HPK1 inhibitor, preparation method and application thereof

Abstract

The invention belongs to the field of medicine, provides an HPK1 inhibitor as well as a preparation method and application thereof, and particularly discloses a compound shown as a formula (I '), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound and the pharmaceutical composition in preparation of drugs for preventing and / or treating HPK1-mediated related diseases. # imgabs0 #

Description

HPK1 inhibitors, preparation methods and uses thereof

[0001] This application claims priority to Chinese application No. 202211160306.4 filed on September 22, 2022, Chinese application No. 202310363790.9 filed on April 6, 2023, Chinese application No. 202310928425.8 filed on July 26, 2023, and Chinese application No. 202311147856.7 filed on September 6, 2023, all of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a compound of formula (I'), a preparation method thereof, a pharmaceutical composition containing the compound, and their use in preparing drugs for preventing and / or treating HPK1-mediated related diseases. Background Art

[0003] HPK1 (Hematopoietic progenitor kinase 1), also known as MAP4K1, is a serine / threonine kinase and a member of the MAP4K family. It is expressed by hematopoietic cells and can activate the JNK / MAPK signaling pathway by binding to adaptor proteins such as SLP76, thereby negatively regulating the TCR (T cell receptor) pathway. It plays an important role in immune regulation, and HPK1 has also become a popular target for tumor immunity.

[0004] MAP4K3 (also known as GLK) is a serine / threonine kinase that belongs to the mammalian Ste20-like kinase family and is a homologous enzyme to HPK1. In T cells, GLK directly interacts with and activates PKCθ by phosphorylating PKCθ at Ser-538, leading to IKK / NF-κB activation. Consequently, GLK-deficient mice exhibit impaired T cell-mediated immune responses and reduced inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of T cells overexpressing GLK is increased in the peripheral blood of patients with autoimmune diseases.

[0005] Given that HPK1 plays an important role in the occurrence and development of tumors and immune-related diseases (solid tumors, hematological tumors, autoimmune diseases, inflammation, etc.), and there are no marketed drugs targeting this target, it is particularly important to develop highly active, highly selective, and druggable HPK1 inhibitors.

[0006] Summary of the Invention

[0007] One object of the present invention is to provide a class of HPK1 inhibitor compounds and a method for preparing the same; another object of the present invention is to provide a class of HPK1 inhibitor compounds for use in tumor immunotherapy; the compounds of the present invention have good HPK1 inhibitory activity and kinase selectivity, good drugability, and can be used to prevent and / or treat HPK1-mediated related diseases.

[0008] The present invention provides a compound of formula (I'), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0009] Wherein, each group is as defined in this application.

[0010] Some embodiments of the present invention relate to salts of the above compounds, preferably hydrochlorides.

[0011] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0012] In some embodiments, the present invention provides the use of a compound of the present invention or a pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing an HPK1-mediated disorder, disease, or condition.

[0013] In some embodiments, the present invention provides a method for treating and / or preventing HPK1-mediated disorders, diseases or conditions using a compound of the present invention or a pharmaceutical composition thereof, comprising administering the compound of the present invention or a pharmaceutical composition thereof to a subject.

[0014] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutical composition thereof for use in treating and / or preventing an HPK-mediated disorder, disease, or condition.

[0015] In some embodiments, the present invention is used to treat and / or prevent proliferative disorders.

[0016] In some embodiments, the proliferative disorder is associated with one or more activating mutations in HPK1.

[0017] In some embodiments, the proliferative disorder is cancer.

[0018] In some embodiments, the HPK1 -mediated disorder, disease, or condition is a chronic viral infection.

[0019] In some embodiments, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition thereof in the preparation of a medicament for increasing the efficacy of vaccination.

[0020] In some embodiments, the present invention relates to a compound of the present invention or a pharmaceutical composition thereof for use in increasing the efficacy of vaccination.

[0021] In some embodiments, the present invention relates to a method of increasing the efficacy of vaccination using a compound of the present invention or a pharmaceutical composition thereof, comprising administering the compound or pharmaceutical composition to a subject.

[0022] Definition and Description

[0023] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0024] definition

[0025] Chemical definition

[0026] Definitions of specific functional groups and chemical terms are described in more detail below.

[0027] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-8 "Alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C 1-8 、C 1-7 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-8 、C 2-7 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-8 、C 3-7 、C 3-6 、C 3-5 、C 3-4 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-8 、C 5-7 、C 5-6 、C 6-8 、C 6-7 and C 7-8 .

[0028] “C 1-8 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms. In some embodiments, C1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), i-Bu(-CH2CH(CH3)2), and t-Bu(-C(CH3)3).

[0029] “C 2-8 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-6 Alkenyl and C 2-4 Alkenyl is preferred. In some embodiments, C 2-6 Alkenyl is preferred. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] “C 2-8 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-6 Alkynyl is preferred. In some embodiments, C 2-4Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] “C 1-8 "Alkylene" refers to the removal of C 1-8 In some embodiments, C 1-6 Alkylene, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. In some embodiments, C 1-2 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0032] “C 0-8 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-8 Alkylene", "C 0-6 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-4 Alkylene", "C 0-3"Alkylene" refers to the chemical bond and the above-mentioned "C 1-3 "Alkylene".

[0033] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0034] “C 1-8 "Haloalkyl" refers to the above-mentioned "C 1-8 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-6 Halogenated alkyl, C 1-4 Halogenated alkyl, C 1-3 Haloalkyl and C 1-2 Haloalkyl is particularly preferred. Exemplary haloalkyl includes, but is not limited to: -CF , -CH F, -CHF , -CHFCH F, -CH CHF , -CF CF , -CCl , -CH Cl , -CHCl , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The haloalkyl group can be substituted at any available point of attachment, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] "3- to 14-membered carbocyclyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, including monocyclic carbocyclyls, bridged carbocyclyls, spirocarbocyclyls, and fused carbocyclyls, optionally containing 1, 2, or 3 double bonds or triple bonds. More specifically, it includes any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic ring or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring. In some embodiments, C 5-10 Cycloalkyl, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C5-7 Cycloalkyl and C 5-6 In some embodiments, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl (C6), cycloheptyl, cycloheptenyl, cycloheptadienyl (C7), cycloheptatrienyl (C7), adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane, bicyclo[2.2.2]octane, fluorenyl, indanyl, adamantyl, and tetrahydronaphthyl. A cycloalkyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] "3- to 14-membered heterocyclyl" refers to a group of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon, and optionally contains 1, 2 or 3 double bonds or triple bonds. Optionally, the nitrogen atom is oxidized to form an N-oxide; the sulfur atom is oxidized to form a sulfone or sulfoxide. The 3- to 14-membered heterocyclyl includes a monocyclic heterocyclyl, a bridged heterocyclyl, a spiro heterocyclyl and a fused heterocyclyl. More specifically, it includes any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic ring. More preferably, it includes a 3- to 8-membered or 3- to 7-membered monocyclic heterocyclyl, a 6- to 10-membered bridged bicyclic heterocyclyl, a 6- to 10-membered spiro bicyclic heterocyclyl and a 6- to 10-membered fused bicyclic heterocyclyl. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. In some embodiments, 4-12 membered heterocyclyl groups are preferred, which are 4-12 membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms selected from N, O and S; in some embodiments, 3-10 membered heterocyclyl groups are preferred, which are 3-10 membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms selected from N, O and S; in some embodiments, 3-8 membered or 3-7 membered heterocyclyl groups are preferred, which are 3-8 membered or 3-7 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms selected from N, O and S; 3-12 membered heterocyclyl groups are preferred, which are 4-12 membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms selected from N, O and S; The heterocyclyl group is preferably a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O, and S; preferably a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O, and S; more preferably a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O, and S; more preferably a 4- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 2 ring heteroatoms selected from N, O, and S. In some embodiments, the heterocyclyl group has 1 O ring heteroatom and 1 N ring heteroatom. In some embodiments, the heterocyclyl group has 1 O ring heteroatom. Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, where the point of attachment is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiirane. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, oxazolidinyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, thiepanyl, heterocycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 7-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, azazepanyl, oxathipanyl, and thiazepanyl nitrogen. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinone. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] "5- to 14-membered heteroaryl" refers to a group of a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 10-membered heteroaryl is preferred, which is a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryls are particularly preferred, which are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, pyridonyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0040] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0041] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2, -SO2R aa 、-SO2ORaa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0042] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNRbb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0043] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0044] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0045] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ccThe groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0046] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2. -NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(Ree )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0047] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0048] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0049] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6- 10 Aryl, C3-7 heterocyclic, C5- 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0050] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb、R cc and R dd As mentioned above.

