 2). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 3 / 1) to obtain compound 10-2. MS m / z (ESI): 436.0 [M+1].

[0554] Step 3: Compound 10-2 (320 mg, 0.74 mmol) and methyl fluorosulfonyldifluoroacetate (141.63 mg, 0.74 mmol) were dissolved in 10 mL of DMF, and then cuprous iodide (28 mg, 0.15 mmol) was added. The reaction solution was reacted at 100°C for 6 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, and EA was extracted (20 mL × 2). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel plate with an eluent system (PE / EA = 1 / 1) to obtain compound 10-3. MS m / z (ESI): 400.0 [M+Na + ].

[0555] Step 4: Compound 10-3 (180 mg, 0.48 mmol) and compound 10-4 (216 mg, 0.96 mmol) were dissolved in a mixed solvent of 2 mL of 1,4-dioxane and 0.2 mL of water. Potassium carbonate (198 mg, 1.44 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (17.5 mg, 0.05 mmol) were added. The mixture was reacted at 85°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) to obtain compound 10-5. MS m / z (ESI): 396.1 [M+H + ].

[0556] Step 5: Compound 10-5 (152 mg, 0.74 mmol) was dissolved in 4 mL of ethanol, and Pd / C (15 mg, 0.37 mmol) was added. The reaction solution was reacted at 25°C for 16 hours. The reaction solution was filtered through celite, the filter cake was rinsed with ethanol (10 mL), and the filtrate was concentrated under reduced pressure to obtain compound 10-6. MS m / z (ESI): 398.1 [M+H + ].

[0557] Step 6: Compound 10-6 (121 mg, 0.30 mmol) was dissolved in a mixed solvent of 4 mL of methanol and 2 mL of water, and LiOH (39 mg, 0.60 mmol) was added. The reaction solution was reacted at 25°C for 16 hours. The reaction solution was diluted with water (10 mL), the methanol was concentrated under reduced pressure, and 0.1 M hydrochloric acid solution was added dropwise to adjust the solution pH to <7. DCM / isopropanol (3 / 1) (8 mL×2) was extracted, and the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was added to 10 mL of PE and slurried, and filtered to obtain compound 10-7. MS m / z (ESI): 370.1 [M+H + ].

[0558] Step 7: Compound 10-7 (80 mg, 0.22 mmol) was dissolved in 3 mL of acetonitrile, and N-methylimidazole (63 mg, 0.77 mmol) and TCFH (68 mg, 0.24 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 0.5 hours. Compound 10-8 (78 mg, 0.32 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was decompressed, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 1) to obtain compound 10-9. MS m / z (ESI): 591.2 [M+H + ].

[0559] Step 8: Compound 10-9 (65 mg, 0.11 mmol) was dissolved in 3 mL of TFA, and TfOH (34 mg, 0.23 mmol) was added. The reaction mixture was reacted at 45°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L of TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 10. MS m / z (ESI): 471.1 [M+H + ]. 1 H NMR (400MHz, DMSO) δ11.96(s,1H),10.24(s,1H),9.28(s,2H),8.41(d,J=8.8Hz,2H),7.78(d,J=8.8 Hz,2H),7.41(s,1H),2.77(t,J=7.3Hz,2H),2.67(s,1H),2.58(t,J=7.6Hz,2H),2.36–2.31(m,3H).

[0560] Example 11

[0561] Step 1: To a solution of compound 11-0 (3.00 g, 8.13 mmol) in NMP (40 mL) at room temperature, methyl fluorosulfonyldifluoroacetate (5.46 g, 28.4 mmol) and cuprous iodide (2.32 g, 12.2 mmol) were added. The reaction mixture was allowed to react at 110°C for 18 hours. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude compound. The crude compound was then purified by silica gel column chromatography (eluent: EA:PE = 25%-40%) to yield compound 11-1. MS m / z (ESI): 312.1 [M+1].

[0562] Step 2: To a solution of compound 11-1 (2.34 g, 7.52 mmol) in acetonitrile (30 mL) was added N-bromosuccinimide (1.34 g, 7.52 mmol) at 25°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified on a silica gel column to obtain compound 11-2. 1H NMR (400MHz, CDCl3) δ7.19–7.04(m,2H),6.92–6.73(m,2H),5.36(s,2H),3.78(d,J=3.5Hz,3H),2.60(s,3H),2.54(q,J=2.3Hz,3H).

[0563] Step 3: To a solution of compound 11-2 (2.40 g, 6.15 mmol) and ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2.78 g, 12.3 mmol) in 1,4-dioxane (30 mL) and water (5 mL) at room temperature were added 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (0.62 g, 0.45 mmol) and potassium carbonate (2.55 g, 18.4 mmol). The mixture was heated to 90°C and stirred for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column (eluent: EA:PE = 10%-35%) to obtain compound 11-3. MS m / z (ESI): 410.1 [M+1].

[0564] Step 4: To a solution of compound 11-3 (2.00 g, 4.89 mmol) in ethanol (30 mL) was added palladium on carbon (200 mg, 10 ww%) at 25°C. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-4. MS m / z (ESI): 412.2 [M+1].

[0565] Step 5: To a solution of compound 11-4 (490 mg, 1.19 mmol) in THF (3 mL) and anhydrous methanol (3 mL) was added a solution of LiOH (85.6 mg, 3.57 mmol) and water (3 mL) at 25°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated and the pH was adjusted to 4-5 with saturated sodium bicarbonate solution. The mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound 11-5. MS m / z (ESI): 384.1 [M+1].

[0566] Step 6: To a solution of compound 11-5 (69 mg, 0.26 mmol) and intermediate 4 (60 mg, 0.26 mmol) in acetonitrile (2 mL) was added N-methylimidazole (99 mg, 0.77 mmol) and TCFH (117 mg, 0.31 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified on silica gel (eluent: EA:PE = 25%-60%) to afford compound 11-7. MS m / z (ESI): 606.4 [M+1].

[0567] Step 7: To a solution of compound 11-7 (70 mg, 0.12 mmol) in TFA (2 mL) was added TfOH (0.20 mL, 2.25 mmol) at room temperature, and the reaction mixture was stirred at 50°C for 3 hours. After completion of the reaction, the crude product was purified by preparative HPLC (column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: A: 0.1% formic acid / water, B: acetonitrile, gradient: 40-70% acetonitrile, flow rate: 25 mL / min) to afford compound 11. MS m / z (ESI): 486.2 [M+1]. 1 H NMR (400MHz, DMSO) δ12.00(s,1H),10.96(s,1H),9.35(s,2H),9.32(d,J=1.8Hz,1H),8.74(dd,J=8.8,2 .3Hz,1H),8.31(d,J=8.8Hz,1H),2.82–2.72(m,2H),2.61–2.53(m,2H),2.34–2.31(m,3H),2.30(s,3H).

[0568] Example 12

[0569] Step 1: Compound 12-0 (500 mg, 2.23 mmol) was dissolved in DMF (5 mL). Sodium hydroxide (107 mg, 4.46 mmol) was added at 0°C and the mixture was incubated for half an hour. 2-(Trimethylsilyl)ethoxymethyl chloride (371.8 mg, 2.23 mmol) was then added dropwise. The reaction system was slowly warmed to room temperature and allowed to react for 16 hours. The reaction solution was quenched by the slow dropwise addition of water (0.1 mL). Saturated ammonium chloride solution (10 mL) was then added. Extraction with EA (20 mL x 2) was performed. The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and purified by silica gel column chromatography using an eluent system (PE:EA = 1 / 1) to yield compound 12-1. MS m / z (ESI): 326.0 [M-27].

[0570] Step 2: Compound 12-1 (300 mg, 0.85 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium carbonate (352 mg, 2.55 mmol), dimethylbutyl 2-(ethoxycarbonyl)vinyl acetate (288 mg, 1.275 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (60 mg, 0.085 mmol), and water (0.5 mL) were added. The reaction system was heated to 90°C under nitrogen and allowed to react for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 1 / 1) to yield compound 12-2. MS m / z (ESI): 376.2 [M+1].

[0571] Step 3: Dissolve compound 12-2 (250 mg, 0.67 mmol) in methanol (10 mL) and add palladium / carbon (10%, 50 mg). The mixture reacts at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture is filtered through celite to remove the palladium / carbon and concentrated under reduced pressure to yield compound 12-3. MS m / z (ESI): 376.2 [M+1].

[0572] Step 4: Dissolve compound 12-3 (250 mg, 0.67 mmol) in ethanol (5 mL), add LiOH (64 mg, 2.68 mmol) and water (5 mL). React at room temperature for 16 hours. The reaction solution is concentrated under reduced pressure to remove methanol, and the pH is adjusted to 5 with 1M aqueous hydrochloric acid. Extract with EA (20 mL x 2). The organic phases are combined and dried over anhydrous sodium sulfate. The desiccant is filtered and the filtrate is concentrated under reduced pressure to obtain compound 12-4. MS m / z (ESI): 348.3 [M+1].

[0573] Step 5: Compound 12-4 (80 mg, 0.23 mmol) was dissolved in 1 mL of acetonitrile. N-methylimidazole (0.06 mL, 0.69 mmol) and TCFH (64 mg, 0.23 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 hours. 4-[5-(trifluoromethyl)pyrimidin-2-yl]aniline (55 mg, 0.23 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography using a 30 / 1 ratio of DCM to MeOH to afford compound 12-5. MS m / z (ESI): 569.4 [M+1].

[0574] Step 6: Compound 12-5 (35 mg, 0.06 mmol) was dissolved in 4 M 1,4-dioxane hydrochloride (1 mL) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 12. MS m / z (ESI): 439.1 [M+1]. 1 H NMR (400MHz, DMSO) δ11.13(s,1H),10.26(s,1H),9.28(s,2H),8.45–8.37(m,2H),8.28–8.21(m,1H),7.85– 7.74(m,4H),7.53(ddd,J=8.1,6.5,1.7Hz,1H),7.02(s,1H),3.02(t,J=7.5Hz,2H),2.70(t,J=7.5Hz,2H).

[0575] Example 13

[0576] Step 1: Dissolve compound 13-0 (5 g, 26.59 mmol) in acetonitrile (50 mL) and add N-iodosuccinimide (17.95 g, 79.78 mmol). Allow to react at room temperature for 18 hours. Pour the reaction mixture into water (50 mL) and add EA (50 mL). Filter the mixture, wash the filter cake with EA (20 mL), and dry the filter cake to obtain compound 13-1. MS m / z (ESI): 313.8 / 315.8 [M+1].

[0577] Step 2: Dissolve compound 13-1 (6.225 g, 19.83 mmol) and potassium carbonate (13.7 g, 99.15 mmol) in DMF (50 mL). Add 4-methoxybenzyl chloride (4.05 mL, 29.74 mmol) and react at 50°C for 18 hours. Pour the reaction solution into ice water (100 mL) and extract with EA (100 mL x 3). The combined organic phases are washed with brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to yield compound 13-2. MS m / z (ESI): 433.9 / 435.9 [M+1].

[0578] Step 3: Compound 13-2 (7.1 g, 16.39 mmol) and methyl fluorosulfonyldifluoroacetate (4.16 mL, 32.78 mmol) were dissolved in DMF (100 mL). Cuprous iodide (0.61 g, 3.28 mmol) was added and the mixture was reacted at 100°C for 18 hours. The reaction mixture was poured into ice water (200 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: PE:EtOAc = 2:1 to 1:1) to afford compound 13-3. MS m / z (ESI): 375.2 / 377.2 [M+1].

[0579] Step 4: Compound 13-3 (1.00 g, 2.66 mmol), dimethylbutyl 2-(ethoxycarbonyl)vinyl acetate (1.20 g, 5.32 mmol, Bis(R)), and potassium carbonate (1.10 g, 7.98 mmol) were added to a solution of 1,4-dioxane (10 mL) and water (1 mL). Bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (97.26 mg, 0.13 mmol) was added. The mixture was purged with nitrogen three times and reacted at 100°C for 18 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluent: PE:EA = 10:1 to 2:1) to afford compound 13-4. MS m / z (ESI): 396.2 [M+1].

[0580] Step 5: Dissolve compound 13-4 (715 mg, 1.81 mmol) in methanol (10 mL). Add palladium on carbon (75 mg, 10% wt). Displace the mixture with hydrogen three times. Allow to react at room temperature for 18 hours. After completion of the reaction, filter the reaction mixture and rinse with methanol (10 mL x 2). Concentrate the filtrate under reduced pressure to yield compound 13-5. MS m / z (ESI): 398.2.1 [M+1].

[0581] Step 6: Compound 13-5 (680 mg, 1.71 mmol) was dissolved in methanol (5 mL) and water (5 mL), and LiOH (123 mg, 5.13 mmol) was added. The mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was added with water (10 mL). The pH was adjusted to 6 with 1 M aqueous hydrochloric acid. The mixture was filtered, washed with water (5 mL), and the filter cake was dried to obtain compound 13-6. MS m / z (ESI): 370.2 [M+1].

[0582] Step 7: Compound 13-6 (123 mg, 0.33 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of TCFH (140 mg, 0.5 mmol) and N-methylimidazole (79.66 μL, 1 mmol). After stirring at room temperature for half an hour, intermediate 4 (80 mg, 0.33 mmol) was added. The reaction was allowed to proceed at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 2:1 to 1:1) to obtain compound 13-7.

[0583] Step 8: Compound 13-7 (160 mg, 0.27 mmol) was dissolved in TFA (5 mL), and TfOH (25 μL, 0.28 mmol) was added. The mixture was reacted at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 13. MS m / z (ESI): 472.1 [M+1]. 1 H NMR (400MHz, DMSO) δ11.98(s,1H),10.92(s,1H),9.34(s,2H),9.32(s,1H),8.73(d,J=9.8Hz ,1H),8.29(d,J=8.8Hz,1H),7.41(s,1H),2.84–2.72(m,2H),2.70–2.61(m,2H),2.32(s,3H).

[0584] Example 14

[0585] Step 1: Compound 20-1 (300 mg, 1.21 mmol) was dissolved in 5 mL of anhydrous 1,4-dioxane. Morpholine (0.21 mL, 2.41 mmol), cesium carbonate (1.18 g, 3.62 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (139 mg, 0.24 mmol), and tris(dibenzylideneacetone)dipalladium (97 mg, 0.12 mmol) were added sequentially. The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 2 / 1) to obtain compound 14-1. MS m / z (ESI): 300.1 [M+1].

[0586] Step 2: Dissolve compound 14-1 (200 mg, 0.67 mmol) in methanol (2 mL), add LiOH (64 mg, 2.6 mmol) and water (1 mL). Reaction was allowed to proceed at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 5 by adding 1M aqueous hydrochloric acid. Extraction was performed with EA (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield compound 14-2. MS m / z (ESI): 286.1 [M+1].