[0051] Other definitions

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0053] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0054] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0055] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0056] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0057] "Disease," "disorder," and "condition" are used interchangeably herein.

[0058] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0059] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0060] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0061] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form.

[0062] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0063] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0064] The term "solvate" refers to a form of a compound or its salt that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0065] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).

[0066] The term "metabolite" refers to substances including products produced during the metabolism of the compounds of the present invention in the body, including intermediate metabolites and terminal metabolites.

[0067] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0068] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 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. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0069] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0070] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0071] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention. DETAILED DESCRIPTION

[0072] Herein, "compounds of the present invention" refers to the compounds of the following formula (I'), formula (I), formula (II), etc., and pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0073] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0074] In one embodiment, the present invention relates to a compound of formula (I'), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0075] V is selected from the group consisting of covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0076] W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0077] Z7 is C;

[0078] Or V and W are not connected, Z7 is C or N, and W is selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H and C 1-6 Alkyl, V is selected from the group consisting of: absent, H, D, halogen, C 1-8 Alkyl and C 1-8 haloalkyl, preferably selected from the group consisting of absent, H, D and halogen;

[0079] Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A)S(O)2-; and Q and Y are not covalent bonds at the same time;

[0080] or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0081] R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0082] R B Selected from H, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0083] R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0084] One of Z1 and Z6 is CR E , the other is CR d1 or N;

[0085] R E Selected from -L-C6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C6- 10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution;

[0086] R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R es replace;

[0087] Or two R e and the atoms to which they are attached together form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R es replace;

[0088] R es Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR' and -L'-NR'R";

[0089] R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0090] Ring A is selected from C6- 10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring;

[0091] R dindependently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0092] Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0093] R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0094] or CR dd R dd To form a 3 to 7 membered carbocyclylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0095] Or two non-adjacent R dd Together they form C 1-8 Alkylene, optionally substituted with one or more of the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl, or -L"-5 to 10-membered heteroaryl;

[0096] Or two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene, or a 5- to 6-membered heteroarylene, which is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0097] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0098] R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl;

[0099] L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0100] R is independently selected from H, D, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -3 to 10-membered carbocyclic group or -L d -3 to 10-membered heterocyclic group;

[0101] or two R together with the C atom to which they are commonly attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene;

[0102] L d Independently selected from a covalent bond or C 1-8 alkylene;

[0103] f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0104] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0105] In one embodiment, the present invention relates to a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0106] V is selected from the group consisting of covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0107] W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0108] Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time;

[0109] or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b-、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0110] R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0111] R B Selected from H, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0112] R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0113] One of Z1 and Z6 is CR E , the other is CR d1 or N;

[0114] R E Selected from -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C6- 10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 Re group substitution;

[0115] R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl;

[0116] R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0117] Ring A is selected from C6- 10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring;

[0118] R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0119] Or two adjacent R dThe 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0120] R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0121] Or two R dd Together they form C 1-8 Alkylene, optionally substituted with one or more of the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl, or -L"-5 to 10-membered heteroaryl;

[0122] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0123] R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl;

[0124] L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0125] R is independently selected from H, D, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -3 to 10-membered carbocyclic group or -L d -3 to 10-membered heterocyclic group;

[0126] or two R together with the C atom to which they are commonly attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene;

[0127] L d Independently selected from a covalent bond or C 1-8 alkylene;

[0128] f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0129] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0130] In another embodiment, the present invention relates to a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0131] V is selected from the group consisting of covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0132] W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0133] Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、 -OC(O)-、 -OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time;

[0134] or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0135] R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0136] R B Selected from H, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0137] R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0138] One of Z1 and Z6 is CR E , the other is CR d1 or N;

[0139] R E Selected from -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C6- 10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution;

[0140] R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl;

[0141] R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0142] Ring A is selected from C6- 10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring;

[0143] R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0144] Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0145] R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0146] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0147] R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl;

[0148] L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0149] f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0150] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0151] V

[0152] In one embodiment, V is a covalent bond; in another embodiment, V is O; in another embodiment, V is S; in another embodiment, V is NR'; in another embodiment, V is S(O); in another embodiment, V is S(O)2; in another embodiment, V is C(O); in another embodiment, V is CR C In another embodiment, V is CR C R C '.

[0153] In a more specific embodiment, V is selected from the group consisting of a covalent bond, a CR C or CR C R C '; In a more specific embodiment, V is selected from a covalent bond, CH, CH2, CD, CHD or CD2; In a more specific embodiment, V is a covalent bond.

[0154] In one embodiment, V is not connected to W; in another embodiment, V is absent; in another embodiment, V is H; in another embodiment, V is D; in another embodiment, V is a halogen, such as F; in another embodiment, V is C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, V is C 1-8 Halogenated alkyl, preferably C 1-6 Halogenated alkyl.

[0155] In a more specific embodiment, V is selected from the group consisting of absent, H, D, halogen, C 1-8 Alkyl and C 1-8 Haloalkyl; in another more specific embodiment, V is selected from the group consisting of absent, H, D, and halogen.

[0156] Z7

[0157] In one embodiment, Z7 is C.

[0158] In one embodiment, V and W are not connected, V does not exist, and Z7 is N.

[0159] W

[0160] In one embodiment, W is NR'; in another embodiment, W is S(O); in another embodiment, W is S(O)2; in another embodiment, W is C(O); in another embodiment, W is CR C In another embodiment, W is CR C R C '.

[0161] In a more specific embodiment, W is CR C or CR C R C '; In another more specific embodiment, W is CR C R C ', for example, CH2, CD, CHD or CD2, for example, CH2.

[0162] In one embodiment, V and W are not connected; in one embodiment, W is H; in another embodiment, W is C 1-6 Alkyl, such as methyl; in another embodiment, W is C 1-6 Halogenated alkyl.

[0163] In a more specific embodiment, W is selected from H and C 1-6 alkyl.

[0164] Q and Y

[0165] In one embodiment, Q is a covalent bond; in another embodiment, Q is -O-; in another embodiment, Q is -S-; in another embodiment, Q is -NR A -; in another embodiment, Q is -S(O)-; in another embodiment; in another embodiment, Q is Q is -S(O)2-; in another embodiment, Q is -C(O)-; in another embodiment, Q is -C(O)O-; in another embodiment, Q is -C(O)NR A -; In another embodiment, Q is -OC(O)-; In another embodiment, Q is -OC(O)NR A -; In another embodiment, Q is -N(R A )C(O)O-; in another embodiment, Q is -N(R A )C(O)-; In another embodiment, Q is -N(R A )S(O)2-; In another embodiment, Q is CR 1a R 1b ;

[0166] Or Q is C 1-8 Alkylene, in one embodiment, one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0167] In one embodiment, Y is a covalent bond; in another embodiment, Y is -O-; in another embodiment, Y is -S-; in another embodiment, Y is -NR A -; In another embodiment, Y is -S(O)-; In another embodiment, Y is -S(O)2-; In another embodiment, Y is -C(O)-; In another embodiment, Y is -C(O)O-; In another embodiment, Y is -C(O)NR A -; In another embodiment, Y is -OC(O)-; In another embodiment, Y is -OC(O)NR A -; In another embodiment, Y is -N(R A)C(O)O-; In another embodiment, Y is -N(R A )C(O)-; In another embodiment, Y is -N(R A )S(O)2-; In another embodiment, Y is CR 1a R 1b ;

[0168] Or Y is C 1-8 Alkylene, in one embodiment, one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0169] And Q and Y are not covalent bonds at the same time.

[0170] In a more specific embodiment, Q and Y are independently selected from a covalent bond, O, S, NR A , S(O), S(O)2, C(O) or CR 1a R 1b ; and Q and Y are not covalent bonds at the same time.

[0171] In another more specific embodiment, Q is selected from O, S or NR A In another more specific embodiment, Q is S or NR A In another more specific embodiment, Q is NR A , for example NH.

[0172] In another more specific embodiment, Y is selected from a covalent bond, O, S or CR 1a R 1b In another more specific embodiment, Y is selected from a covalent bond, O or CR 1a R 1b In another more specific embodiment, Y is selected from a covalent bond, O, CH2, CF2 or C(CH3)2; In another more specific embodiment, Y is C(CH3)2; In another more specific embodiment, Y is

[0173] R A

[0174] In one embodiment, R A is H; in another embodiment, R A C 1-8 Alkyl; in another embodiment, R A C 1-8 Alkoxy; in another embodiment, R A C 1-8 haloalkyl; in another embodiment, R A -L"-C6- 10 Aryl; In another embodiment, R A is -L"-3 to 14-membered carbocyclyl; in another embodiment, R A is -L"-3 to 14-membered heterocyclyl or -L"-5 to 14-membered heteroaryl; in another embodiment, R A C 1-6 Alkyl; in another embodiment, R A C 1-6 haloalkyl; in another embodiment, R A is -L"-3 to 10-membered carbocyclyl; in another embodiment, R A is -L"-3 to 10-membered heterocyclic group.

[0175] In a more specific embodiment, R A Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl, or -L"-3 to 10-membered heterocyclyl; in another more specific embodiment, R A Selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R A For H.

[0176] R B

[0177] In one embodiment, R B is H; in another embodiment, R B C 1-8 Alkyl; in another embodiment, R B is C2-8 alkenyl; in another embodiment, R B is C2-8 alkynyl; in another embodiment, R B C 1-8 haloalkyl; in another embodiment, R B is -L-OR'; in another embodiment, R B is -L-NR'R"; in another embodiment, RB is -LC(O)NR'R"; in another embodiment, R B For-L-C6- 10 Aryl; In another embodiment, R B is -L-3 to 14 membered carbocyclyl; in another embodiment, R B is -L-3 to 14 membered heterocyclyl; in another embodiment, R B is -L-5 to 14 membered heteroaryl; in another embodiment, R B C 1-6 Alkyl; in another embodiment, R B C 1-6 haloalkyl; in another embodiment, R B is -L-3 to 10 membered carbocyclyl; in another embodiment, R B It is -L-3 to 10-membered heterocyclic group.

[0178] In a more specific embodiment, R B Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; in another more specific embodiment, R B Selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R B For H.

[0179] R C and R' C

[0180] In one embodiment, R C is H; in another embodiment, R C is D; in another embodiment, R C is halogen; in another embodiment, R C is -CN; in another embodiment, R C C 1-8 Alkyl; in another embodiment, R C is C2-8 alkenyl; in another embodiment, R C is C2-8 alkynyl; in another embodiment, R C C 1-8 haloalkyl; in another embodiment, R C is -L-OR'; in another embodiment, R Cis -L-NR'R"; in another embodiment, R C is -LC(O)NR'R"; in another embodiment, R C For-L-C6- 10 Aryl; In another embodiment, R C is -L-3 to 14 membered carbocyclyl; in another embodiment, R C is -L-3 to 14 membered heterocyclyl; in another embodiment, R C is -L-5 to 14 membered heteroaryl; in another embodiment, R C C 1-6 Alkyl; in another embodiment, R C C 1-6 haloalkyl; in another embodiment, R C is -L-3 to 10 membered carbocyclyl; in another embodiment, R C It is -L-3 to 10-membered heterocyclic group.

[0181] In one embodiment, R' C is H; in another embodiment, R' C is D; in another embodiment, R' C is halogen; in another embodiment, R' C is -CN; in another embodiment, R' C C 1-8 Alkyl; in another embodiment, R' C is C2-8 alkenyl; in another embodiment, R' C is C2-8 alkynyl; in another embodiment, R' C C 1-8 Haloalkyl; in another embodiment, R' C is -L-OR'; in another embodiment, R' C is -L-NR'R"; in another embodiment, R' C is -LC(O)NR'R"; in another embodiment, R' C For-L-C6- 10 Aryl; in another embodiment, R' C is -L-3 to 14 membered carbocyclyl; in another embodiment, R' C is -L-3 to 14 membered heterocyclyl; in another embodiment, R' C is -L-5 to 14 membered heteroaryl; in another embodiment, R' C C 1-6 Alkyl; in another embodiment, R' C C1-6 Haloalkyl; in another embodiment, R' C is -L-3 to 10 membered carbocyclyl; in another embodiment, R' C It is -L-3 to 10-membered heterocyclic group.

[0182] In a more specific embodiment, R C and R' C Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl or -L-3 to 10-membered heterocyclyl; in another more specific embodiment, R C and R' C Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R C and R' C are independently H or D.

[0183] R 1a and R 1b

[0184] In one embodiment, R 1a is H; in another embodiment, R 1a is D; in another embodiment, R 1a is halogen; in another embodiment, R 1a is -CN; in another embodiment, R 1a C 1-8 Alkyl; in another embodiment, R 1a is C2-8 alkenyl; in another embodiment, R 1a is C2-8 alkynyl; in another embodiment, R 1a C 1-8 haloalkyl; in another embodiment, R 1a is -L-OR'; in another embodiment, R C is -L-NR'R"; in another embodiment, R 1a is -LC(O)NR'R"; in another embodiment, R 1a For-L-C6- 10 Aryl; In another embodiment, R 1a is -L-3 to 14 membered carbocyclyl; in another embodiment, R C is -L-3 to 14 membered heterocyclyl; in another embodiment, R 1ais -L-5 to 14 membered heteroaryl; in another embodiment, R 1a C 1-6 Alkyl; in another embodiment, R 1a C 1-6 haloalkyl; in another embodiment, R 1a is -L-3 to 10 membered carbocyclyl; in another embodiment, R 1a is -L-3 to 10 membered heterocyclyl; in another embodiment, R 1a is F; in another embodiment, R 1a is Me; in another embodiment, R 1a For Et.

[0185] In one embodiment, R 1b is H; in another embodiment, R 1b is D; in another embodiment, R 1b is halogen; in another embodiment, R 1b is -CN; in another embodiment, R 1b C 1-8 Alkyl; in another embodiment, R 1b is C2-8 alkenyl; in another embodiment, R 1b is C2-8 alkynyl; in another embodiment, R 1b C 1-8 haloalkyl; in another embodiment, R 1b is -L-OR'; in another embodiment, R 1b is -L-NR'R"; in another embodiment, R 1b is -LC(O)NR'R"; in another embodiment, R 1b For-L-C6- 10 Aryl; In another embodiment, R 1b is -L-3 to 14 membered carbocyclyl; in another embodiment, R 1b is -L-3 to 14 membered heterocyclyl; in another embodiment, R 1b is -L-5 to 14 membered heteroaryl; in another embodiment, R 1b C 1-6 Alkyl; in another embodiment, R 1b C 1-6 haloalkyl; in another embodiment, R 1b is -L-3 to 10 membered carbocyclyl; in another embodiment, R 1b is -L-3 to 10 membered heterocyclyl; in another embodiment, R 1bis F; in another embodiment, R 1b is Me; in another embodiment, R 1b For Et.

[0186] In a more specific embodiment, R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; in another more specific embodiment, R 1a and R 1b Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1a and R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1a and R 1b Independently selected from H, D, halogen, C 1-3 Alkyl or C 1-3 In another more specific embodiment, R 1a and R 1b are independently selected from H, D, F or Me; in another more specific embodiment, R 1a and R 1b For Me.

[0187] In a more specific embodiment, R 1a and R 1b Independently selected from C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1a and R 1b Independently selected from C 1-3 Alkyl or C 1-3 In another more specific embodiment, R 1a and R 1b Independently selected from Me or Et.

[0188] Z1 and Z6

[0189] In one embodiment, Z1 is CR E , Z6 is CR d1 In another embodiment, Z1 is CR E, Z6 is N; in another embodiment, Z6 is CR E , Z1 is CR d1 In another embodiment, Z6 is CR E , Z1 is N.