[0587] Step 3: Compound 14-2 (120 mg, 0.42 mmol) was dissolved in 2 mL of DMF. DIPEA (163 mg, 1.26 mmol) and HATU (240 mg, 0.63 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (166 mg, 0.42 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted with EA (5 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield compound 14-3. MS m / z (ESI): 662.3 [M+1].

[0588] Step 4: Compound 14-3 (100 mg) was dissolved in 4 M 1,4-dioxane hydrochloride solution (1 mL). The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 14. MS m / z (ESI): 532.2 [M+1]. 1 H NMR (400MHz, DMSO) δ12.44(s,1H),8.62(s,2H),8.53(t,J=5.7Hz,1H),8.33(d,J=8.2Hz,2H),7.96–7.82(m,3H),6.3 4(s,1H),3.99(s,1H),3.78(t,J=4.9Hz,4H),3.32–3.25(m,6H),1.55(d,J=6.4Hz,3H),1.18(dd,J=10.6,6.3Hz,3H).

[0589] Example 15

[0590] Step 1: Compound 15-0 (3.37 g, 13.89 mmol, Bis(R)) and compound 3-1 (5 g, 27.78 mmol) were dissolved in 12 mL of anhydrous THF. Potassium phosphate (8.85 g, 41.67 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.69 g, 0.40 mmol), and palladium acetate (0.16 mg, 0.40 mmol) were added sequentially. The reaction mixture was stirred at 60°C under nitrogen for 24 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 4 / 1) to obtain compound 15-2. MS m / z (ESI): 297.9 [M+H].

[0591] Step 2: Compound 15-2 (283 mg, 0.95 mmol) and morpholine (414 mg, 4.76 mmol) were dissolved in anhydrous 1,4-dioxane (15 mL). Cesium carbonate (642 mg, 1.97 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (61 mg, 0.10 mmol), and palladium acetate (11 mg, 0.05 mmol) were added sequentially. The mixture was stirred at 100°C under nitrogen for 12 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 5 / 1) to obtain compound 15-3. MS m / z (ESI): 305.0 [M+H].

[0592] Step 3: Compound 15-3 (64 mg, 0.21 mmol) was dissolved in a mixture of 2 mL of methanol and 1 mL of water. LiOH (18 mg, 0.42 mmol) was added and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (5 mL), the methanol was concentrated under reduced pressure, and 0.1 M hydrochloric acid was added dropwise to adjust the solution to pH <7. The solution was extracted with DCM / IPA (3 / 1) (3 mL x 2). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 15-4. MS m / z (ESI): 291.0 [M+H].

[0593] Step 4: Compound 15-4 (67 mg, 0.23 mmol) was dissolved in 3 mL of DMF, and DIPEA (0.11 mL, 0.69 mmol) and HATU (132 mg, 0.35 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (91 mg, 0.23 mmol) was added, and the reaction mixture was allowed to react at room temperature for 2 hours. 10 mL of water was added to the reaction mixture, and EA was extracted (6 mL × 2). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 4 / 1) to obtain compound 15-5. MS m / z (ESI): 667.2 [M+H + ].

[0594] Step 5: Compound 15-5 (70 mg, 0.10 mmol) was dissolved in 5 mL of DCM, and 1 mL of TFA was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 15. MS m / z (ESI): 537.2 [M+H]. 1 H NMR (400MHz, DMSO) δ12.44(s,1H),8.52(d,J=5.9Hz,1H),7.95–7.78(m,5H),7.19(s,1 H),6.34(s,1H),3.98(s,1H),3.75(dd,J=6.0,3.8Hz,4H),1.65(d,J=7.8Hz,0H),1.54 (s, 4H), 1.17 (dd, J = 12.5, 6.3Hz, 4H).

[0595] Example 16

[0596] Step 1: Compound 15-2 (265 mg, 0.89 mmol) and 3-fluoroazetidine hydrochloride (2000 mg, 11.11 mmol) were dissolved in 6 mL of anhydrous 1,4-dioxane. Cesium carbonate (869 mg, 2.67 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (103 mg, 0.18 mmol), and tris(dibenzylideneacetone)dipalladium (81 mg, 0.09 mmol) were added sequentially. The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) to obtain compound 16-1. MS m / z (ESI): 293.0 [M+H].

[0597] Step 2: Compound 16-1 (150 mg, 0.49 mmol) was dissolved in a mixture of 5 mL of methanol and 2.5 mL of water. LiOH (41 mg, 0.98 mmol) was added and stirred at 25°C for 16 hours. The reaction solution was diluted with water (10 mL), the methanol was concentrated under reduced pressure, and 0.1 M hydrochloric acid solution was added dropwise to adjust the solution to pH <7. The solution was extracted with DCM / isopropanol (3 / 1) (8 mL x 2). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16-2. MS m / z (ESI): 279.0 [M+H].

[0598] Step 3: Compound 16-2 (130 mg, 0.47 mmol) was dissolved in 4 mL of DMF. DIPEA (181 mg, 1.40 mmol) and HATU (266 mg, 0.70 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (203 mg, 0.51 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. 10 mL of water was added to the reaction mixture, and EA was extracted (5 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using an eluent system (PE / EA = 1 / 1) to obtain compound 16-3. MS m / z (ESI): 655.2 [M+H + ].

[0599] Step 4: Compound 16-3 (105 mg, 0.16 mmol) was dissolved in 2.5 mL of DCM, and 0.5 mL of TFA was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 16. MS m / z (ESI): 525.1 [M+H]. 1 H NMR (400MHz, DMSO) δ12.44(s,1H),8.52(t,J=5.4Hz,1H),7.94–7.78(m,5H),6.96(s,1H),6.33(s,1H),4.25(ddd,J=21 .0,9.4,5.7Hz,2H),4.05(dd,J=24.8,8.6Hz,2H),3.99–3.90(m,1H),3.27(s,2H),1.54(s,4H),1.17(t,J=6.4Hz,3H).

[0600] Example 17

[0601] Step 1: Compound 17-0 (230 mg, 0.99 mmol) and compound 3-1 (196 mg, 1.09 mmol) were dissolved in 10 mL of anhydrous THF. Potassium phosphate (631 mg, 2.97 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115 mg, 0.20 mmol), and palladium acetate (22 mg, 0.10 mmol) were added sequentially. The reaction mixture was stirred at 60°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 3 / 1) to obtain compound 17-2. MS m / z (ESI): 288.0 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.64 (q, J = 1.3 Hz, 1H), 8.23–8.09 (m, 4H), 3.90 (d, J = 1.8 Hz, 3H).

[0602] Step 2: Compound 17-2 (215 mg, 0.75 mmol) was dissolved in a mixture of 5 mL of methanol and 2.5 mL of water. LiOH (63 mg, 1.50 mmol) was added and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL), the methanol was concentrated under reduced pressure, and 0.1 M hydrochloric acid was added dropwise to adjust the solution to pH <7. The solution was extracted with DCM / isopropanol (3 / 1) (8 mL x 2). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 17-3. MS m / z (ESI): 274.0 [M+H].

[0603] Step 3: Compound 17-3 (150 mg, 0.55 mmol) was dissolved in 2.5 mL of DMF. DIPEA (213 mg, 1.65 mmol) and HATU (313 mg, 0.82 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 h. Intermediate 7 (217 mg, 0.55 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 h. 10 mL of water was added to the reaction mixture, and the mixture was extracted with EA (5 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield compound 17-4. MS m / z (ESI): 650.2 [M+H+].

[0604] Step 4: Compound 17-4 (346 mg, 0.53 mmol) was dissolved in 3 mL of 4 M 1,4-dioxane hydrochloride solution and stirred at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 17. MS m / z (ESI): 520.1 [M+H]. 1 H NMR (400MHz, DMSO) δ12.43 (s, 1H), 8.66 (s, 0H), 8.60 (d, J = 1.4Hz, 1H), 7.99 (d, J = 8. 4Hz, 1H), 7.93 (s, 1H), 3.98 (s, 1H), 3.29 (d, J = 6.0Hz, 0H), 1.55 (s, 3H), 1.16 (s, 3H).

[0605] Example 18

[0606] Step 1: Dissolve 3-ethynylpyridine (2.99 g, 29.02 mmol) in 50 mL of THF. Then, add butyl lithium (2.5 N, 11.96 mL, 29.89 mmol) dropwise at -78°C. Stir for 2 h. Then, add a 50 mL THF solution of compound 18-0 (4500 mg, 11.59 mmol) dropwise. Slowly warm to room temperature and stir for 2 h. The reaction mixture was concentrated with 10 mL of saturated ammonium chloride, extracted with EA, washed with saturated brine, and dried. The concentrated residue was purified by column chromatography (PE / EA = 1 / 1) to afford compound 18-1. MS m / z (ESI): 310.2 [M+1].

[0607] Step 2: Compound 18-1 (6200 mg, 20.0 mmol) and manganese dioxide (26.14 g, 300 mmol) were dissolved in chloroform (20 mL), stirred at room temperature for 2 hours, and the reaction solution was filtered and concentrated to obtain compound 18-2. MS m / z (ESI): 308.2 [M+1].

[0608] Step 3: To a solution of compound 18-2 (2500 mg, 8.13 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was added hydroxylaminesulfonic acid (965 mg, 9.76 mmol) at 0°C and allowed to react at room temperature for 36 hours. Subsequently, sodium bicarbonate (717 mg, 8.54 mmol) and sodium hydrosulfide (781 mg, 8.54 mmol) were added sequentially and allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, extracted with EA, washed with saturated brine, and dried. The concentrated residue was purified by column chromatography (PE / EA = 1 / 2) to afford compound 18-3. MS m / z (ESI): 339.2 [M+1].

[0609] Step 4: Compound 18-3 (1.0 g, 2.95 mmol) was dissolved in TFA-DCM (20%, 20 mL), reacted at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 18-4. MS m / z (ESI): 283.0 [M+1].

[0610] Step 5: Compound 18-4 (100 mg, 0.35 mmol), intermediate 7 (167 mg, 0.43 mmol), HATU (161 mg, 0.43 mmol), and DIPEA (915 mg, 7.08 mmol) were dissolved in 3 mL of DMF and reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using a solvent system (methanol / DCM = 1:20) to obtain compound 18-5. MS m / z (ESI): 659.2 [M+1].

[0611] Step 6: Compound 18-5 (130 mg, 0.2 mmol) was dissolved in 5 mL of 4 M hydrogen chloride-1,4-dioxane and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 2% to 32%, flow rate: 30 mL / min) to obtain compound 18. MS m / z (ESI): 529.0 [M+1]. 1 H NMR (400MHz, DMSO) δ12.46(s,1H),9.09(d,J=1.8Hz,1H),8.68(dd,J=4.8,1.5Hz,1H),8.64–8.56(m,2H),8.31–8.22(m,1H),8.18(d,J=8.4Hz,2H) ,8.06–7.88(m,3H),7.59(dd,J=7.9,4.8Hz,1H),6.37(d,J=4.6Hz,1H),4 .00(s,1H),3.32–3.23(m,2H),1.77–1.43(m,4H),1.19(d,J=6.3Hz,3H).

[0612] Example 19

[0613] Step 1: Compound 15-2 (300 mg, 1.01 mmol) and cyclopropylboronic acid (173 mg, 2.01 mmol) were dissolved in 6 mL of anhydrous 1,4-dioxane. Cesium carbonate (984 mg, 3.02 mmol) and 1,1-bis(diphenylphosphino)diboronium palladium chloride (74 mg, 0.10 mmol) were added. The reaction mixture was stirred at 90°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 5 / 1) to obtain compound 19-1. MS m / z (ESI): 260.0 [M+H].

[0614] Step 2: Compound 19-1 (102 mg, 0.39 mmol) was dissolved in a mixture of 5 mL of methanol and 2.5 mL of water. LiOH (33 mg, 0.78 mmol) was added and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL) and concentrated under reduced pressure. 0.1 M hydrochloric acid was added dropwise to adjust the pH to <7. The solution was extracted with DCM / isopropanol (3 / 1) (8 mL x 2). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 19-2. MS m / z (ESI): 246.0 [M+H].

[0615] Step 3: Compound 19-2 (97 mg, 0.40 mmol) was dissolved in 4 mL of DMF, and DIPEA (155 mg, 1.20 mmol) and HATU (228 mg, 0.60 mmol) were added in sequence. The reaction solution was reacted at room temperature for 0.5 hours. Intermediate 7 (156 mg, 0.40 mmol) was added, and the reaction solution was reacted at room temperature for 16 hours. 10 mL of water was added to the reaction solution, and EA was extracted (5 mL × 2). The organic phases were combined and washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain compound 19-3. MS m / z (ESI): 622.2 [M+H + ].

[0616] Step 4: Compound 19-3 (286 mg, 0.46 mmol) was dissolved in 5 mL of 4 M hydrochloric acid in 1,4-dioxane. The mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 19. MS m / z (ESI): 492.1 [M+H]. 1 H NMR(400MHz,MeOD)δ8.90(d,J=6.0Hz,3H),8.83(d,J=6.0Hz,2H),7.65(s,1H),4.00(m,1H),3.45(t ,J=6.4Hz,2H),2.20(m,1H),1.70(m,J=6.0Hz,4H),1.27(d,J=2.4Hz,3H),1.12(m,2H),0.70(m,2H).

[0617] Example 20

[0618] Step 1: Compound 20-0 (2.0 g, 13.43 mmol) was dissolved in 40 mL of 1,4-dioxane. Compound 3-1 (2.42 g, 13.43 mmol), potassium carbonate (5.57 g, 40.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.1 g, 1.34 mmol), and water (8 mL) were added sequentially. The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 10 / 1 -> 3 / 1) to obtain compound 20-1. MS m / z (ESI): 249.1 [M+1].

[0619] Step 2: Compound 20-1 (250 mg, 1.01 mmol) was dissolved in 5 mL of anhydrous 1,4-dioxane. 3-Fluoroazetidine hydrochloride (112 mg, 1.01 mmol), cesium carbonate (982 mg, 3.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (116 mg, 0.2 mmol), and tris(dibenzylideneacetone)dipalladium (81 mg, 0.1 mmol) were added sequentially. The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE:EA = 10 / 1 -> 2 / 1) to obtain compound 20-2. MS m / z (ESI): 288.1 [M+1].