[0190] In a more specific embodiment, Z6 is CR E , Z1 is CH or CD; in another more specific embodiment, Z1 is CR E , Z6 is CH or CD.

[0191] R E

[0192] In one embodiment, R E For-L-C6- 10 Aryl; In another embodiment, R E is -L-3 to 14 membered carbocyclyl; in another embodiment, R E is -L-3 to 14 membered heterocyclyl; in another embodiment, R E is -L-5 to 14 membered heteroaryl; in another embodiment, R E is phenyl; in another embodiment, R E is pyridinyl; in another embodiment, R E is pyridonyl; in another embodiment, R E is pyrimidinyl; in another embodiment, R E is pyrazinyl; in another embodiment, R E is pyrrolyl; in another embodiment, R E is pyrazolyl; in another embodiment, R E is imidazolyl; in another embodiment, R E is oxazolyl; in another embodiment, R E is triazolyl; in another embodiment, R E is pyrrolopyridinyl; in another embodiment, R E is pyrrolopyridazinyl; in another embodiment, R E is pyrrolopyrimidinyl; in another embodiment, R E is pyrrolopyrazinyl; in another embodiment, R E is imidazopyridinyl; in another embodiment, R E is imidazopyridazinyl; in another embodiment, R E is imidazopyrimidinyl; in another embodiment, R E is imidazopyrazinyl; in another embodiment, R Eis pyrazolopyridinyl; in another embodiment, R E is pyrazolopyridazinyl; in another embodiment, R E is pyrazolopyrimidinyl; in another embodiment, R E is pyrazolopyrazinyl; in another embodiment, R E is pyridopyridinyl; in another embodiment, R E is dihydropyridoxazinyl; in another embodiment, R E is indolyl; in another embodiment, R E is triazolopyridinyl; in another embodiment, R E is triazolopyridinyl; in another embodiment, R E is tetrahydroimidazopyrazinyl; in another embodiment, R E is dihydropyrrolopyridinyl; in another embodiment, R E is thienopyridinyl; in another embodiment, R E is benzimidazolyl; in another embodiment, R E is dihydroimidazooxazinyl; in another embodiment, R E is tetrahydropyrazolopyridinyl; in another embodiment, R E is tetrahydropyrrolopyridinyl; in another embodiment, R E is dihydropyrazoloxazinyl; in another embodiment, R E is dihydropyrroloimidazolyl; in another embodiment, R E is oxazolopyridinyl; in another embodiment, R E is imidazocyclohexyl; in another embodiment, R E is pyrazoloazepanyl; in another embodiment, R E is pyrazoloazepine; in another embodiment, R E is pyrazoloazacyclopentyl; in another embodiment, R E is imidazoazepine; in another embodiment, R E is imidazolyl; in another embodiment, R E is imidazolyl alkyl; in another embodiment, R E is imidazopyrazinone; in another embodiment, R E is imidazodiazepine; in another embodiment, R E is imidazopiperazinone; in another embodiment, R E is pyrazolodiazepanyl; in another embodiment, R Eis pyrazolodiazepine; in another embodiment, R E is pyrazolodiazepine; in another embodiment, R E is dihydropyrazoloxazinyl; in another embodiment, R E is triazoloazacyclohexyl; in another embodiment, R E is thienopyridinyl; in another embodiment, R E Optionally 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R e Group substitution.

[0193] In a more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for wherein g=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; in another more specific embodiment, g=0, 1, 2, 3, 4, 5 or 6; in another more specific embodiment, g=0, 1, 2, 3 or 4; in another more specific embodiment, g=0, 1 or 2.

[0194] In a more specific embodiment, R E Together with the substituent R thereon e Formed together In another more specific embodiment, R E Together with the substituent R thereon e Formed together In another more specific embodiment, R E Together with the substituent R thereon e Formed together In another more specific embodiment, R E Together with the substituent R thereon e Formed together In another more specific embodiment, R E Together with the substituent R thereon e Formed together Among them, X1 is CR e6 , N, O, S or NR' e6 , preferably CR e6 , N or NR' e6 , preferably N, preferably CR e6 , preferably O, preferably S, preferably NR' e6 ; X2 is C or N, preferably C, preferably N; X3 is C or N, preferably C, preferably N; X4 is CR e4 or N, preferably CR e4 , preferably N; X5 is CR e5 , N, O, S or NR' e5 , preferably CR e5 , O, N or NR' e5, preferably CR e5 , N or NR' e5 , preferably CR e5 or N, preferably CR e5 , preferably N, preferably O, preferably S, preferably NR' e5 ; X6 is C or N, preferably C, preferably N; X7 is CR e1 or N, preferably CR e1 , preferably N; X8 is CR e2 or N, preferably CR e2 , preferably N; X9 is CR e3 or N, preferably CR e3 , preferably N; X 10 Selected from CR e7 , O, S, N or NR' e7 , preferably CR e7 , N or NR' e7 , preferably CR e7 or NR' e7 , preferably CR e7 , preferably NR' e7 , preferably O, preferably S, preferably N; X 11 CR e8 , O, S, N, or NR' e8 , preferably CR e8 , O, N or NR' e8 , preferably CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 , preferably CR e8 , preferably NR' e8 , preferably O, preferably S, preferably N; E is selected from CR e12 or N, preferably CR e12 , preferably N; J is selected from CR e13 or N, preferably CR e13 , preferably N.

[0195] In a more specific embodiment, X 10 and X 11 The substituents on the 3-5 Alkylene, which optionally contains a double bond, the C 3-5 The alkylene group is optionally substituted by 1, 2, 3 or 4 R eIn another more specific embodiment, X is optionally substituted with one or more methylene units, wherein one or more methylene units are optionally and independently replaced by NR"-, -N(R")C(O)-, -C(O)N(R")-, -N(R")S(O)2-, -S(O)2N(R")-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-, preferably one, two or three methylene units are optionally and independently replaced by -NR"-, -N(R")C(O)-, -C(O)N(R")-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S- or -S(O)-; in another more specific embodiment, X is optionally substituted with one or more methylene units, wherein one or more methylene units are optionally and independently replaced by ... 10 and X 11 The substituents on the 3-5 Alkylene, preferably forming -(CH2)4-, which optionally contains a double bond, the C 3-5 Alkylene or -(CH2)4- is optionally substituted by 1, 2, 3 or 4 R e substituted, and wherein 1, 2 or 3 methylene units are optionally and independently replaced by -NR"-, -C(O)N(R")-, -C(O)- or -O-, preferably wherein 1 methylene unit is optionally and independently replaced by -O-; in another more specific embodiment, X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably

[0196] In another more specific embodiment, X 10 and X 11 The substituents on Preferably not Preferably selected from:

[0197] In a more specific embodiment, R e1 、R e2 、R e3 、R e4 、R e5 and R e6 Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C 1-8Haloalkyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", 3 to 7 membered carbocyclic group or 3 to 7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' or -NR'R"; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -O-3 to 7 membered carbocyclic group or 3 to 7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl or -OR'; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR', -O-3 to 7 membered carbocyclic group, preferably selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl or -OR'; in another more specific embodiment, R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl or Preferably selected from H, F, Cl, CN, Me, CHF2, OCH3 or OEt, preferably R e2is not OEt; in another more specific embodiment, R e1 and R e2 independently selected from H, F, CN, Me, OMe, OEt, OCHF2 or -O-cyclopropyl, preferably selected from H, F, CN, Me, OCH3, OEt, OCHF2 or -O-cyclopropyl, preferably selected from H, Me, OCH3 or OEt;

[0198] In a more specific embodiment, R e3 、R e4 、R e5 and R e6 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R' e5 and R' e6 Independently selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e3 、R e4 、R e5 and R e6 are independently H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e3 、R e4 and R e5 are independently H or D; in another more specific embodiment, R e3 、R e4 and R e5 is H; in a more specific embodiment, R' e5 and R' e6 Independently selected from H, C 1-8 Alkyl or C 1-8 In another more specific embodiment, R' e5 and R' e6 Independently selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R' e5 Selected from H, C 1-3 Alkyl or C 1-3 In another more specific embodiment, R' e5 is Me; in another more specific embodiment, R e5 For H.

[0199] In a more specific embodiment, R e5 Selected from H, D, halogen, CN, C1-6 Alkyl or C 1-6 In another more specific embodiment, R e5 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e5 Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 In another more specific embodiment, R e5 is H or D; in another more specific embodiment, R e5 is selected from H, D, F, Br and Me; in another more specific embodiment, R e5 For H.

[0200] In one embodiment, R e1 / R e2 is H; in another embodiment, R e1 / R e2 is D; in another embodiment, R e1 / R e2 is halogen; in another embodiment, R e1 / R e2 is CN; in another embodiment, R e1 / R e2 C 1-6 Alkyl; in another embodiment, R e1 / R e2 C 1-6 haloalkyl; in another embodiment, R e1 / R e2 C 2-6 alkenyl; in another embodiment, R e1 / R e2 C 2-6 Alkynyl; in another embodiment, R e1 / R e2 is -L'-OR'; in another embodiment, R e1 / R e2 is -L'-SR'; in another embodiment, R e1 / R e2 is -L'-NR'R"; in another embodiment, R e1 / R e2 is -L'-3 to 7 membered carbocyclyl; in another embodiment, R e1 / R e2 is -L'-3 to 7 membered heterocyclyl; in another embodiment, R e1 / R e2Optionally 1, 2 or 3 R es In another embodiment, R e1 / R e2 Not replaced.

[0201] In one embodiment, R e1 The configuration in the general formula is In another embodiment, R e1 The configuration in the general formula is In another embodiment, R e2 The configuration in the general formula is In another embodiment, R e2 The configuration in the general formula is

[0202] In a more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", -O-3 to 7 membered carbocyclyl, -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl; in another more specific embodiment, R e1 and R e2 is independently not -NR'R"; in another more specific embodiment, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6Alkynyl, -OR', -O-3 to 7 membered carbocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl; in another more specific embodiment, R e1 Not a heterocyclic group.

[0203] In one embodiment, R e1 / R e2 is H; in another embodiment, R e1 / R e2 is F; in another embodiment, R e1 / R e2 is Cl; in another embodiment, R e1 / R e2 is CN; in another embodiment, R e1 / R e2 is Me; in another embodiment, R e1 / R e2 is Et; in another embodiment, R e1 / R e2 is n-Bu; in another embodiment, R e1 / R e2 is CHF2; in another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 is OH; in another embodiment, R e1 / R e2 is OCH3; in another embodiment, R e1 / R e2 is OEt; in another embodiment, R e1 / R e2 is OCHF2; in another embodiment, R e1 / R e2 is -NHCH3; in another embodiment, R e1 / R e2 is -O-cyclopropyl; in another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 is cyclopropyl; in another embodiment, R e1 / Re2 for In another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 for In another embodiment, R e1 / R e2 for

[0204] In a more specific embodiment, R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OH, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably not Preferably selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, cyclopropyl,

[0205] In a more specific embodiment, R e1 Not for In another more specific embodiment, R e2 Not for OEt.

[0206] In a more specific embodiment, R e1 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -NR'R", -O-3 to 7 membered carbocyclyl, -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl; in another more specific embodiment, R e1is not -NR'R" and 3 to 7 membered heterocyclyl; in another more specific embodiment, R e1 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -O-3 to 7 membered carbocyclyl and 3 to 7 membered carbocyclyl; in another more specific embodiment, R e1 Selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, and cyclopropyl, preferably selected from H, F, CN, Me, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and cyclopropyl.

[0207] In a more specific embodiment, R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl; in another more specific embodiment, R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OMe, -O-halomethyl, 3 to 7 membered carbocyclyl, and 3 to 7 membered heterocyclyl; in another more specific embodiment, R e2 Selected from H, F, Cl, CN, Me, CHF2, OCH3, OEt, OCHF2, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, CHF2, OCH3, OCHF2, cyclopropyl,

[0208] In a more specific embodiment, when R e1 / R e2 When it is a heterocyclic group, R es independently selected from H, D, halogen (F), C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably selected from H, D, F and Me, and is preferably halogen (F).

[0209] In a more specific embodiment, Re1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR', -O-3 to 7 membered carbocyclyl and -O-3 to 7 membered heterocyclyl, preferably not halogen, preferably selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -O-3 to 7 membered carbocyclyl; in another more specific embodiment, R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 In another more specific embodiment, preferably R e2 H, D or C 1-6 alkyl halide;

[0210] In a more specific embodiment, R e1 and R e2 independently selected from H, F, CN, Me, CHF2, OH, OMe, OEt, OCHF2, -O-cyclopropyl and Preferably selected from H, CN, Me, CHF2, OH, OCH3, OEt, -O-cyclopropyl and Preferably selected from H, Me, CHF2, OCH3, OEt and -O-cyclopropyl; in another more specific embodiment, R e2 is selected from H, F, CN, Me, CHF2, OH and OMe; in another more specific embodiment, R e2 is H or CHF2.

[0211] In a more specific embodiment, R' e1 and R' e2 Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, halogen and C 1-6 Alkyl; in another more specific embodiment, R' e1 and R' e2 Independently selected from H, F and Me.

[0212] In a more specific embodiment, CR e1 R' e1 To form a 3- to 7-membered carbocyclic group and a 3- to 7-membered heterocyclic group, preferably to form a 3- to 7-membered heterocyclic group (e.g. For example ), preferably forming a 3 to 7 membered heterocyclyl 3 to 7 membered carbocyclyl; in another more specific embodiment, CR e1 R' e1 form In another more specific embodiment, CR e1 R' e1 No ring is formed.

[0213] In a more specific embodiment, R e7 and R e8 Independently selected from H, D, halogen, CN, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 10-membered carbocyclyl or -L'-3 to 10-membered heterocyclyl; in another more specific embodiment, R' e7 and R' e8 Independently selected from H, D, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-3 to 10-membered carbocyclyl, or -L'-3 to 10-membered heterocyclyl; in another more specific embodiment, R e7 and R e8 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R' e7 and R' e8 Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R e7 Selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; in another more specific embodiment, R' e7 Selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; in another more specific embodiment, R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R' e8 Selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e7 Selected from C 1-6 Alkyl, C 1-6haloalkyl, 3 to 7 membered carbocyclyl, 3 to 7 membered heterocyclyl or -O-3 to 7 membered heterocyclyl; in another more specific embodiment, R' e7 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, preferably 3 to 7 membered carbocyclyl; in another more specific embodiment, when R e7 or R' e7 When it is a heterocyclic group, it is a 3- to 7-membered oxo heterocyclic group, preferably a 4- to 6-membered oxo heterocyclic group, preferably a 5-membered oxo heterocyclic group; in another more specific embodiment, R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 In another more specific embodiment, R' e8 Selected from C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, In another more specific embodiment, R' e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or morpholinyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl or tetrahydropyranyl, preferably selected from Me, Et, cyclopropyl or tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl or Preferably cyclopropyl; In another more specific embodiment, in another more specific embodiment, R e8 is selected from H, Me or Et, preferably H or Me, preferably Me; in another more specific embodiment, R' e8 is Me or Et, preferably Me.

[0214] In a more specific embodiment, R e7 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 7 membered carbocyclyl, tetrahydrofuranyl, morpholinyl, and -O-3 to 7 membered heterocyclyl; in another more specific embodiment, R e7 Selected from Me, Et, cyclopropyl, In another more specific embodiment, R e7 Selected from Me, Et, cyclopropyl, In another more specific embodiment, R e7 is a 3- to 7-membered carbocyclic group; in another more specific embodiment, R e7 It is cyclopropyl.

[0215] In a more specific embodiment, R' e7 is selected from Me, Et and cyclopropyl; in another more specific embodiment, R' e7 It is cyclopropyl.