[0620] Step 3: Dissolve compound 20-2 (200 mg, 0.7 mmol) in methanol (2 mL), add LiOH (67 mg, 2.8 mmol) and water (1 mL). React at room temperature for 16 hours. The reaction solution is concentrated under reduced pressure to remove methanol, and the pH is adjusted to 5 with 1M aqueous hydrochloric acid. Extract with EA (10 mL x 2). The organic phases are combined and dried over anhydrous sodium sulfate. The desiccant is filtered and the filtrate is concentrated under reduced pressure to obtain compound 20-3. MS m / z (ESI): 274.1 [M+1].

[0621] Step 4: Compound 20-3 (100 mg, 0.37 mmol) was dissolved in 2 mL of DMF. DIPEA (142 mg, 1.1 mmol) and HATU (208 mg, 0.55 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (144 mg, 0.37 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted with EA (5 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield compound 20-4. MS m / z (ESI): 650.3 [M+1].

[0622] Step 5: Compound 20-4 (100 mg) was dissolved in DCM (2 mL), and TFA (1 mL) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 20. MS m / z (ESI): 520.2 [M+1]. 1 H NMR (400MHz, DMSO) δ12.42(d,J=12.4Hz,1H),8.52(t,J=5.7Hz,1H),8.30(d,J=8.5Hz,2H),8.22(s,2H),7.96–7.84(m,3H),6.34(s,1H),5.7 0–5.26(m,1H),4.36(ddd,J=21.2,10.0,5.8Hz,2H),4.18–4.05(m,2H),3.99(s,1H),1.66(d,J=8.2Hz,1H),1.55(s,3H),1.20–1.13(m,3H).

[0623] Example 21

[0624] Step 1: Dissolve 3-fluoro-4-(methoxycarbonyl)benzoic acid (300 mg, 1.51 mmol) in thionyl chloride (5 mL) and react at 85°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 21-1. MS m / z (ESI): 213.0 [M-3].

[0625] Step 2: Compound 21-1 (325 mg, 1.50 mmol) was dissolved in DCM (5 mL). Glycine methyl ester hydrochloride (188 mg, 1.50 mmol) and triethylamine (0.62 mL, 4.5 mmol) were added at 0°C. The reaction was allowed to react for 2 hours at 0°C. Water (10 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield compound 21-2. MS m / z (ESI): 270.2 [M-3].

[0626] Step 3: Compound 21-2 (350 mg, 1.30 mmol) was dissolved in chloroform (10 mL), and phosphorus pentasulfide (578 mg, 2.60 mmol) and 4A molecular sieves (300 mg) were added. The reaction was allowed to proceed at 85°C for 16 hours. The molecular sieves were removed by filtration, and the filtrate was concentrated under reduced pressure. Compound 21-3 was purified by silica gel column chromatography using an eluent system (PE:EA = 10 / 1 -> 1 / 1) to obtain compound 21-3. MS m / z (ESI): 268.1 [M+1].

[0627] Step 4: Dissolve compound 21-3 (200 mg, 0.75 mmol) in methanol (5 mL), add LiOH (72 mg, 3.0 mmol) and water (5 mL). React at room temperature for 16 hours. The reaction solution is concentrated under reduced pressure to remove methanol, and the pH is adjusted to 5 by adding 1M aqueous hydrochloric acid. Extract with EA (10 mL x 2). The organic phases are combined and dried over anhydrous sodium sulfate. The desiccant is filtered and the filtrate is concentrated under reduced pressure to obtain compound 21-4. MS m / z (ESI): 254.0 [M+1].

[0628] Step 5: Compound 21-4 (75 mg, 0.30 mmol) was dissolved in 2 mL of DMF. DIPEA (116 mg, 0.90 mmol) and HATU (171 mg, 0.45 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (117 mg, 0.30 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. 10 mL of water was added to the reaction mixture, and EA was extracted twice (5 mL). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to yield compound 21-5 (150 mg). MS m / z (ESI): 630.2 [M+1].

[0629] Step 6: Compound 21-5 (150 mg) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (2 mL). The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 21. MS m / z (ESI): 500.1 [M+1]. 1H NMR (400MHz, DMSO) δ8.40(s,1H),7.93(s,1H),7.66(q,J=3.4Hz,3H),7.40(s,1H),6.35(s ,1H),3.99(s,4H),3.25(d,J=6.0Hz,2H),1.67(s,1H),1.53(s,3H),1.19(d,J=6.3Hz,3H).

[0630] Example 22

[0631] Step 1: Compound 22-0 (5 g, 25.18 mmol, Bid) was dissolved in 80 mL of anhydrous DCM. Triethylamine (10.5 mL, 75.53 mmol) was added. The reaction mixture was maintained at 0°C-10°C under nitrogen. Methyl glycine hydrochloride (3.36 g, 37.76 mmol) was dissolved in 10 mL of anhydrous DCM and added dropwise. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound 22-1. MS m / z (ESI): 252.0 [M+H].

[0632] Step 2: Compound 22-1 (2 g, 7.96 mmol) was dissolved in chloroform (18 mL), and phosphorus pentasulfide (3.54 g, 15.92 mmol) and 4A molecular sieves (4 g) were added. The reaction mixture was purged with nitrogen and stirred at 60°C under sealed conditions for 6 hours. After cooling to room temperature, the reaction mixture was filtered through celite, and the filter cake was rinsed with DCM (20 mL × 2). The mixture was concentrated under reduced pressure to obtain compound 22-2 (2.1 g). MS m / z (ESI): 250.0 [M+H].

[0633] Step 3: Compound 022-2 (150 mg, 0.60 mmol) was dissolved in a mixture of 5 mL of methanol and 2.5 mL of water. LiOH (51 mg, 1.2 mmol) was added and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (8 mL), the methanol was concentrated under reduced pressure, and 0.1 M hydrochloric acid was added dropwise to adjust the solution to a pH <7. The solution was extracted with DCM / isopropanol (3 / 1) (6 mL x 2). The organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 22-3. MS m / z (ESI): 236.0 [M+H].

[0634] Step 4: Compound 22-3 (73 mg, 0.31 mmol) was dissolved in 3 mL of DMF, and DIPEA (120 mg, 0.93 mmol) and HATU (132 mg, 0.47 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (122 mg, 0.31 mmol) was added, and the reaction mixture was allowed to react at room temperature for 3 hours. 10 mL of water was added to the reaction mixture, and EA was extracted (6 mL × 2). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) to obtain compound 22-4. MS m / z (ESI): 612.2 [M+H + ].

[0635] Step 5: Compound 22-4 (152 mg, 0.25 mmol) was dissolved in 5 mL of 4 M 1,4-dioxane hydrochloride solution and stirred at 45°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 22. MS m / z (ESI): 482.1 [M+H]. 1 H NMR (400MHz, DMSO) δ12.46 (s, 1H), 8.58 (t, J = 5.7Hz, 1H), 7.96–7.82 (m, 5H), 7.37 (s, 1H), 6.36 (d, J = 7. 9Hz, 1H), 3.98 (s, 3H), 3.26 (d, J = 6.7Hz, 2H), 1.65 (d, J = 8.2Hz, 0H), 1.54 (s, 3H), 1.18 (d, J = 6.3Hz, 3H).

[0636] Example 23

[0637] Step 1: Compound 29-1 (70 mg, 0.28 mmol) was dissolved in 3 mL of DMF. DIPEA (106 mg, 0.82 mmol) and HATU (156 mg, 0.41 mmol) were added sequentially, and the reaction mixture was allowed to react at room temperature for 0.5 hours. Intermediate 7 (108 mg, 0.28 mmol) was added, and the reaction mixture was allowed to react at room temperature for 2 hours. 10 mL of water was added to the reaction mixture, and EA was extracted (5 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography using a developing solvent system (DCM / methanol = 20 / 1) to obtain compound 23-1. MS m / z (ESI): 633.2 [M+H + ].

[0638] Step 2: Compound 23-1 (30 mg, 0.05 mmol) was dissolved in 2 mL of 4 M 1,4-dioxane hydrochloride solution and stirred at 45°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 23. MS m / z (ESI): 503.1 [M+H]. 1 H NMR (400MHz, DMSO) δ9.21(dd,J=2.2,0.8Hz,1H),8.98(t,J=6.1Hz,1H),8.55(dd,J=8.2,2.3Hz,1H),8.39(t,J=2.3Hz,1H),8.16(dd,J=8 .2,0.9Hz,1H),7.92(s,1H),7.53(t,J=54.4Hz,1H),6.33(dd,J=8.9,3.7Hz,1H),3.99(s,1H),1.71–1.49(m,5H),1.18(d,J=6.3Hz,4H).

[0639] Example 24

[0640] Step 1: Dissolve compound 4-2 (500 mg, 1.66 mmol), 2-bromo-5-methylthiazole (325 mg, 1.83 mmol), and PdCl2(PPh3)2 in 10 mL of 1,4-dioxane. Stir under nitrogen at 120°C for 24 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) to obtain compound 24-1. MS m / z (ESI): 236.0 [M+1].

[0641] Step 2: Dissolve compound 24-1 (770 mg, 3.27 mmol) in THF (3 mL), add methanol (3 mL), water (1 mL), and LiOH (391 mg, 16.36 mmol). Stir and react at room temperature for 3 hours. The reaction mixture is filtered and concentrated under reduced pressure to obtain compound 24-2. MS m / z (ESI): 222.0 [M+1].

[0642] Step 3: Compound 24-2 (50 mg, 0.23 mmol), compound intermediate 7 (89.16 mg, 0.23 mmol), HATU (85.94 mg, 0.23 mmol), and DIPEA (29.21 mg, 0.23 mmol) were dissolved in 1 mL of DMF. The mixture was reacted at room temperature for 12 hours. Water was added to the reaction solution and extracted with EA. The organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (DCM / methanol = 20 / 1) to obtain compound 24-3. MS m / z (ESI): 598.2 [M+1].

[0643] Step 4: Compound 24-3 (60 mg, 0.1 mmol) was dissolved in methanol (1 mL), and 3 mL of 4 M hydrochloric acid in 1,4-dioxane was added. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 24. MS m / z (ESI): 468.1 [M+1]. 1 H NMR (400MHz, DMSO) δ12.43(s,1H),9.27(d,J=1.4Hz,1H),9.16(d,J=1.4Hz,1H),9.07(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H) ,7.85(d,J=1.1Hz,1H),6.46–6.16(m,1H),3.99(s,1H),3.31(s,2H),2.56(s,3H),1.69–1.49(m,4H),1.17(d,J=6.3Hz,3H).

[0644] Example 25

[0645] Step 1: Intermediate 10 (50 mg, 0.19 mmol) and Intermediate 7 (84.36 mg, 0.21 mmol) were dissolved in DMF (1 mL). HATU (88.70 mg, 0.23 mmol) and DIPEA (0.13 mL, 0.78 mmol) were then added and allowed to react at room temperature for 12 hours. After completion, the reaction was diluted with 5 mL of water and extracted with 10 mL of EA. The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel plate using an eluent system (DCM / methanol = 20 / 1) to afford compound 25-1. MS m / z (ESI): 634.2 [M+1].

[0646] Step 2: Compound 25-1 (53 mg, 0.08 mmol) was dissolved in 0.5 mL of hydrochloric acid-1,4-dioxane solution and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 35%-50%, flow rate: 30 mL / min) to obtain compound 25. MS m / z (ESI): 504.2 [M+1]. 1 H NMR (400MHz, DMSO) δ12.44(s,1H),9.36(d,J=1.3Hz,1H),9.23(d,J=1.4Hz,1H),9.15(t,J=6.0Hz,1H),8.47(s,1H),7.93(s,1H),7. 56(dd,J=72.1,36.8Hz,1H),6.35(s,1H),3.98(d,J=9.7Hz,1H),3.32(s,2H),1.60(dt,J=23.6,12.4Hz,4H),1.18(t,J=7.1Hz,3H).

[0647] Example 26

[0648] Step 1: Intermediate 12 (45 mg, 0.16 mmol) and intermediate 7 (77 mg, 0.20 mmol), HATU (74 mg, 0.2 mmol), and DIPEA (445 mg, 3.27 mmol) were dissolved in 3 mL of DMF and reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using a 1 / 20 ratio of methanol to DCM to afford compound 26-1. MS m / z (ESI): 675.2 [M+1].

[0649] Step 2: Compound 26-1 (40 mg, 0.06 mmol) was dissolved in 5 mL of 4 M hydrogen chloride in 1,4-dioxane and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 2% to 32%, flow rate: 30 mL / min) to obtain compound 26. MS m / z (ESI): 522.2 [M+1]. 1 H NMR (400MHz, DMSO) δ12.43(s,1H),9.38(d,J=1.3Hz,1H),9.25(d,J=1.4Hz,1H),9.17(t,J=6.0Hz,1H),8.78(d,J=1. 0Hz, 1H), 7.92 (s, 1H), 6.35 (s, 1H), 3.99 (s, 1H), 3.32 (s, 3H), 1.60 (dt, J = 24.2, 12.6Hz, 4H), 1.17 (d, J = 6.3Hz, 3H).

[0650] Example 27

[0651] Step 1: At room temperature, intermediate 5 (0.05 g, 0.19 mmol) and compound 21-4 (0.047 g, 0.19 mmol) were dissolved in dimethylformamide (1 mL). HATU (0.105 g, 0.28 mmol) and DIPEA (0.09 mL, 0.56 mmol) were added to the reaction solution. The reaction was allowed to react at room temperature for 18 hours until the reaction was complete. After completion, water (3 mL) and EA (3 mL) were added to the reaction solution. The organic phase was washed with saturated brine (3 mL x 3), dried over 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 (eluent: anhydrous methanol:DCM = 45%-55%) to obtain compound 27-1. MS m / z (ESI): 513.1 [M+1].

[0652] Step 2: Compound 27-1 (40 mg, 0.08 mmol) was dissolved in NMP (1 mL) at room temperature, and iodotrimethylsilane (31 mg, 0.16 mmol) was added. The reaction was stirred at 85°C for 1 hour to complete. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: acetonitrile 27%-95%, flow rate: 20 mL / min) to give compound 27. MS m / z (ESI): 499.1 [M+1]. 1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.45–8.33(m,1H),7.68–7.63(m,3H),7.40(s,1H),7.31–7.19(m,1H),5.95–5.91 (m,1H),5.82–5.75(m,1H),3.99(s,3H),3.77–3.65(m,1H),3.26–3.21(m,2H),1.65–1.48(m,4H),1.15(d,J=6.2Hz,3H).