[0216] In a more specific embodiment, R e9 、R e10 、R e11 、R e12 and R e13 Selected from H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 10-membered carbocyclyl, -L'-3 to 10-membered heterocyclyl or -Y5-C 0-8 Alkylene-R6; In a more specific embodiment, R e9 、R e10 、R e11 、R e12 and R e13 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, -L'-3 to 7 membered heterocyclyl or -Y5-C 0-6 Alkylene-R6; In a more specific embodiment, R e9 Selected from H, D, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl, 3 to 7 membered heterocyclyl or -Y5-C 0-6 Alkylene-R6, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR' or -NR'R"; in a more specific embodiment, R e10 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In a more specific embodiment, R e11 、R e12 and R e13 H, D, C 1-6 Alkyl or C 1-6 In a more specific embodiment, R e9 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl, -NR'R", 3 to 7 membered heterocyclic group or -OC 0-4 Alkylene-3-7 membered heterocyclic group, preferably selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl or -NR'R"; in a more specific embodiment, R e10 Selected from H, D, C 1-6 Alkyl or C 1-6 In a more specific embodiment, R e11 、R e12 and R e13 is H or D; in a more specific embodiment, R e9 Selected from H, -NHMe, Preferably selected from H, -NHMe or In a more specific embodiment, R e10 is selected from H or Me; in a more specific embodiment, R e11 、R e12 and R e13 For H.

[0217] In a more specific embodiment, R e9 、R e13 and the carbon atoms to which they are connected together form a 5-10 membered carbocyclic group, a 5-10 membered heterocyclic group, a C6- 10Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e10 and the carbon atoms to which they are connected together form a 5-10 membered carbocyclic group, a 5-10 membered heterocyclic group, a C6- 10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered heterocyclic group, preferably a dihydrooxazinyl group, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a dihydrooxazinyl or a 5-membered azaheteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e In another more specific embodiment, R e9 、R e13 and the carbon atoms they are connected to form In another more specific embodiment, R e9 、R e10 and the carbon atoms they are connected to form Preferred Formation

[0218] In a more specific embodiment, in another more specific embodiment, R e9 、R e10and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace.

[0219] In a more specific embodiment, R e9 、R e10 and the carbon atoms they are connected to form Preferred Formation

[0220] In a more specific embodiment, Selected from: Preferably selected from: Preferably

[0221] In a more specific embodiment, Y5 is selected from O, S or NR5, preferably O or NR5, preferably O; in another more specific embodiment, R5 is selected from H, C 1-8 Alkyl or C 1-8 Halogenated alkyl, preferably H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R6 is selected from 3 to 10-membered carbocyclyl or 3 to 10-membered heterocyclyl, preferably 3 to 7-membered carbocyclyl or 3 to 7-membered heterocyclyl, preferably 3 to 7-membered heterocyclyl.

[0222] In a more specific embodiment, R E Together with the substituent R thereon e Formed together In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for In another more specific embodiment, R E for

[0223] In a more specific embodiment, R E Selected from -L-3 to 10-membered carbocyclyl, -L-3 to 10-membered heterocyclyl, -LC 6-10 Aryl or -L-5 to 10 membered heteroaryl, preferably -LC 6-10 Aryl or -L-5 to 10 membered heteroaryl, preferably -L-5 to 10 membered heteroaryl, preferably 5 to 10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R e replace.

[0224] In a more specific embodiment, R E Together with the substituent R thereon e Formed together Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation

[0225] In a more specific embodiment, R E Together with the substituent R thereon e Formed together Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation

[0226] R e

[0227] In one embodiment, R e is H; in another embodiment, R e is D; in another embodiment, R e is halogen; in another embodiment, R e is -CN; in another embodiment, R e is oxo; in another embodiment, R e C 1-8 Alkyl; in another embodiment, R e C 1-8 haloalkyl; in another embodiment, R e C 2-8 Alkenyl, preferably C 2-6 Alkenyl, preferably C 2-4 In one embodiment, R e C 2-8 Alkynyl, preferably C 2-6 Alkynyl, preferably C 2-4 Alkynyl; in another embodiment, R e is -L'-OR'; in another embodiment, R e is -L'-NR'R"; in another embodiment, R e is -NO2; in another embodiment, R e is -L'-SR'; in another embodiment, R e is -L'-C(O)OR'; in another embodiment, R e is -L'-C(O)NR'R"; in another embodiment, R e is -L'-S(O)2R'; in another embodiment, R e is -L'-S(O)2NR'R"; in another embodiment, R e is -L'-OC(O)R'; in another embodiment, R e is -L'-OC(O)NR'R"; in another embodiment, R e -L'-C6- 10 Aryl; In another embodiment, R e is -L'-3 to 14 membered carbocyclyl; in another embodiment, R e is -L'-3 to 14 membered heterocyclyl; in another embodiment, R e is -L'-5 to 14 membered heteroaryl; in another embodiment, R e C 1-6Alkyl; in another embodiment, R e C 1-6 haloalkyl; in another embodiment, R e is -L'-3 to 10-membered carbocyclyl, preferably -L'-3 to 7-membered carbocyclyl, preferably 3 to 7-membered carbocyclyl; in another embodiment, R e is -L'-3 to 10-membered heterocyclic group, preferably -L'-3 to 7-membered heterocyclic group, preferably 3 to 7-membered heterocyclic group; in another embodiment, R e is -OR'; in another embodiment, R e is -SR'; in another embodiment, R e is -NR'R"; in another embodiment, R e is F; in another embodiment, R e is Cl; in another embodiment, R e is -CN; in another embodiment, R e is -OCH3; in another embodiment, R e is Me; in another embodiment, R e Optionally 1, 2 or 3 independent R es In another embodiment, R e is unsubstituted; in another embodiment, R e Such as R e1 In another embodiment, R e Such as R e2 defined.

[0228] In one embodiment, the two geminal R e and the atoms to which they are attached together form a 3- to 7-membered carbocyclic group; in another embodiment, the two geminal R e and the atoms to which they are attached together form a 3- to 7-membered heterocyclic group; in another embodiment, the two geminal R e and the atoms to which they are attached together to form a cyclic group optionally substituted by 1, 2 or 3 independent R es In another embodiment, the two geminal R e and the ring group formed by the atoms to which they are commonly attached are unsubstituted; in another embodiment, the two geminal R e and the atoms to which they are commonly bonded do not form a ring.

[0229] In a more specific embodiment, R e are independently selected from H, D, halogen, -CN, oxo, C 1-6 Alkyl, C 1-6haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl; in another more specific embodiment, R e independently selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e independently selected from H, D, halogen, -CN, -OR', C 1-6 Alkyl or C 1-6 In another more specific embodiment, R e Independently selected from H, D, Me, F, Cl, -CN or -OCH3.

[0230] In a more specific embodiment, R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; in another more specific embodiment, R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR' or -NR'R"; in another more specific embodiment, R e Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, preferably H or Me.

[0231] In a more specific embodiment, R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; in another more specific embodiment, R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR' or -NR'R".

[0232] In a more specific embodiment, R e Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; in another more specific embodiment, R e Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; in another more specific embodiment, R e Independently selected from Me and OMe.

[0233] In a more specific embodiment, the two geminal R e and the atoms to which they are attached together form a 3- to 7-membered carbocyclic group or a 3- to 7-membered heterocyclic group.

[0234] R es

[0235] In one embodiment, R es is H; in another embodiment, R es is D; in another embodiment, R es is halogen; in another embodiment, R es is CN; in another embodiment, R es C 1-6 Alkyl; in another embodiment, R es C 1-6 haloalkyl; in another embodiment, R es is -L'-OR'; in another embodiment, R es -L'-NR'R".

[0236] In a more specific embodiment, R es Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR' and -L'-NR'R"; in another more specific embodiment, R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; in another more specific embodiment, R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; in another more specific embodiment, R es are independently selected from H, D, F, Me and OH; in another more specific embodiment, R es independently selected from H, D, halogen (F), C 1-6 Alkyl and C 1-6 In another more specific embodiment, R es are independently selected from H, D, F and Me; in another more specific embodiment, R es is halogen (F).

[0237] R d1

[0238] In one embodiment, R d1 is H; in another embodiment, R d1 is D; in another embodiment, R d1 is halogen; in another embodiment, R d1 is -CN; in another embodiment, R d1 C 1-8 Alkyl; in another embodiment, R d1 is C2-8 alkenyl; in another embodiment, R d1 is C2-8 alkynyl; in another embodiment, R d1 C 1-8 haloalkyl; in another embodiment, R d1 is -L-OR'; in another embodiment, R d1 is -L-NR'R"; in another embodiment, R d1 is -LC(O)NR'R"; in another embodiment, R d1 For-L-C6- 10 Aryl; In another embodiment, R d1 is -L-3 to 14 membered carbocyclyl; in another embodiment, Rd1 is -L-3 to 14 membered heterocyclyl; in another embodiment, R d1 is -L-5 to 14 membered heteroaryl; in another embodiment, R d1 C 1-6 Alkyl; in another embodiment, R d1 C 1-6 haloalkyl; in another embodiment, R d1 is -L-3 to 10 membered carbocyclyl; in another embodiment, R d1 It is -L-3 to 10-membered heterocyclic group.

[0239] In a more specific embodiment, R d1 Selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; in another more specific embodiment, R d1 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R d1 It is H or D.

[0240] Ring A

[0241] In one embodiment, Ring A is C6- 10In another embodiment, ring A is a 3- to 14-membered carbon ring; In another embodiment, ring A is a 3- to 14-membered heterocyclic ring; In another embodiment, ring A is a 5- to 14-membered heteroaromatic ring; In another embodiment, ring A is a benzene ring; In another embodiment, ring A is a furan ring; In another embodiment, ring A is a furazan ring; In another embodiment, ring A is an imidazolidine ring; In another embodiment, ring A is an imidazoline ring; In another embodiment, ring A is an imidazole ring; In another embodiment, ring A is an isothiazole ring; In another embodiment, ring A is an isoxazole ring; In another embodiment, ring A is a morpholine ring; In another embodiment, ring A is an oxadiazole ring In another embodiment, ring A is a 1,2,3-oxadiazole ring; In another embodiment, ring A is a 1,2,4-oxadiazole ring; In another embodiment, ring A is a 1,2,5-oxadiazole ring; In another embodiment, ring A is a 1,3,4-oxadiazole ring; In another embodiment, ring A is an oxazolidine ring; In another embodiment, ring A is an oxazole ring; In another embodiment, ring A is an oxetane ring; In another embodiment, ring A is an azetidine ring; In another embodiment, ring A is a pyrimidine ring; In another embodiment, ring A is a piperazine ring; In another embodiment, ring A is a piperidine ring; In another embodiment, ring A is a pyran ring; In another embodiment, ring A is a pyrazine ring; in another embodiment, ring A is a pyrazolidine ring; in another embodiment, ring A is a pyrazoline ring; in another embodiment, ring A is a pyrazole ring; in another embodiment, ring A is a pyridazine ring; in another embodiment, ring A is a pyridine ring; in another embodiment, ring A is a pyrrolidine ring; in another embodiment, ring A is a pyrroline ring; in another embodiment, ring A is a 2H-pyrrole ring; in another embodiment, ring A is a pyrrole ring; in another embodiment, ring A is a tetrahydrofuran ring; in another embodiment, ring A is a tetrahydropyran ring; in another embodiment, ring A is a thiazole ring; in another embodiment In another embodiment, ring A is a thiophene ring; in another embodiment, ring A is a triazine ring; in another embodiment, ring A is a 1,2,3-triazole ring; in another embodiment, ring A is a 1,2,4-triazole ring; in another embodiment, ring A is a 1,2,5-triazole ring; in another embodiment, ring A is a 1,3,4-triazole ring; in another embodiment, ring A is a xanthene ring; in another embodiment, ring A is a tetrahydroquinoline ring; in another embodiment, ring A is a tetrahydroisoquinoline ring and a hexahydropyrazinoquinoline ring; preferably selected from a benzene ring; in another embodiment, ring A is a pyridine ring; in another embodiment, ring A is a pyrazole ring; in another embodiment, ring A is an imidazole ring.

[0242] In a more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for wherein f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; in another more specific embodiment, f=0, 1, 2, 3, 4, 5 or 6; in another more specific embodiment, f=0, 1, 2, 3 or 4; in another more specific embodiment, f=0, 1 or 2.

[0243] In a more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R dTogether for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and Rd Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for

[0244] In a more specific embodiment, Ring A and R d Together for Preferably Preferably Among them, Z2 is selected from CR d2 or N, preferably CR d2 , preferably N; Z3 is selected from CR d3 or N, preferably CR d3 , preferably N; Z4 is selected from CR d4 or N, preferably CR d4 , preferably N; Z5 is selected from a covalent bond, CR d5 or N, preferably CR d5 or N, preferably CR d5 , preferably N.

[0245] In a more specific embodiment, R d3 and R d4 One of them is -NR' d6 C(O)R d6 , -L'-3 to 7 membered carbocyclic group or -L'-3 to 7 membered heterocyclic group, another d2 and R d5 Independently selected from H, D, halogen, CN, C1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd In another more specific embodiment, R d3 and R d4 One of them is -NR' d6 C(O)R d6 or -L'-3 to 7 membered heterocyclic group, preferably -L'-3 to 7 membered heterocyclic group, another d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R d2 、R d4 and R d5 Independently selected from H, D, halogen, C 1-3 Alkyl or C 1-3 In another more specific embodiment, R d2 and R d5 are independently selected from H, D or halogen; in another more specific embodiment, R d5 is H or D; in another more specific embodiment, R d2 、R d4 and R d5 are independently selected from H, F, Me or CHF2; in another more specific embodiment, R d2 and R d5 are independently selected from H or F; in another more specific embodiment, R d5 For H.

[0246] In a more specific embodiment, R d3 and R d4 One of them is -NR' d6 C(O)R d6 、-C(O)NR d7 R' d7 , -L'-3 to 7 membered carbocyclic group or -L'-3 to 7 membered heterocyclic group, preferably -NR' d6 C(O)R d6 、-C(O)NR d7 R' d7 or -L'-3 to 7 membered heterocyclic group, another with R d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, OR' and NR'R".

[0247] In one embodiment, R d2 / R d4 / R d5 is H; in another embodiment, R d2 / R d4 / R d5 is D; in another embodiment, R d2 / R d4 / R d5 is halogen, such as F; in another embodiment, R d2 / R d4 / R d5 is CN; in another embodiment, R d2 / R d4 / R d5 C 1-6 Alkyl; in another embodiment, R d2 / R d4 / R d5 C 1-6 Haloalkyl, such as CHF2; in another embodiment, R d2 / R d4 / R d5 is -L'-OR', preferably OR', such as OCH3; in another embodiment, R d2 / R d4 / R d5is -L'-SR', preferably SR'; in another embodiment, R d2 / R d4 / R d5 is -L'-NR'R", preferably NR'R"; in another embodiment, R d2 / R d4 / R d5 is -L'-3 to 7 membered carbocyclyl, preferably 3 to 7 membered carbocyclyl; in another embodiment, R d2 / R d4 / R d5 It is -L'-3 to 7-membered heterocyclic group, preferably a 3 to 7-membered heterocyclic group.

[0248] In a more specific embodiment, R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; in another more specific embodiment, R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-4 Alkyl, C 1-4 haloalkyl and -OR'; in another more specific embodiment, R d2 、R d4 and R d5 are independently selected from H and D; in another more specific embodiment, R d2 、R d4 and R d5 is independently selected from H, F, CN, Me, CHF2 and OCH3; in another more specific embodiment, R d2 、R d4 and R d5 For H.

[0249] In a more specific embodiment, R d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl; in another more specific embodiment, R d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6haloalkyl, OR' and NR'R"; in another more specific embodiment, R d2 and R d5 Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R d2 and R d5 are independently selected from H, D and halogen; in another more specific embodiment, R d2 and R d5 Independently selected from H and F.

[0250] In one embodiment, R d3 / R d4 -NR' d6 C(O)R d6 In another embodiment, R d3 / R d4 -C(O)NR d7 R' d7 In another embodiment, R d3 / R d4 is -L'-3 to 7 membered carbocyclyl; in another embodiment, R d3 / R d4 is -L'-3 to 7 membered heterocyclyl; in another embodiment, R d3 / R d4 for In another embodiment, R d3 / R d4 for In another embodiment, R d3 / R d4 for

[0251] In one embodiment, R d7 and R' d7 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably independently H or C 1-6 Alkyl, preferably Me.