[0653] Example 28

[0654] Step 1: Compound 28-0 (15 g, 59.08 mmol, Bidler), potassium carbonate (12.25 g, 88.62 mmol), and 4-methoxybenzyl chloride (10.46 mL, 76.81 mmol, Titanium) were dissolved in acetonitrile (150 mL). The reaction was stirred at 80°C for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was slurried in 30 mL of methanol for 1 hour, filtered, and washed with methanol (10 mL x 2). The resulting solid was dried under nitrogen at room temperature to obtain compound 28-1. MS m / z (ESI): 374.9 [M+1]. 1 HNMR (400MHz, CDCl3) δ7.78 (s, 1H), 7.40 (d, J = 8.7Hz, 2H), 6.88–6.82 (m, 2H), 5.25 (s, 2H), 3.78 (s, 3H).

[0655] Step 2: Compound 28-1 (6 g, 16.04 mmol) was dissolved in methanol (60 mL) and potassium hydroxide (3.60 g, 64.17 mmol) was added. The reaction was carried out at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was slurried in 30 mL of water for 1 hour. The residue was filtered and washed with water (10 mL x 2). The resulting solid was dissolved in DCM (60 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield compound 28-2. MS m / z (ESI): 327.0 [M+1]. 1 H NMR (400MHz, CDCl3) δ7.70 (s, 1H), 7.40 (d, J = 8.6Hz, 2H), 6.84 (d, J = 8.6Hz, 2H), 5.29 (s, 2H), 4.03 (s, 3H), 3.78 (s, 3H).

[0656] Step 3: Compound 28-2 (2 g, 6.15 mmol), zinc cyanide (1.09 g, 9.29 mmol), and Pd(PPh3)4 (0.71 g, 0.62 mmol, Bid) were dissolved in DMF (15 mL). The reaction was carried out at 140 ° C for 5 hours under nitrogen atmosphere. The reaction solution was purified by reverse phase C18 column chromatography (Waters-2545, column: Santai C18 (SW-8201-040-IR), 40-63 μm, 55g; mobile phase: water (containing 10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 40mL / min) to obtain compound 28-3. MS m / z (ESI): 258.1 [M+1].

[0657] Step 4: Compound 28-3 (410 mg, 1.59 mmol) was dissolved in DMF (6 mL) and cooled to 0-5°C. Oxalyl chloride (273.35 μL, 3.19 mmol) was then added dropwise. The reaction mixture was allowed to react at 20°C for 6 hours. 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, and EA was used for extraction (15 mL x 3). The organic phases were combined and washed with semi-saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain compound 28-4. MS m / z (ESI): 298.0 [M+Na].

[0658] Step 5: Dissolve intermediate 2 (360 mg, 1.34 mmol) in acetonitrile (10 mL) and add triethylamine (742.75 μL, 5.36 mmol), followed by compound 28-4 (387.78 mg, 1.41 mmol). The mixture was reacted at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (PE:EA = 10 / 1 -> 1 / 2) to afford compound 28-5. MS m / z (ESI): 472.2 [M+1].

[0659] Step 6: Dissolve compound 28-5 (260 mg, 0.55 mmol) in ethanol (10 mL). Add hydrazine hydrate (552.07 mg, 11.03 mmol) and react at 20°C for 3 hours. After completion of the reaction, the reaction mixture was filtered and rinsed with acetonitrile (20 mL x 2). The filtrate was concentrated under reduced pressure to yield compound 28-6. MS m / z (ESI): 342.1 [M+1].

[0660] Step 7: Compound 29-1 (82.55 mg, 0.32 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of TCFH (180.80 mg, 0.64 mmol) and N-methylimidazole (128.42 μL, 1.61 mmol). After stirring at room temperature for 0.5 hour, compound 28-6 (110 mg, 0.32 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was added with 50 mL of water. The mixture was extracted with EA (15 mL x 3). The organic phases were combined and washed with half-saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (DCM:MeOH = DCM->10 / 1) to afford compound 28-7. MS m / z (ESI): 580.2 [M+1].

[0661] Step 8: Compound 28-7 (150 mg, 0.26 mmol) was dissolved in TFA (5 mL), and TfOH (45.96 μL, 0.52 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 28. MS m / z (ESI): 460.2 [M+1]. 1 H NMR (400MHz, DMSO) δ9.22(d,J=1.9Hz,1H),9.01(t,J=6.0Hz,1H),8.55(dd,J=8.2,2.2Hz,1H),8.40(d,J=2.2Hz,1H),8. 16(d,J=8.2Hz,1H),7.52(dd,J=66.2,42.6Hz,2H),4.06(s,1H),3.33–3.22(m,2H),1.60(s,4H),1.20(d,J=6.0Hz,3H).

[0662] Example 29

[0663] Step 1: Dissolve intermediate 9 (0.17 g, 0.63 mmol) in THF (1 mL), methanol (1 mL), and water (1 mL) at room temperature, then add sodium hydroxide (0.05 g, 1.25 mmol). Stir at room temperature for 2 hours and allow the reaction to complete. The reaction mixture was concentrated under reduced pressure, dissolved in water, and the pH was adjusted to 4-5 with 1 M aqueous hydrochloric acid. The precipitated solid was filtered, and the filter cake was dried under reduced pressure to yield compound 29-1. MS m / z (ESI): 258.0 [M+1].

[0664] Step 2: Compound 29-1 (0.025 g, 0.10 mmol) and intermediate 5 (0.040 g, 0.15 mmol) were dissolved in dimethylformamide (1 mL) at room temperature. HATU (0.054 g, 0.15 mmol) and DIPEA (0.05 mL, 0.29 mmol) were added to the reaction mixture and allowed to react at room temperature for 18 hours until the reaction was complete. After completion, 3 mL of water and 3 mL of EA were added to the reaction mixture. The organic phase was washed with saturated brine (3 mL x 3), dried over 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 (eluent: EA:PE = 45%-55%) to obtain compound 29-2. MS m / z (ESI): 516.0 [M+1].

[0665] Step 3: Compound 29-2 (0.025 g, 0.05 mmol) was dissolved in NMP (1 mL) at room temperature, and iodotrimethylsilane (0.009 g, 0.05 mmol) was added. The reaction was stirred at 85°C for 1 hour to complete. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: acetonitrile 35%-95%, flow rate: 20 mL / min) to give compound 29. MS m / z (ESI): 502.0 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.22(d,J=1.6Hz,1H),9.00(t,J=6.0Hz ,1H),8.55(dd,J=8.2,2.2Hz,1H),8.39(s,1H),8.16(d,J=8.2Hz,1H),7.53(t, J=54.4Hz,1H),7.28–7.19(m,1H),5.92(d,J=7.8Hz,1H),5.83–5.75(m,1H),3 .81–3.62(m,1H),3.32–3.28(m,2H),1.70–1.41(m,4H),1.14(d,J=6.2Hz,3H).

[0666] Example 30

[0667] Step 1: Intermediate 5 (0.125 g, 0.45 mmol) and compound 24-2 (0.1 g, 0.45 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature. HATU (0.257 g, 0.68 mmol) and DIPEA (0.22 mL, 1.36 mmol) were added to the reaction mixture and allowed to react at room temperature for 18 hours until the reaction was complete. After completion, 3 mL of water and 3 mL of EA were added to the reaction mixture. The organic phase was washed with saturated brine (3 mL x 3), dried over 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 (eluent: EA:PE = 25%-33%) to obtain compound 30-1. MS m / z (ESI): 482.1 [M+1].

[0668] Step 2: Compound 30-1 (0.024 g, 0.05 mmol) was dissolved in NMP (1 mL) at room temperature, and iodotrimethylsilane (0.02 g, 0.10 mmol) was added. The reaction was stirred at 85°C for 1 hour to complete. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: acetonitrile 30%-95%, flow rate: 20 mL / min) to give compound 30. MS m / z (ESI): 467.2 [M+1]. 1 H NMR(400MHz,DMSO d6)δ10.91–10.80(m,1H),9.33–9.23(m,1H),9.19–9.13(m,1H),9.11–9.03(m,1H),7.85(d,1H),7. 26–7.21(m,1H),5.98–5.75(m,2H),3.29–3.14(m,3H),2.57(s,3H),1.59(s,4H),1.20–1.11(m,3H).

[0669] Example 31

[0670] Step 1: At room temperature, Intermediate 5 (0.04 g, 0.14 mmol) and Intermediate 12 (0.047 g, 0.17 mmol) were dissolved in DMF (1 mL). HATU (0.082 g, 0.22 mmol) and DIPEA (0.07 mL, 0.43 mmol) were added to the reaction solution. The reaction was allowed to react at room temperature for 18 hours until completion. After completion, 3 mL of water and 3 mL of EA were added to the reaction solution. The organic phase was washed with saturated brine (3 mL x 3), dried over 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 (eluent: EA:PE = 30%-35%) to obtain compound 31-1. MS m / z (ESI): 535.2 [M+1].

[0671] Step 2: Compound 31-1 (0.03 g, 0.06 mmol) was dissolved in NMP (1 mL) at room temperature, and iodotrimethylsilane (0.023 g, 0.11 mmol) was added. The reaction was stirred at 85°C for 1 hour to complete. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: acetonitrile 43%-95%, flow rate: 20 mL / min) to obtain compound 31. MS m / z (ESI): 521.1 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),9.38(d,J=1.4Hz,1H),9.25(d,J=1.4Hz,1H),9.13–9.08(m,1H),8.76(s,1H),7.26–7.19( m,1H),5.92(d,J=7.6Hz,1H),5.79–5.70(m,1H),3.78–3.65(m,1H),3.36–3.31(m,2H),1.64–1.50(m,4H),1.15(d,J=6.2Hz,3H).

[0672] Example 32

[0673] Step 1: At room temperature, Intermediate 5 (0.036 g, 0.14 mmol) and Intermediate 10 (0.040 g, 0.14 mmol) were dissolved in DMF (1 mL). HATU (0.082 g, 0.22 mmol) and DIPEA (0.056 g, 0.43 mmol) were added to the reaction solution. The reaction was allowed to react at room temperature for 18 hours until the reaction was complete. After completion, 3 mL of water and 3 mL of EA were added to the reaction solution. The organic phase was washed with saturated brine (3 mL x 3), dried over 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 (eluent: EA:PE = 25%-33%) to obtain compound 32-1. MS m / z (ESI): 513.1 [M+1].

[0674] Step 2: Compound 32-1 (0.07 g, 0.08 mmol) was dissolved in NMP (1 mL) at room temperature, and iodotrimethylsilane (0.031 g, 0.16 mmol) was added. The reaction was stirred at 85°C for 1 hour to complete. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: acetonitrile 30%-95%, flow rate: 20 mL / min) to give compound 32. MS m / z (ESI): 503.1 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.36(d,J=1.4Hz,1H),9.24(d,J=1.4Hz,1H),9.13(t,J=5.8Hz,1H),8.47(t,J=2.0Hz,1H),7.53(t,J=54.4Hz, 1H),7.24(d,J=6.8Hz,1H),5.92(d,J=7.8Hz,1H),5.83–5.75(m,1H),3.78 –3.66(m,1H),3.32–3.28(m,2H),1.62–1.49(m,4H),1.14(d,J=6.2Hz,3H).

[0675] Example 33

[0676] Step 1: Compound 1-3 (300 mg, 1 mmol) was added to N,N-dimethylformamide (3 mL). HATU (455.60 mg, 1.2 mmol) and DIPEA (387.2 mg, 1.2 mmol) were added sequentially. After stirring at room temperature for half an hour, compound 33-1 (216 mg, 1 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with EA (5 mL x 3). The organic phases were combined and washed with semi-saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE:EA = 2:1 to 1:1) to obtain compound 33-2. MS m / z (ESI): 397.1 [M-100+H].

[0677] Step 2: Compound 33-2 (380 mg, 0.77 mmol) was dissolved in 4 M hydrochloric acid EA (3 mL, 12 mmol) solution, reacted at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain compound 33-3.

[0678] Step 3: Compound 33-3 (200 mg, 0.50 mmol) and compound 35-2 (85.0 mg, 0.50 mmol) were added to isopropanol (3 mL), followed by DIPEA (0.25 mL, 1.5 mmol). The mixture was reacted at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (DCM:anhydrous methanol = 100:1 to 20:1) to obtain compound 33-5. MS m / z (ESI): 529.4 [M+1].

[0679] Step 4: Compound 33-5 (106 mg, 0.2 mmol) was dissolved in DCM (2 mL), the atmosphere was replaced with nitrogen three times, and the temperature was cooled to -78°C. Boron tribromide (56.88 μL, 0.6 mmol) was added dropwise. After complete addition, the mixture was allowed to react at room temperature for 1 hour. The temperature was then cooled to -78°C, and 1 mL of methanol was added dropwise. The mixture was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to afford compound 33. MS m / z (ESI): 515.2 [M+1]. 1H NMR (400MHz, DMSO) δ10.67–9.68(m,2H),9.29(s,2H),8.03(d,J=1.4Hz,1H),7.94(dd,J=7.8,1.5Hz,1H),7.27(d,J=7.Hz,1H),6 .43–6.23(m,1H),5.73(s,1H),3.92–3.65(m,1H),3.56–3.20(m,2H),2.89(s,3H),2.08(s,3H),1.81–1.31(m,4H),1.16(s,3H).

[0680] Example 34

[0681] Step 1: To a solution of compound 4-4 (175 mg, 0.65 mmol) and compound 33-1 (140 mg, 0.65 mmol) in DMF (4 mL) at room temperature, DIPEA (251 mg, 1.94 mmol) and HATU (195 mg, 0.78 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with EA (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography (eluent: EA:PE = 25%-50%) to obtain compound 34-1. MS m / z (ESI): 369.1 [M+1-100].

[0682] Step 2: To a solution of compound 34-1 (200 mg, 0.43 mmol) in 1,4-dioxane (2 mL) was added a solution of hydrochloric acid (2 mL, 8.0 mmol) in 1,4-dioxane at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield compound 34-2. MS m / z (ESI): 369.1 [M+1].

[0683] Step 3: To a solution of compound 35-2 (28 mg, 0.16 mmol) and compound 34-2 (60 mg, 0.16 mmol) in isopropanol (1 mL) at room temperature was added DIPEA (63 mg, 0.49 mmol). The mixture was heated to 80°C and stirred for 18 h. After completion of the reaction, the crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water, B: acetonitrile, gradient: acetonitrile 21-95%, flow rate: 25 mL / min) to give compound 34. MS m / z (ESI): 501.2 [M+1]. 1H NMR (400MHz, DMSO) δ11.26–10.73(m,1H),9.65–9.45(m,3H),9.03(dd,J=7.2,1.4Hz,1H),6.94–6.38(m,1H),5.99–5.56(m,1H),3.5 9–3.47(m,1H),3.33–3.22(m,2H),3.01(d,J=24.8Hz,3H),2.07(d,J=21.2Hz,3H),1.78–1.29(m,4H),1.14(dd,J=38.4,6.3Hz,3H).

[0684] Example 35

[0685] Step 1: To a solution of malononitrile (3.78 mL, 59.47 mmol, Bid) in THF (5 mL) at 0°C, sodium hydride (3.09 g, 77.32 mmol, 60% purity) was added and stirred for 1 hour. Compound 35-0 (5.0 g, 59.47 mmol, Bid) was then added to the reaction mixture and the reaction continued at room temperature for 2 hours. After 2 hours of reaction, the mixture was adjusted to a pH of 5-6 with 4N hydrochloric acid (50 mL, 200 mmol), then concentrated under reduced pressure to remove the THF, and additional 4N hydrochloric acid (50 mL, 200 mmol) was added. The mixture was heated to 100°C and stirred overnight. After the reaction was complete, the mixture was cooled and allowed to stand, then filtered, and the filter cake was dried under vacuum to yield compound 35-1. MS m / z (ESI): 151.1 [M+1]. 1 H NMR (400MHz, DMSO) δ12.38(s,1H),11.70(s,1H),5.82(s,1H),2.17(s,3H).

[0686] Step 2: To a solution of compound 35-1 (2.55 g, 12.7 mmol) in chloroform (30 mL) at 0°C, phosphorus oxychloride (3.91 g, 25.5 mmol) and phosphorus pentachloride (5.30 g, 25.5 mmol) were added. The reaction mixture was heated to 75°C and stirred for 18 hours. After completion of the reaction, the mixture was poured into water (100 mL) and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was slurried with a mixture of DCM / methanol to obtain compound 35-2. MS m / z (ESI): 169.0 [M+1]. 1H NMR (400MHz, DMSO) δ12.94(s,1H),6.53(s,1H),2.29(s,3H).

[0687] Step 3: To a solution of intermediate 2 (232 mg, 1.00 mmol) and compound 35-2 (168 mg, 1.00 mmol) in isopropanol (3 mL) was added DIPEA (0.83 mL, 4.98 mmol) at room temperature. The mixture was heated to 80°C and stirred for 18 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column (eluent: EA:PE = 25%-75%) to obtain compound 35-3. MS m / z (ESI): 365.1 [M+1].

[0688] Step 4: To a solution of compound 35-3 (200 mg, 0.33 mmol) in ethanol (3 mL) at 25°C, add hydrazine hydrate (165 mg, 3.25 mmol) and stir overnight at room temperature. After the reaction is complete, concentrate under reduced pressure to obtain the crude product. The crude product is slurried in acetonitrile (6 mL) to obtain compound 35-4. MS m / z (ESI): 235.1 [M+1].

[0689] Step 5: To a solution of compound 4-4 (69 mg, 0.26 mmol) and compound 35-4 (60 mg, 0.26 mmol) in DMF (2 mL) were added DIPEA (99 mg, 0.77 mmol) and HATU (117 mg, 0.31 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the crude product was purified by preparative HPLC (column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: A: 0.1% formic acid / water, B: acetonitrile, gradient: acetonitrile 0-32%, flow rate: 25 mL / min) to afford compound 35. MS m / z (ESI): 487.2 [M+1]. 1 H NMR (400MHz, DMSO) δ11.13–10.83(m,1H),9.61(d,J=1.4Hz,1H),9.54(s,2H),9.37(d,J=1.4Hz,1H),9.19(t,J=5.8Hz,1H),6.7 3–6.44(m,1H),6.02–5.60(m,1H),3.90–3.61(m,1H),3.39–3.33(m,2H),2.08(s,3H),1.73–1.44(m,4H),1.15(d,J=6.4Hz,3H).

[0690] Example 36

[0691] Step 1: Dissolve compound 4-1 (500 mg, 2.90 mmol), morpholine (252.42 mg, 2.90 mmol), and DIPEA in 3 mL of 1,4-dioxane and stir at 60°C for 3 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (DCM / methanol = 50 / 1) to obtain compound 36-1. MS m / z (ESI): 224.1 [M+1].

[0692] Step 2: Dissolve compound 36-1 (900 mg, 4.03 mmol) in methanol (4 mL) and water (2 mL), add LiOH (338 mg, 8.06 mmol), and stir at room temperature for 2 hours. The reaction mixture is filtered and concentrated under reduced pressure to obtain compound 36-2. MS m / z (ESI): 210.0 [M+1].

[0693] Step 3: Compound 36-2 (500 mg, 2.39 mmol) was dissolved in DMF (15 mL), followed by the addition of TCFH (1005.86 mg, 3.58 mmol) and N-methylimidazole (762.09 μL, 9.56 mmol). The mixture was reacted at 20°C for 30 minutes, followed by the addition of Intermediate 6 (155.10 mg, 0.72 mmol). The reaction was continued at 20°C for 16 hours. 80 mL of water was added to the reaction solution, and the mixture was extracted with EA (15 mL x 3). The organic phases were combined and washed with semi-saturated brine. The organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a solvent system (DCM:MeOH = 30 / 1) to afford compound 36-3. MS m / z (ESI): 408.2 [M+1].

[0694] Step 4: Compound 36-3 (230 mg, 0.56 mmol) was dissolved in 4M hydrochloric acid in 1,4-dioxane (10 mL), reacted at 20°C for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 36-4. MS m / z (ESI): 308.2 [M+1].

[0695] Step 5: Compound 36-4 (200 mg, 0.65 mmol) was dissolved in acetonitrile (12 mL). Triethylamine (0.45 mL, 3.25 mmol) and intermediate 1 (207.34 mg, 0.65 mmol) were added, and the mixture was reacted at 85°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (DCM:MeOH = 100 / 1 -> 10 / 1) to obtain compound 36-5. MS m / z (ESI): 590.3 [M+1].

[0696] Step 6: Compound 36-5 (380 mg, 0.23 mmol) was dissolved in TFA (10 mL), and TfOH (0.5 mL, 5.63 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 36. MS m / z (ESI): 470.2 [M+1]. 1 H NMR (400MHz, DMSO) δ12.44(s,1H),8.34(s,1H),8.24(s,0H),8.14(s,0H),7.88(d,J=37.4Hz,1H),6.31(d,J=31.8Hz,1H),3 .71(t,J=4.8Hz,4H),3.60(s,4H),3.44(s,2H),3.28(s,1H),2.98(d,J=37.7Hz,3H),1.73–1.28(m,4H),1.21–1.11(m,3H).

[0697] Example 37

[0698] Step 1: Dissolve 4-1 (683 mg, 3.96 mmol) in 1,4-dioxane (10 mL). Under nitrogen, add 1-cyclopropylpiperazine (500 mg, 3.96 mmol) and DIPEA (1.97 mL, 11.89 mmol). The mixture is stirred at 100°C for 16 hours. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography using a 10 / 1 ratio of DCM to MeOH to afford compound 37-1. MS m / z (ESI): 263.1 [M+1]. 1 H NMR(400MHz,DMSO)δ8.65(d,J=1.0Hz,1H),8.37(d,J=1.0Hz,1H),3.81(s,3H),3.74–3.6 4(m,4H),2.67–2.57(m,4H),1.72–1.61(m,1H),0.48–0.41(m,2H),0.37(d,J=3.2Hz,2H).

[0699] Step 2: Dissolve compound 37-1 (800 mg, 3.05 mmol) in methanol (8 mL) and water (4 mL), add LiOH (73 mg, 3.05 mmol), and stir at room temperature for 16 hours. The reaction mixture is filtered and concentrated under reduced pressure to obtain compound 37-2. MS m / z (ESI): 249.1 [M+1]. 1 H NMR (400MHz, DMSO) δ12.88(s,1H),8.70(d,J=1.0Hz,1H),8.47(s,1H),4.63(d,J=12 .7Hz, 2H), 3.57 (t, J = 12.5Hz, 6H), 2.84 (s, 1H), 1.22 (s, 2H), 0.80 (d, J = 6.0Hz, 2H).

[0700] Step 3: Compound 37-2 (344.34 mg, 1.39 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of TCFH (648.53 mg, 2.31 mmol) and N-methylimidazole (474.47 mg, 5.78 mmol). The mixture was reacted at 20°C for 0.5 h. Intermediate 6 (250 mg, 1.16 mmol) was then added and the mixture was allowed to react at 20°C for 16 h. 5 mL of water was added to the reaction solution, and the mixture was extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a developing solvent system (DCM:MeOH = 10 / 1) to afford compound 37-3. MS m / z (ESI): 447.4 [M+1].

[0701] Step 4: Dissolve compound 37-3 (310 mg, 0.69 mmol) in 5 mL of 4M HCl in 1,4-dioxane. Incubate at 20°C for 2 hours. Concentrate the reaction mixture under reduced pressure to obtain compound 37-4. MS m / z (ESI): 347.2 [M+1].

[0702] Step 5: Compound 37-4 (220 mg, 0.63 mmol) was dissolved in acetonitrile (5 mL), and intermediate 1 (222.58 mg, 0.70 mmol) and triethylamine (0.09 mL, 3.15 mmol) were added. The mixture was reacted at 85°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the remaining solution was added with water (10 mL). The mixture was extracted with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (DCM:MeOH = 20 / 1) to obtain compound 37-5. MS m / z (ESI): 629.4 [M+1].

[0703] Step 6: Compound 37-5 (200 mg, 0.32 mmol) was dissolved in TFA (2 mL), and methanesulfonic acid (0.2 mL) was added. The reaction mixture was reacted at 20°C for 1 hour. Methanol (10 mL) was added to the reaction solution, which was concentrated under reduced pressure. EA (20 mL) was added to the remaining solution, and the solution was neutralized with saturated sodium bicarbonate solution to pH 8. The aqueous phase was extracted with EA (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative purification to yield compound 37. MS m / z (ESI): 509.3 [M+1]. 1 H NMR (400MHz, DMSO) δ12.44(s,1H),8.32(s,1H),8.19(d,J=4.0Hz,1H),7.89(t,J=4.0Hz,1H),6.35–6.28(m,1H),3.99–3.81(m, 1H), 3.59(s,4H), 3.44(s,2H), 3.04–2.93(m,3H), 2.64–2.61(m,4H), 1.67–1.60(m,5H), 1.18–1.15(m,3H), 0.46–0.37(m,4H).

[0704] Example 38

[0705] Step 1: To a 50 mL single-necked flask at room temperature, compound 6-2 (0.5 g, 2.74 mmol), compound 38-1 (0.345 g, 2.74 mmol), and DIPEA (0.708 g, 5.48 mmol) were added, followed by N,N-dimethylformamide (7.0 mL). The temperature was raised to 50°C under nitrogen and the reaction was allowed to proceed for 4 hours. After completion of the reaction, 10 mL of water and 10 mL of EA were added to the reaction solution. The organic phase was washed with saturated brine (15 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: PE:EA = 15%-20%) to afford compound 38-2. MS m / z (ESI): 273.0 [M+1].

[0706] Step 2: At room temperature, compound 38-2 (0.46 g, 1.69 mmol) and iodotrimethylsilane (6.0 mL) were added to a 25 mL single-necked flask. The temperature was raised to 90°C and the reaction was allowed to proceed for 4 hours. After completion, 10 mL of water and 10 mL of EA were added to the reaction solution. The organic phase was washed with saturated brine (15 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound 38-3. MS m / z (ESI): 259.0 [M+1].

[0707] Step 3: Compound 38-3 (0.13 g, 0.51 mmol) and intermediate 7 (0.2 g, 0.51 mmol) were dissolved in DMF (2 mL) at room temperature. HATU (0.29 g, 0.76 mmol) and DIPEA (0.25 mL, 1.52 mmol) were added to the reaction mixture and allowed to react at room temperature for 18 hours until the reaction was complete. After completion, 3 mL of water and 3 mL of EA were added to the reaction mixture. The organic phase was washed with saturated brine (3 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: EA:PE = 15%-20%) to afford compound 38-4. MS m / z (ESI): 633.2 [M-1].

[0708] Step 4: Compound 38-4 (0.23 g, 0.36 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (3 mL) at room temperature and stirred for 2 hours. The reaction was completed. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: acetonitrile 20%-95%, flow rate: 20 mL / min) to yield compound 38. MS m / z (ESI): 505.1 [M+1]. 1 HNMR(400MHz,DMSO-d6)δ12.43(s,1H),9.37(s,2H),9.23(s,1H),8.49–8.42(m,1H),8.23(s,1H),7.93(s,1H), 6.38–6.30(m,1H),4.06–3.92(m,1H),3.27–3.19(m,2H),1.72–1.63(m,1H),1.53(s,3H),1.19(d,J=6.4Hz,3H).

[0709] Example 39

[0710] Step 1: Dissolve compound 39-0 (2.086 g, 6.62 mmol) and compound 39-1 (1.0 g, 6.62 mmol) in THF (15 mL) at room temperature. Add triethylamine (4.6 mL, 33.1 mmol) to the reaction mixture and allow to react at room temperature for 18 hours until the reaction is complete. After completion, the reaction is concentrated under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column (eluent: EA:PE = 5%-10%) to obtain compound 39-2. 1H NMR (400MHz, DMSO-d6) δ6.93(s,1H),4.41–4.29(m,2H),1.55–1.17(m,21H),0.87–0.81(m,9H).

[0711] Step 2: Compound 39-2 (0.708 g, 1.65 mmol) and compound 6-2 (0.3 g, 1.65 mmol) were dissolved in toluene (10 mL) at room temperature. Pd(PPh3)4 (0.19 g, 0.165 mmol) was added and stirred at 120°C for 18 hours to complete the reaction. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (eluent: EA:PE = 16%-20%) to obtain compound 39-4. MS m / z (ESI): 288.1 [M+1].

[0712] Step 3: Compound 39-4 (0.1 g, 0.17 mmol) was dissolved in THF (1 mL), methanol (1 mL), and water (1 mL) at room temperature. LiOH (0.013 g, 0.52 mmol) was added to the reaction mixture and allowed to react at room temperature for 2 hours until the reaction was complete. After completion, the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in water, the pH was adjusted to 4-5 with 1 M hydrochloric acid solution, and the filter cake was filtered and dried under reduced pressure to obtain compound 39-5. MS m / z (ESI): 260.0 [M+1].

[0713] Step 4: At room temperature, intermediate 3 (0.1 g, 0.26 mmol) and compound 39-5 (0.067 g, 0.26 mmol) were dissolved in N,N-dimethylformamide (1 mL). HATU (0.148 g, 0.39 mmol) and DIPEA (0.135 mL, 0.78 mmol) were added to the reaction solution. The reaction was allowed to react at room temperature for 18 hours until completion. After completion, 3 mL of water and 3 mL of EA were added to the reaction solution. The organic phase was washed with saturated brine (3 mL x 3), dried over 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 (eluent: EA:PE = 25%-33%) to obtain compound 39-6. MS m / z (ESI): 626.2 [M+1].

[0714] Step 5: Compound 39-6 (0.080 g, 0.13 mmol) was dissolved in TFA (1 mL) at room temperature, followed by the addition of TfOH (0.2 mL). The reaction was stirred at 50°C for 1 hour to complete. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: acetonitrile 30%-95%, flow rate: 20 mL / min) to afford compound 39. MS m / z (ESI): 506.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ12.41(s,1H),9.49(s,2H),9.07–8.98(m,1H),7.94(s,1H),7.62(s,1H),6 .42–6.31(m,1H),4.05–3.92(m,1H),3.32–3.23(m,2H),1.71–1.50(m,4H),1.18(d,J=6.2Hz,3H).

[0715] Example 40

[0716] Step 1: Compound 22-0 (2 g, 10.07 mmol, Bid) was dissolved in 10 mL of anhydrous DCM. Triethylamine (4.19 mL, 30.21 mmol) was added. The reaction mixture was maintained at 0°C-10°C under nitrogen. 2-Amino EA hydrochloride (1.56 g, 15.11 mmol) was dissolved in 5 mL of anhydrous DCM and added dropwise. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound 40-1. MS m / z (ESI): 266.1 [M+H].

[0717] Step 2: Compound 40-1 (900 mg, 3.58 mmol) was dissolved in chloroform (10 mL). Phosphorus pentasulfide (1.59 g, 7.16 mmol) and 4A molecular sieves (1.8 g) were added. The reaction mixture was purged with nitrogen and stirred at 60°C under sealed conditions for 6 hours. After cooling to room temperature, the reaction mixture was filtered through celite. The filter cake was rinsed with DCM (15 mL x 2) and concentrated under reduced pressure to obtain compound 40-2. MS m / z (ESI): 264.0 [M+H].

[0718] Step 3: Compound 40-2 (200 mg, 0.76 mmol) was dissolved in a mixture of 5 mL of methanol and 2.5 mL of water. LiOH (64 mg, 1.52 mmol) was added and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (8 mL), the methanol was concentrated under reduced pressure, and 0.1 M hydrochloric acid was added dropwise to adjust the solution to pH <7. The solution was extracted with DCM / isopropanol (3 / 1) (6 mL x 2). The organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 40-3. MS m / z (ESI): 250.0 [M+H].

[0719] Step 4: Compound 40-3 (82 mg, 0.33 mmol) was dissolved in 3 mL of DMF, and DIPEA (128 mg, 0.99 mmol) and HATU (188 mg, 0.49 mmol) were added in sequence. The reaction solution was reacted at room temperature for 0.5 hours. Intermediate 7 (130 mg, 0.33 mmol) was added, and the reaction solution was reacted at room temperature for 3 hours. 10 mL of water was added to the reaction solution, and EA was extracted (6 mL × 2). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain compound 40-4. MS m / z (ESI): 626.2 [M+H + ].

[0720] Step 5: Compound 40-4 (244 mg, 0.39 mmol) was dissolved in 5 mL of 4 M hydrochloric acid in 1,4-dioxane. The mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L TFA) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain compound 40. MS m / z (ESI): 496.1 [M+H]. 1 H NMR (400MHz, DMSO) δ12.45(s,1H),8.57(t,J=5.4Hz,1H),7.98–7.81(m,5H),7.36(s,1H),6.36(d,J=5.5Hz,1H),4.22(q,J=7. 0Hz, 2H), 3.98 (s, 1H), 3.27 (d, J = 5.2Hz, 2H), 1.65 (d, J = 7.9Hz, 1H), 1.54 (s, 3H), 1.38 (t, J = 7.0Hz, 3H), 1.18 (d, J = 6.3Hz, 3H).

[0721] Example 41

[0722] Step 1: Compound 42-1 (230 mg, 0.89 mmol) and 10% Pd / C (123 mg, 1.16 mmol) were added to MeOH (2 mL). Under hydrogen protection, the mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was filtered through Celite, rinsed with methanol (10 mL x 1), and the filtrate was concentrated under reduced pressure to obtain compound 41-0. MS m / z (ESI): 262.0 [M+1].

[0723] Step 2: Compound 41-1 (200 mg, 0.78 mmol) and LiOH (73.86 mg, 1.76 mmol) were added to a mixture of MeOH (20 mL) and water (10 mL). The mixture was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EA (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain compound 41-2. MS m / z (ESI): 248.0 [M+1].

[0724] Step 3: Compound 41-2 (50 mg, 0.20 mmol) was added to MeCN (4 mL), followed by TCFH (56.73 mg, 0.20 mmol), N-methylimidazole (81.59 μL, 1.01 mmol), and intermediate 3 (77.72 mg, 0.20 mmol). The mixture was allowed to react at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 1 / 1 ratio of PE:EA to afford compound 41-3. MS m / z (ESI): 614.4 [M+1].

[0725] Step 4: Compound 41-3 (90.0 mg, 0.15 mmol) was dissolved in TFA (2 mL), TfOH (1.3 μL) was added, and the mixture was reacted at room temperature for 1 hour. Methanol (10 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure. EA (20 mL) was added to the remaining solution, and the mixture was neutralized with saturated sodium bicarbonate solution to pH = 8. The aqueous phase was extracted with EA (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (Waters-2545, c...

Claims

1. A compound of formula I or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug: in, Ring A is selected from C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl; Ring B is selected from C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, C6-10 aryl and 5-6 membered heterocycloalkyl, C6-10 aryl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl; $L5 represents the site of attachment to L5, and #L represents the site of attachment to L; Ring C is selected from: The end is connected to L; L is a linking group between ring B and ring C, and the number of main chain atoms of the linking group is between 2 and 7, preferably between 4 and 7; L5 is selected from a bond, $B-(CH2)sO-#A, $BO-(CH2)s-#A, $B-(CH2)s-NRd-#A, $B-NRd-(CH2)s-#A, wherein s is 0, 1 or 2, and the $B-(CH2)sO-#A, $BO-(CH2)s-#A, $B-(CH2)s-NRd-#A, $B-NRd-(CH2)s-#A are optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, $B represents the site for connecting ring B, and #A represents the site for connecting ring A; Preferably, L5 is selected from a bond, $B-(CH2)s-NRd-#A, wherein the $B-(CH2)s-NRd-#A is optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-3 alkyl, C1-3 alkoxy, halo-C1-3 alkyl, halo-C1-3 alkoxy; Further preferably, L5 is selected from a bond, $B-(CH2)s-NRd-#A, wherein the $B-(CH2)s-NRd-#A is optionally substituted with one or more C1-3 alkyl groups; More preferably, L5 is selected from a bond; Each R1, R2, and R3 is independently selected from H, D, halogen, hydroxy, -CN, -NReRf, -NReC(=O)Rf, -C(=O)-NReRf, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6 membered heteroaryl, -C1-6 alkylene-5-6 wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6-membered heteroaryl, -C1-6 alkylene-5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, -C1-6 alkylene-4-7-membered heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated substituted by a substituent of a C1-6 alkoxy group; optionally, two R1 or R2 attached to the same carbon atom form C=O with the carbon atom; Rd is selected from H, C1-6 alkyl, halogenated C1-6 alkyl; Re and Rf are each independently selected from H, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy; m1, m2 and m3 each independently represent an integer of 0-4.

2. The compound of claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Ring A is selected from 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl; Preferably, ring A is selected from 5-6 membered heteroaryl, 6 membered heterocycloalkyl, 7-10 membered spiroheterocycloalkyl; Further preferably, ring A is selected from 5-6 membered heteroaryl; Further preferably, ring A is selected from pyrimidinyl, pyridinyl, Piperazine, morpholinyl, Thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (e.g., 1,2,4-triazolyl, 1,3,4-triazolyl), oxazolyl, isoxazolyl, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole; The end is connected to L5; More preferably, ring A is selected from pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl; more preferably, ring A is selected from pyrimidinyl (e.g. ), pyridyl (e.g. )、 Piperazine (e.g. ), morpholinyl (e.g. )、 Thiazolyl (e.g. ), isothiazolyl (e.g. ), imidazole (e.g. ), pyrazolyl (e.g. ), 1,2,4-triazolyl (e.g. ), 1,3,4-triazolyl (e.g. ), oxazolyl (e.g. ), isoxazolyl (e.g. ), 1,2,4-oxadiazole (e.g. )、1,3,4-thiadiazole 1,2,4-thiadiazole (e.g. )； The end is connected to L5; More preferably, ring A is selected from The end is connected to L5.

3. The compound according to claim 1 or 2, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: R1 is independently selected from halogen, hydroxyl, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C1-6 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf, -C(=O)-NReRf, wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl Alkyl, 4-7 membered heterocycloalkyl, -C1-6 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl; optionally, two R1s attached to the same carbon atom form C=O with the carbon atom; Re and Rf are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, or Re and Rf are connected together with the atoms to which they are attached to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl; Preferably, R1 is independently selected from halogen, hydroxyl, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf; wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, The membered heteroaryl is optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl; optionally, two R1s attached to the same carbon atom form C=O with the carbon atom; Re and Rf are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, or Re and Rf are connected together with the atoms to which they are attached to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl; Preferably, R1 is independently selected from halogen, hydroxyl, -CN, C1-3 alkyl, C2-6 alkynyl, C1-3 alkoxy, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -NReRf; wherein the C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 1 to 3 substituents selected from halogen and C1-3 alkyl; optionally, two R1s connected to the same carbon atom form C=O with the carbon atom; Re and Rf are independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, or Re and Rf are connected together with the atoms to which they are connected to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 halogens; Preferably, R1 is each independently selected from halogen, hydroxyl, -CN, C1-3 alkyl, C2-6 alkynyl, C1-3 alkoxy, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C1-3 alkylene-4-7 membered heterocycloalkyl, 5-6 membered heteroaryl; Preferably, R1 is independently selected from F, Cl, -CN, methyl, -CH2CH2CH3, -CHF2, -CF3, methoxy, ethoxy, cyclopropyl, Piperidinyl (e.g. ), morpholinyl (e.g. )、 Oxazolyl (e.g. ), pyridyl (e.g. )、-N(CH3)2、 Optionally, two R1s attached to the same carbon atom form C=O with the carbon atom; The end is connected to ring A; Preferably, R1 is independently selected from halogen, -CN, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, C3-6 cycloalkyl, -C1-3 alkylene-C3-6 cycloalkyl, pyridyl (e.g. ), -NReRf; Re and Rf are each independently selected from C1-3 alkyl, C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl, and the 4-7 membered heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl; The end is connected to ring A; Preferably, R1 is selected from F, -CN, methyl, -CHF2, -CF3, methoxy, cyclopropyl, Pyridyl (e.g. )、-N(CH3)2、 The end is connected to ring A; More preferably, R1 is selected from -CF3, -N(CH3)2; The end is connected to ring A; Preferably, m1 is 0, 1 or 2; More preferably, m1 is 0 or 1; Most preferably, m1 is 1.

4. A compound according to any one of claims 1 to 3 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Said Selected from The end is connected to L5; Preferably, Selected from The end is connected to L5; More preferably, Selected from The end is connected to L5; More preferably, Selected from The end is connected to L5.

5. A compound according to any one of claims 1 to 4, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: The conditions are: 1) is not a group E, the group E is selected from: Where $L5 represents a point connected to L5, and #L represents a point connected to L; or 2) is not a group E, the group E is selected from: Among them, R E is selected from C1-6 alkyl (preferably methyl), halogen (preferably fluorine, chlorine), m4 is selected from an integer of 0 to 5, $L5 represents the point of connection with L5, and #L represents the point of connection with L; or 3) is not a group E, the group E is selected from: X 1 Selected from N, C=O, CR F1 , C-(R F1 )2; X 2 Selected from N, NR F2 , CR F3 , C-(R F3 )2; X 3 Selected from N, CR F4 ; X 4 Selected from N, CR F4 ; X 5 Selected from N, CR F4 ; Where R F1 , R F3 , R F4 Each is independently selected from H, halogen, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR F5 、C(O)-R F5 、C(O)-N(R F6 )(R F7 )、N(R F6 )(R F7 )、N(R F6 )C(O)-R F5 、N(R F6 )C(O)OR F5 、N(R F6 )S(O)2(R F5 )、-N(R F6 )C(O)-N(R F7 )(R F7 )、S(O)2R F5 、-SF5、S(O)2N(R F6 )(R F7 )、S(O)(NH)R F6 、S(O)(NR F6 )NR F7 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace; R F2 , R F6 , R F7 Each is independently selected from H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocycloalkyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally replaced by one or more R F5 replace; R F5 independently selected from: H, C=O, halogen, -NO2, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocycloalkyl, -OH, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocycloalkyl), -NH2, -NH -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocycloalkyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-1 2-membered heteroaryl)2, -N(4-12-membered heterocycloalkyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-12-membered heteroaryl), -N(C1-9 alkyl)(4-12-membered heterocycloalkyl), -C(O)(C1-9 alkyl) , -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocycloalkyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocycloalkyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl), -C(O)N(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocycloalkyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl), -C(O)N(C2-6 -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, -C(O)N(4-12 membered heterocycloalkyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocycloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocycloalkyl), -NHC(O) alkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocycloalkyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)O( HC(O)NH(5-12 membered heteroaryl), -NHC(O)NH(4-12 membered heterocycloalkyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocycloalkyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(NH)(C3-9 cycloalkyl),-S(O)(NC1-9 alkyl)(C1-9 alkyl), -S(O)(NH)(C6-10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)(C6-10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocycloalkyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more of halogen, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocycloalkyl) )、-N(C1-9 alkyl)2、-N(C3-15 cycloalkyl)2、-NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocycloalkyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocycloalkyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocycloalkyl),or -O(C1-9 alkyl); wherein $L5 represents the point of connection to L5, and #L represents the point of connection to L.

6. A compound according to any one of claims 1 to 4, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; preferably, ring B is selected from phenyl, pyridyl, pyrazolyl, pyrazinyl, oxazolyl, isoxazolyl, benzopyrazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiadiazolyl, indolyl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, isoindolyl, pyridopyridinyl, pyrrolopyrimidinyl; Preferably, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g. 1,2,3-triazolyl), thiadiazolyl (e.g. 1,3,4-thiadiazolyl), 5-membered nitrogen-containing heterocycloalkyl and phenyl, phenyl and pyrazolyl, phenyl and 5-membered nitrogen-containing heterocycloalkyl (e.g. phenyl and tetrahydropyrrole), pyrimidinyl and 5-membered nitrogen-containing heterocycloalkyl, 6-membered nitrogen-containing heterocycloalkyl and 5-membered nitrogen-containing heterocycloalkyl, 6-membered nitrogen-containing heterocycloalkyl and pyrazolyl; Preferably, ring B is selected from phenyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; Preferably, ring B is selected from phenyl, 5-6 membered heteroaryl; Preferably, ring B is selected from phenyl, 6-membered heteroaryl; Preferably, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g. 1,2,3-triazolyl), thiadiazolyl (e.g. 1,3,4-thiadiazolyl); Preferably, ring B is selected from phenyl, pyridyl, pyrazinyl, isoxazolyl; Preferably, ring B is selected from phenyl, pyridyl, pyrazinyl; Preferably, ring B is selected from the following groups: The end is connected to the L end or L5; Preferably, ring B is selected from The end is connected to the L end or L5; Preferably, ring B is selected from $L5 indicates the site for connecting L5, and #L indicates the site for connecting L; Preferably, ring B is selected from $L5 indicates the site for connecting L5, and #L indicates the site for connecting L; More preferably, ring B is selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

7. A compound according to any one of claims 1 to 6, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: R2 is selected from halogen, hydroxyl, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, C3-4 cycloalkyl, -C1-2 alkylene-C3-4 cycloalkyl, -NReRf; Re and Rf are each independently selected from H and C1-3 alkyl; optionally, two R2 attached to the same carbon atom form C=O with the carbon atom; Preferably, R2 is selected from F, Cl, hydroxyl, amino, methyl; optionally, two R2 attached to the same carbon atom form C=O with the carbon atom; Preferably, R2 is selected from F or hydroxyl; More preferably, R2 is F; Preferably, m2 is an integer from 0 to 2; Preferably, m2 is 0 or 1; Preferably, m2 is 0.

8. A compound according to any one of claims 1 to 7 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Said Selected from $L5 indicates the site for connecting L5, and #L indicates the site for connecting L; Preferably, Selected from $L5 indicates the site for connecting L5, and #L indicates the site for connecting L; More preferably, Selected from $L5 indicates the site for connecting L5, and #L indicates the site for connecting L; More preferably, Selected from $L5 indicates the site where L5 is connected, and #L indicates the site where L is connected.

9. A compound according to any one of claims 1 to 8, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, wherein: L is a linking group represented by formula L: $B-L1-L2-X1-L3-L4-#C (L); Among them, $B indicates the site of connection to loop B, and #C indicates the site of connection to loop C; L1 is selected from a bond, -C(=O)-, $BC(=O)-NRa-#L2, -NRb-, $B-NRb-C(=O)-#L2, t is 1, 2 or 3, Optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; Ra and Rb are each independently selected from H, D, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl; $B represents the site of attachment to ring B, #L2 represents the site of attachment to L2; Preferably, Ra and Rb are each independently selected from H, C1-6 alkyl; Preferably, Ra and Rb are each independently selected from H, C1-3 alkyl; Preferably, L1 is selected from a bond, -C(=O)-, $BC(=O)NH-#L2, $BC(=O)N(CH3)-#L2, $B-NH(C=O)-#L2, -NH-, (For example )； Further preferably, L1 is selected from -C(=O)-, $BC(=O)NH-#L2, $B-NH(C=O)-#L2; More preferably, L1 is selected from $BC(=O)NH-#L2, $B-NH(C=O)-#L2; L2 is selected from a bond, C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; Preferably, L2 is selected from a bond, C1-6 alkylene; wherein the C1-6 alkylene is optionally substituted by 1 to 3 halogen, oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl as C1-6 alkylene substituents are optionally substituted by one or more substituents selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, halo C1-3 alkyl, halo C1-3 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; More preferably, L2 is selected from a bond, C2-5 alkylene; wherein the C2-5 alkylene is optionally substituted by 1 or 2 oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)N(R L2 )2, a 4-7 membered nitrogen-containing saturated heterocycloalkyl or -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl as a C2-5 alkylene substituent is optionally substituted by a substituent selected from halogen, cyano, or C1-3 alkyl; R L2 Each is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and the C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; Further preferably, L2 is selected from a bond, a C2-5 alkylene group; wherein the C2-5 alkylene group is optionally selected from a C1-3 alkyl group, a C3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclohexyl), a 4-7 membered heterocycloalkyl group (e.g., oxetanyl, oxetanyl, )、 -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 5-6 membered heteroaryl (e.g., pyridyl), and the C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; More preferably, L2 is selected from C2-5 alkylene, wherein the C2-5 alkylene is optionally selected from C1-3 alkyl, cyclopropyl, -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (e.g., azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen (such as F, Cl), C1-3 alkyl (such as methyl, isopropyl), q is selected from 0, 1; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 6 membered heteroaryl (e.g., pyridyl), and the 4-7 membered heterocycloalkyl, 6 membered heteroaryl is optionally substituted with a substituent selected from C1-3 alkyl; X1 is selected from a bond, O, S; Preferably, X1 is selected from a bond, O; Further preferably, X1 is selected from a bond; L3 is selected from a bond, C1-6 alkylene, C3-10 cycloalkyl-(CH2) k -#L4, 4-10 membered heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4; wherein C1-6 alkylene, C3-10 cycloalkyl-(CH2) k -#L4, 4-10 membered heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; k is selected from 0, 1, 2, 3; #L4 represents the site of attachment of L4; Preferably, L3 is selected from a bond, a C1-3 alkylene group, a C3-6 cycloalkyl group-(CH2) k -#L4, 4-6 membered monocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered bridged heterocyclic alkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4; wherein the C1-3 alkylene, C3-6 cycloalkyl-(CH2) k -#L4, 4-6 membered monocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered bridged heterocyclic alkyl-(CH2) k -#L4 or 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted by a substituent selected from halogen, hydroxy, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, -O-C3-6 cycloalkyl; More preferably, L3 is selected from a bond, a C1-3 alkylene group, a 4-6 membered monocyclic heterocycloalkyl group -(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, pyrrolyl-(CH2) k -#L4; wherein the C1-3 alkylene, 4-6 membered monocyclic heterocycloalkyl-(CH2) k -#L4, 6-10 membered spirocyclic heterocycloalkyl-(CH2) k -#L4, pyrrolyl-(CH2) k -#L4 is optionally substituted by a substituent selected from C1-3 alkyl, C1-3 alkoxy, -O-C3-6 cycloalkyl; More preferably, L3 is selected from a bond, a C1-3 alkylene group; L4 is selected from a bond, O, S, -NRc-; Rc is selected from H, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl; Preferably, L4 is selected from a bond, O, -NRc-; Rc is selected from H, C1-3 alkyl; More preferably, L4 is selected from -NH-.

10. The compound of claim 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: When L1 is selected from $BC(=O)-NRa-#L2, any of the following conditions is met: (1) L2 is selected from C1-6 alkylene; wherein the C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy alkyl, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond, O, -NRc-, Rc is selected from H, C1-3 alkyl; Preferably, L2 is selected from C2-6 alkylene; wherein the C2-6 alkylene is optionally replaced by C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group, R' is selected from halogen, hydroxyl, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxacyclohexyl, pyridyl, and the oxacyclohexyl is optionally substituted with a substituent selected from C1-3 alkyl; (2) L2 is selected from a bond, C1-6 alkylene; X1 is selected from a bond; L3 is selected from C3-10 cycloalkyl-(CH2) k -#L4, 4-10 membered heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4, wherein C3-10 cycloalkyl-(CH2) k -#L4, 4-10 membered heterocycloalkyl-(CH2) k -#L4, 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; k is selected from 0, 1, 2, 3; #L4 represents the site of attachment of L4; L4 is selected from a bond or -NRc-; Preferably, L2 is selected from a bond, C1-3 alkylene; X1 is selected from a bond; L3 is selected from C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl-(CH2) k -#L4, wherein C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl-(CH2) k -#L4 is optionally substituted by one or more substituents selected from C1-3 alkyl, C1-3 alkoxy, -O-C3-6 cycloalkyl; k is selected from 0, 1, 2; #L4 represents the site of attachment of L4; L4 is selected from a bond or -NRc-; when L1 is selected from $B-NRb-C(=O)-#L2, any of the following conditions is satisfied: (1) L2 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond or O; Preferably, L2 is selected from C1-3 alkylene, wherein C1-3 alkylene is optionally substituted by one substituent selected from C1-3 alkyl, C3-6 cycloalkyl; X1 is selected from a bond, L3 is selected from a bond, and L4 is selected from a bond or O; (2) L2 is selected from C1-6 alkylene; X1 is selected from O; L3 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; L4 is selected from -NRc-; Preferably, L2 is selected from C1-3 alkylene, X1 is selected from O; L3 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted by 1 substituent selected from C1-3 alkyl; L4 is selected from -NRc-; When L1 is selected from -C(=O)-, any of the following conditions is satisfied: (1) L2 is selected from a bond; X1 is selected from a bond; L3 is selected from a 4-10 membered heterocycloalkyl-(CH2) k -#L4, wherein 4-10 membered heterocyclic ring Alkyl-(CH2) k -#L4 is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; k is selected from 0, 1, 2, 3; #L4 represents the site of attachment of L4, and L4 is selected from -NRc-; Preferably, L3 is selected from 4-10 membered heterocycloalkyl-(CH2) k -#L4, wherein 4-10 membered heterocycloalkyl-(CH2) k -#L4 is optionally substituted by 1 substituent selected from C1-3 alkyl; (2) L2 is selected from C1-6 alkylene; X1 is selected from O; L3 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; L4 is selected from -NRc-; Preferably, L2 is selected from C1-3 alkylene; X1 is selected from O; L3 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted by 1 substituent selected from C1-3 alkyl; L4 is selected from -NRc-; When L1 is selected from -NRc-, L2 is selected from C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, and L4 is selected from -NRc-; Preferably, L2 is selected from C1-6 alkylene; wherein C1-6 alkylene is optionally substituted by one or more selected from halogen, hydroxyl, oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)-4-7 membered heterocycloalkyl as C1-6 alkylene substituents are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, halogenated C1-3 alkoxy; R L2 Each is independently selected from H, D, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; X1 is selected from a bond, L3 is selected from a bond, and L4 is selected from -NRc-; When L1 is selected from a bond, any of the following conditions is met: (1) L2 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2; C3-10 cycloalkyl, -O-C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)-4-10 membered heterocycloalkyl as a C1-6 alkylene substituent are optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with substituents selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; X1 is selected from a bond, L3 is selected from a bond, L4 is selected from a bond or -NRc-; Preferably, L2 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by 1 substituent selected from C1-3 alkyl; (2) L2 is selected from C1-6 alkylene, X1 is selected from O, L3 is selected from C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted by one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; L4 is selected from -NRc-; Preferably, L2 is selected from C1-3 alkylene, X1 is selected from O, and L3 is selected from C1-3 alkylene, wherein the C1-3 alkylene is optionally substituted with 1 substituent selected from C1-3 alkyl; When L1 is selected from When L2 is selected from a bond; X1 is selected from O, S; L3 is selected from a bond, C1-6 alkylene, wherein the C1-6 alkylene is optionally substituted with one or more substituents selected from D, halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-4-10 membered heterocycloalkyl; and L4 is selected from a bond, $B represents the site of attachment to ring B, and #L2 represents the site of attachment to L2; Preferably, L2 is selected from a bond; X1 is selected from O, L3 is selected from a bond; L4 is selected from a bond; wherein t, Ra, Rb, and Rc are as defined in claim 9.

11. The compound of claim 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: When L1 is selected from $BC(=O)-NRa-#L2, L2 is selected from: wherein $L1 represents the site of attachment to L1, #X1 represents the site of attachment to X1, n is an integer selected from 0, 1, 2, 3, 4, or 5, and wherein Rs is selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, -C(=O)NR ii R iii , where R ii and R iii may independently represent hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl or aryl, or R ii and R iii Together with the atoms to which it is attached, it forms a 4-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 substituents selected from halogen, -OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, wherein Ra is as defined in claim 9; or When L1 is selected from $BC(=O)-NRa-#L2, L2 is selected from: wherein $L1 represents the site of attachment to L1, #X1 represents the site of attachment to X1, n is an integer selected from 0, 1, 2, 3, 4, or 5, and Rs is selected from H, D, halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; Preferably, Rs is selected from H, D, halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, D, C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with substituents selected from halogen, hydroxyl, cyano, C1-3 alkyl, C1-3 alkoxy.

12. The compound of claim 11 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: n is selected from 3, Rs is selected from: methyl, cyclopropyl, cyclobutyl, cyclohexyl, Preferably, Rs is selected from methyl, 13. The compound of claim 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: When L1 is selected from $B-NRb-C(=O)-#L2, X1, L3 and L4 all represent a single bond, and L2 is selected from substituted or unsubstituted C1-4 alkylene, preferably substituted or unsubstituted methyl, ethyl or propyl; or When L1 is selected from $B-NRb-C(=O)-#L2, X1 is selected from O or S, L2 and L3 are each independently selected from substituted or unsubstituted C1-4 alkylene, preferably substituted or unsubstituted methyl, ethyl or propyl, and L4 is selected from -NRc-, Wherein, Rb and Rc are as defined in claim 9.

14. The compound of claim 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: When L1 is selected from a single bond, X1 is selected from O, S, L2 and L3 are each independently selected from substituted or unsubstituted C1-4 alkylene, and L4 is selected from -NRc-, wherein Rb, Rc are as defined in claim 9, Preferably, the carbon atom where L2 is attached to ring B is substituted with =O to form a carbonyl group.

15. The compound of claim 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: When L1 is selected from When X1 is selected from O, L2, L3 and L4 all represent single bonds, and t is selected from 1; $B represents the site for connecting ring B, and #L2 represents the site for connecting L2.

16. A compound according to any one of claims 1 to 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: L is selected from: wherein $B represents the connection site with ring B, #C represents the connection site with ring C, Ra, Rb and Rc are as defined in claim 9, Rs is as defined in claim 11, and R" is selected from C1-6 alkoxy, -O-C3-6 cycloalkyl; Preferably, Ra, Rb and Rc are each independently selected from H or methyl; Preferably, Rs is selected from H, methyl, cyclopropyl, cyclobutyl, cyclohexyl, 17. A compound according to any one of claims 1 to 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: L is selected from: wherein $B represents the connection site with ring B, #C represents the connection site with ring C, Ra, Rb and Rc are as defined in claim 9, and Rs is as defined in claim 11; Preferably, L is selected from: More preferably, L is selected from: Preferably, Ra, Rb and Rc are each independently selected from H or methyl; Preferably, Rs is selected from H, D, halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group, R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, D, C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and C1-4 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; More preferably, Rs is selected from C1-3 alkyl, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl), -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (e.g., azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen (such as F, Cl), C1-3 alkyl (such as methyl, isopropyl), q is selected from 0, 1; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 6 membered heteroaryl (e.g., pyridyl), and the 4-7 membered heterocycloalkyl, 6 membered heteroaryl is optionally substituted with a substituent selected from C1-3 alkyl; Preferably, Rs is selected from H or substituted or unsubstituted groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

18. A compound according to any one of claims 1 to 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: L is selected from $B-CH2-CH2-#C、$B-CH2-CH2-CH2-#C、 $B indicates the site for connecting loop B, and #C indicates the site for connecting loop C; Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from 19. A compound according to any one of claims 1 to 18, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, wherein: Ring C is selected from the following groups: Preferably, ring C is selected from: More preferably, ring C is selected from 20. A compound according to any one of claims 1 to 19 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Selected from: Preferably, Selected from: Preferably, Selected from: Preferably, Selected from: Preferably, Selected from: Preferably, R3 is selected from halogen, -CN, C1-3 alkyl, halogenated C1-3 alkyl, -NReRf, -NReC(=O)Rf, -C(=O)-NReRf, wherein Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are connected to form a 4-7 membered heterocycloalkyl (e.g., a 7 membered nitrogen-containing spiroheterocycloalkyl); More preferably, R3 is selected from Cl, methyl, -CF3, -CN, -NHC(=O)CH3, -C(=O)NH2, Further preferably, R3 is selected from -CF3, -CN, Further preferably, R3 is selected from -CF3, More preferably, R3 is selected from -CF3, methyl, Preferably, m3 is selected from 1, 2, and 3; more preferably, m1 is selected from 1 or 2.

21. A compound according to any one of claims 1 to 20, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, having a structure as shown in any one of Formulas I-1 to I-4, I-7 to I-10: in, Ring A, Ring C, R1, R2, R3, L, L5, m1, m2 and m3 are as defined in claim 1 or 9.

22. A compound according to any one of claims 1 to 21 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which has a structure as shown in Formula I-5 or I-6: in, In formula I-5, ring B is selected from phenyl or 6-membered heteroaryl, Z1, Z2, Z3, and Z4 are each independently selected from N or CH, and ring A, ring C, R1, R2, R3, L, m1, m2, and m3 are as defined in claim 1; Preferably, at most 2 of Z1, Z2, Z3, and Z4 are N; Preferably, ring B is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl; Preferably, ring B is selected from phenyl, pyridyl, pyrazinyl; Preferably, ring B is selected from the following groups 1)-5): 1) Z1, Z2, Z3 and Z4 are all CH; 2) Z1 and Z2 are both CH, and Z3 and Z4 are both N; 3) Z1 and Z4 are both CH, and Z2 and Z3 are both N; 4) Only one of Z1, Z2, Z3, and Z4 is N; 5) Z1 and Z3 are both CH, one of Z2 and Z4 is N and the other is CH; In formula I-6, ring B is selected from 5-membered heteroaryl, U1, U2, and U3 are each independently selected from N, O, S, and CH, and at most one of U1, U2, and U3 is S, and at most one of U1, U2, and U3 is O, W1 and W2 are each independently selected from N and CH, and ring A, ring C, R1, R2, R3, L, m1, m2, and m3 are as defined in claim 1; Preferably, Ring B contains 2 or 3 heteroatoms each independently selected from N, O, S; Preferably, ring B is selected from pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl (eg 1,2,3-triazolyl), thiadiazolyl (eg 1,3,4-thiadiazolyl); Preferably, at least one of U1, U2, and U3 is N; at most one of W1 and W2 is N; Preferably, at most two of U1, U2, and U3 are heteroatoms; Preferably, U1, U2, and U3 are each independently selected from N, O, and CH; Preferably, U1 and W2 are CH; U3 and W1 are CH and N; U2 is O and N; Preferably, ring B is selected from isoxazolyl, pyrazolyl; Preferably, U1 is CH, U2 is O, U3 is N, W1 is CH, and W2 is CH; or W1 and U2 are N, and U1, W2 and U3 are CH.

23. A compound according to any one of claims 1 to 22, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, having a structure as shown in any one of Formula II-1 or II-2: in, L1 is selected from $BC(=O)-NRa-#L2, $B-NRb-C(=O)-#L2; Ra, Rb are as defined in claim 9; L2 is selected from C1-6 alkylene, wherein C1-6 alkylene is optionally substituted by 1 or 2 oxo, C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)N(R L2 )2, the 4-7 membered nitrogen-containing saturated heterocycloalkyl, -C(=O)-4-7 membered nitrogen-containing saturated heterocycloalkyl as a C1-6 alkylene substituent is optionally substituted by a substituent selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, halogenated C1-3 alkoxy; R L2 Each is independently selected from H, D, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; L4 is selected from a bond, O, -NRc-, wherein Rc is selected from H, C1-3 alkyl; Preferably, L2 is selected from C2-5 alkylene; wherein C2-5 alkylene is optionally selected from C1-3 alkyl, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl), 4-7 membered heterocycloalkyl (e.g. oxetanyl, oxetanyl, )、 -C(=O)N(R L2 )2 is substituted by a substituent; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (e.g., azetidinyl, azopentyl, morpholinyl, ), R' is selected from halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 5-6 membered heteroaryl (e.g., pyridyl), and the C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxyl, cyano, C1-3 alkyl, C1-3 alkoxy.

24. A compound according to any one of claims 1 to 21 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which has a structure as shown in any one of Formulas III-1 to III-6: in, Z1, Z2, Z3, Z4, U1, U2, U3, W1, W2 are as defined in claim 22; L1, L2, L3, L4, Ra, Rb are as defined in claim 9; Ring A, R1, R2, R3, m1, m2 and m3 are as defined in claim 1.

25. A compound as described in any one of claims 1 to 24, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof, having a structure as shown in any one of Formulas IV-1 to IV-4: in, V1 and V2 are each independently selected from N and CH, Y1 is N or CH, Y2, Y3, and Y4 are each independently selected from N, CH, and S, ring A is a 5-membered heteroaromatic ring, and ring B, ring C, L, R1, R2, R3, m1, m2, and m3 are as defined in claim 1; L1, L2, and L4 are as defined in claim 9; Preferably, at least one of V1 and V2 is N; more preferably, both V1 and V2 are N; Preferably, only 2 of Y1, Y2, Y3, and Y4 are heteroatoms; Preferably, Y2 is N, and one of Y1, Y3, and Y4 is a heteroatom; Preferably, Y1 and Y2 are N, and Y3 and Y4 are CH; or Y1 and Y3 are CH, and Y2 and Y4 are S and N respectively; or Y1 and Y4 are CH, Y2 is N, and Y3 is S.

26. The compound of claim 1 or 2, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, having a structure as shown in any one of Formulas V-1 to V-4: in, Ring A, Ring B, Ring C, L, R1, R2, R3, m1, m2 and m3 are as defined in claim 1; L1, L2 and L4 are as defined in claim 9.

27. A compound according to any one of claims 1 to 26, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof, having a structure as shown in any one of Formulas VI-1 to VI-6: in, L1, L2, L3, L4, Ra, Rb are as defined in claim 9; Z1, Z2, Z3, Z4, U1, U2, U3, W1, W2 are as defined in claim 22; Ring A, V1, V2, Y1, Y2, Y3, Y4 are as defined in claim 25.

28. The compound of claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Selected from and / or Selected from: and / or Selected from wherein R1 is selected from halogen, -OH, -CN, -NReRf, -CF3, -CHF2, substituted or unsubstituted C3-6 cycloalkyl, Re and Rf are each independently selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl; Each R2 is independently selected from halogen, -OH, -CN, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-6 cycloalkyl; Each R3 is independently selected from halogen, -OH, -CN, -NReRf, -CF3, -CHF2, substituted or unsubstituted C3-6 cycloalkyl, Re and Rf are each independently selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or Re and Rf together with the atoms to which they are attached are linked to form a 4-7 membered heterocycloalkyl; and / or m2 and m3 are each independently selected from 0, 1, 2 or 3.

29. The compound of claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Ring A is selected from phenyl, pyrimidinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, oxazolyl, isoxazolyl, Ring B is selected from phenyl, pyridyl, pyrazolyl, pyrazinyl, oxazolyl, isoxazolyl, benzopyrazolyl, thiazolyl, isothiazole, pyridazinyl, pyrimidinyl, triazolyl, thiadiazole, indolyl, benzimidazolyl, dihydrobenzimidazolyl, indolyl, indazolyl, isoindolyl, pyridopyridinyl, pyrrolopyrimidinyl; Ring C is selected from the following groups: The end is connected to L; L5 is selected from a bond; and L is selected from: in, $B represents the attachment site to ring B, #C represents the attachment site to ring C, Ra, Rb and Rc are as defined in claim 9, and Rs is as defined in claim 11; Preferably, Ra, Rb and Rc are each independently selected from H or methyl; Preferably, Rs is selected from H or the following groups: methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 30. The compound of claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: Ring A is selected from pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl; Ring B is selected from: The end is connected to the L end or L5; Ring C is selected from: L5 is a key; L is selected from: $B indicates the attachment site to ring B, and #C indicates the attachment site to ring C; Ra, Rb and Rc are as defined in claim 9, and Rs is as defined in claim 11; Preferably, Ra, Rb and Rc are each independently selected from H or methyl; Preferably, Rs is selected from H or the following groups: methyl, cyclopropyl, cyclobutyl, cyclohexyl, 31. A compound according to any one of claims 1 to 30, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, wherein: m1 is selected from 1, 2 or 3, and each R1 is independently selected from halogen, -OH, -CN, -NReRf, -C(=O)-NReRf, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, wherein the C3-6 cycloalkyl, -C1-6 alkylene-C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 1 to 3 substituents selected from halogen, C1-3 alkyl; Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf are connected together with the atoms to which they are connected to form a 4-7 membered heterocycloalkyl; preferably, R1 is each independently selected from halogenated C1-3 alkyl (e.g., -CF3), cyclopropyl, -N(CH3)2; and / or m2 is selected from 0 or 1, and each R2 is independently selected from -OH, halogen, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, preferably -F, hydroxyl; and / or m3 is selected from 1, 2 or 3, and each R3 is independently selected from -CN, C1-3 alkyl, halogenated C1-3 alkyl (e.g. -CF3), -NReRf, -C(=O)-NReRf; wherein Re and Rf are each independently selected from H, C1-3 alkyl, or Re and Rf together with the atoms to which they are attached are connected to form a 4-7 membered heterocycloalkyl (e.g. a 7 membered nitrogen-containing spiroheterocycloalkyl).

32. A compound as claimed in any one of claims 1 to 31 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: At least one of the R1s is selected from halogenated C1-6 alkyl groups, and / or at least one of the R3s is selected from halogenated C1-6 alkyl groups; Preferably, at least one of the R1s is selected from halogenated C1-3 alkyl, and / or at least one of the R3s is selected from halogenated C1-3 alkyl; Preferably, at least one of the R1s is a trifluoromethyl group, and / or at least one of the R3s is a trifluoromethyl group.

32. A compound as described in any one of claims 1 to 31 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which has a structure as shown in Formula VII-1 or VII-2: in, Selected from V1 and V2 are each independently selected from CH and N; preferably, at least one of V1 and V2 is N; Ring A' is a 5-membered heteroaromatic ring, Y1 is N or CH, and Y2, Y3, and Y4 are each independently selected from N, CH, and S; preferably, Y1 and Y2 are N, and Y3 and Y4 are CH; or Y1 is CH, Y2 is N, and one of Y3 and Y4 is S and the other is CH; more preferably, Y1 and Y3 are CH, Y2 is N, and Y4 is S; R1 is as defined in claim 1, 3, 28 or 31; preferably, R1 is selected from halogenated C1-3 alkyl, -C1-3 alkylene-C3-6 cycloalkyl, -NReRf; Re and Rf are each independently selected from H, C1-3 alkyl; more preferably, R1 is -CF3; Ring B is phenyl or a 6-membered heteroaromatic ring, and Z1, Z2, Z3, and Z4 are each independently selected from N or CH; preferably, ring B is phenyl, or only one of Z1, Z2, Z3, and Z4 is N, or both Z1 and Z4 are CH, and both Z2 and Z3 are N; R2 is as defined in claim 1, 7, 28 or 31; preferably, R2 is selected from H, halogen, hydroxyl, C1-3 alkyl; more preferably, R2 is selected from H or F; more preferably, the condition is: when Z1 and Z4 are both CH, Z2 and Z3 are both N, R2 is H; when ring B is phenyl, or one N in Z2 or Z4, Z1 and Z3 are both CH, R2 is H or F, and F is ortho to -CONRa- in formula VII-1; more preferably, R2 is H; Ra and Rb are each independently selected from H or methyl; preferably, Ra is H; preferably, Rb is H; Rs is as defined in claim 11, 12, 16 or 17, preferably, Rs is selected from C1-3 alkyl, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl), 4-7 membered heterocycloalkyl (e.g. oxetanyl, oxetanyl, )、 -C(=O)N(R L2 )2; wherein ring G is a 4-10 membered nitrogen-containing saturated heterocyclic alkyl group (e.g., azetidinyl, Azocyclopentyl, morpholinyl, ), R' is selected from halogen (e.g., F, Cl), cyano, C1-3 alkyl (e.g., methyl, isopropyl), C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, q is selected from 0, 1 or 2; R L2 Each is independently selected from H, C1-3 alkyl (e.g., methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), 4-7 membered heterocycloalkyl (e.g., oxacyclohexyl), 5-6 membered heteroaryl (e.g., pyridyl), and the C1-3 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with a substituent selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy; L4 is selected from NH or O, preferably NH; R3 is as defined in claim 1, 20, 28 or 31, preferably, R3 is selected from halogenated C1-3 alkyl; more preferably, R3 is selected from -CF3; R3' and R3" are each independently R3; preferably, R3' is selected from a halogenated C1-3 alkyl group, R3" is selected from -NReRf, and Re and Rf together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl group (e.g., a 7-membered nitrogen-containing spiro heterocycloalkyl group); more preferably, R3' is -CF3, and R3" is 34. The compound of claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, wherein: The compound is selected from the following compounds:

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

36. Use of the compound of any one of claims 1 to 34 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition of claim 35 in the preparation of a medicament for inhibiting PARP7 in a subject in need thereof, or for treating or preventing a PARP7-mediated disease; preferably, the PARP7-mediated disease is selected from cancer, immune disease, inflammation or viral infection.

37. A method for treating or preventing a PARP7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 34 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition of claim 35, wherein the PARP7-mediated disease is selected from cancer, immune disease, inflammation or viral infection.

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