[0252] In a more specific embodiment, R d3 Selected from -NR' d6 C(O)R d6 and -C(O)NR d7 R' d7 In another more specific embodiment, R d3 Selected from or -NR' d6C(O)R d6 , preferably Preferably -NR' d6 C(O)R d6 In another more specific embodiment, for In another more specific embodiment, for

[0253] In one embodiment a / b is 0; in another embodiment a / b is 1; in another embodiment a / b is 2; in another embodiment a / b is 3.

[0254] In a more specific embodiment, a and b are independently 0, 1, 2 or 3, preferably independently 0, 1 or 2, preferably a is 1 or 2, b is 1, preferably a and b are 1; in another more specific embodiment, a+b≤5, preferably a+b≤3; in another more specific embodiment, n=0, 1, 2, 3 or 4, preferably n=0, 1 or 2. In a more specific embodiment, a is 0 or 1; in another more specific embodiment, b is 0 or 1.

[0255] In a more specific embodiment, Y1 and Y2 are independently selected from CR dd R dd , O, S or NR' dd , or when Y1 is connected to L', Y1 is CR dd or N; in another more specific embodiment, Y1 is CR dd R dd or NR' dd ; or when Y1 is connected to L', Y1 is CH, CD or N; in another more specific embodiment, Y2 is CR dd R dd , O or NR' dd In another more specific embodiment, at least one of Y1 and Y2 is a heteroatom group; In another more specific embodiment, Y1 is NR' dd , preferably NH; or when Y1 is connected to L', Y1 is CH, CD or N; in another more specific embodiment, Y2 is CR dd R dd , O or NR' dd In another more specific embodiment, Y1 is NH, CH or N, preferably CH or N, preferably N; In another more specific embodiment, Y2 is CR dd R dd , O or NR' dd , preferably O.

[0256] In a more specific embodiment, Y2 is selected from CR dd R dd 、O、S、S(O),NR' dd and S(O)2; in another more specific embodiment, Y2 is selected from CR dd R dd 、O、NR' dd and S(O)2; in another more specific embodiment, Y2 is selected from CR dd R dd and O.

[0257] In a more specific embodiment, when Y1 is linked to L', Y1 is selected from CH, C(OH) and N, preferably selected from CH and N, preferably N.

[0258] In a more specific embodiment, Ring A and R d Together for In another more specific embodiment, Ring A and R d Together for Preferably not In another more specific embodiment, Ring A and R d Together for

[0259] In a more specific embodiment, Ring A and R d Together for Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably Preferably

[0260] In one embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for In another embodiment, R d3 for

[0261] R d

[0262] In one embodiment, R d is H; in another embodiment, R dis D; in another embodiment, R d is halogen; in another embodiment, R d is -CN; in another embodiment, R d -L'-S(O) 0-2 R'; In another embodiment, R d is -L'-S(O)2NR'R"; in another embodiment, R d is -L'-S(O)NR'R"; in another embodiment, R d is -L'-OR'; in another embodiment, R d is -L'-NR'R"; in another embodiment, R d is -L'-C(O)OR'; in another embodiment, R d is -L'-C(O)NR'R"; in another embodiment, R d C 1-8 Alkyl; in another embodiment, R d C 2-8 alkenyl; in another embodiment, R d C 2-8 Alkynyl; in another embodiment, R d C 1-8 haloalkyl; in another embodiment, R d -L'-C6- 10 Aryl; In another embodiment, R d is -L'-3 to 14 membered carbocyclyl; in another embodiment, R d is -L'-3 to 14 membered heterocyclyl; in another embodiment, R d is or -L'-5 to 14 membered heteroaryl; in another embodiment, R d C 1-6 Alkyl; in another embodiment, R d C 1-6 haloalkyl; in another embodiment, R d is -L'-3 to 10-membered carbocyclyl or -L'-3 to 10-membered heterocyclyl; in another embodiment, two adjacent R d Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic heterocyclic group; in another embodiment, two adjacent R d Together with the atoms to which they are attached, they form a 6- to 10-membered bridged bicyclic heterocyclic group; in another embodiment, two adjacent R d Together with the atoms to which they are attached, they form a 6- to 10-membered spiro bicyclic heterocyclic group; in another embodiment, two adjacent R dTogether with the atoms to which they are attached, they form a 6- to 10-membered fused bicyclic heterocyclyl; in another embodiment, R d Optionally 1, 2, 3, 4, 5, 6, 7 or 8 R dd In another embodiment, R d is unsubstituted; in another embodiment, R d Such as R d2 In another embodiment, R d Such as R d3 In another embodiment, R d Such as R d4 In another embodiment, R d Such as R d5 defined.

[0263] In a more specific embodiment, R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Independently selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace.

[0264] In another more specific embodiment, R d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0265] In another more specific embodiment, R d Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R" or -L'-4 to 6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The haloalkyl or 4 to 6 membered heterocyclic group is optionally substituted by 1 or 2 Rdd replace;

[0266] In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d is F; in another more specific embodiment, R d is -OH; in another more specific embodiment, R d is -OCH3; in another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for In another more specific embodiment, R d for

[0267] R dd

[0268] In one embodiment, R dd is H; in another embodiment, R dd is D; in another embodiment, Rdd is halogen, such as F; in another embodiment, R dd is -CN; in another embodiment, R dd is -NO2; in another embodiment, R dd is oxo; in another embodiment, R dd C 1-8 Alkyl; in another embodiment, R dd C 2-8 alkenyl; in another embodiment, R dd C 2-8 Alkynyl; in another embodiment, R dd C 1-8 haloalkyl; in another embodiment, R dd is -L"-OR', preferably OR', such as OH; in another embodiment, R dd is -L"-NR'R", preferably NR'R"; in another embodiment, R dd is -L"-C(O)OR'; in another embodiment, R dd is -L"-C(O)NR'R"; in another embodiment, R dd -L"-S(O) 0-2 R'; In another embodiment, R dd is -L"-S(O)2NR'R"; in another embodiment, R dd is -L"-S(O)NR'R"; in another embodiment, R dd is -L"-OC(O)R'; in another embodiment, R dd is -L"-OC(O)NR'R"; in another embodiment, R dd -L"-C6- 10 Aryl; In another embodiment, R dd is -L"-3 to 14-membered carbocyclyl; in another embodiment, R dd is -L"-3 to 14-membered heterocyclyl; in another embodiment, R dd is -L"-5 to 14 membered heteroaryl; in another embodiment, R dd C 1-6 Alkyl; in another embodiment, R dd C 1-6 haloalkyl; in another embodiment, R dd is -L"-3 to 10-membered carbocyclyl, preferably -L"-3 to 7-membered carbocyclyl; in another embodiment, R ddis -L"-3 to 10-membered heterocyclyl, preferably -L"-3 to 7-membered heterocyclyl, preferably -L"-3 to 7-membered carbocyclyl; in another embodiment, R dd is Me; in another embodiment, R dd is N(CH3)2; in another embodiment, R dd It is C(CH3)2OH.

[0269] In another embodiment, R dd is -CH2OH; in another embodiment, R dd is -CH2OMe; in another embodiment, R dd for In another embodiment, R dd is -NHMe; in another embodiment, R dd It is -CH2-cyclopropyl.

[0270] In a more specific embodiment, R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R" or -L"-3 to 7 membered carbocyclyl; in another more specific embodiment, R ddIndependently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR' or NR'R"; in another more specific embodiment, R dd Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl or -L"-OR'; in another more specific embodiment, R dd independently selected from H, F, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, and -NHMe; in another more specific embodiment, R dd independently selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, and -NHMe; in another more specific embodiment, R dd independently selected from H, OH, Me, -C(CH3)2OH, -CH2OMe and In another more specific embodiment, R dd Independently selected from H, OH, Me, -CH2OMe and -C(CH3)2OH.

[0271] In one embodiment, two R dd Together they form C 1-8 Alkylene; In another embodiment, two non-adjacent R dd Together they form C 1-6 Alkylene; In another embodiment, two non-adjacent R dd Together they form C 1-4 Alkylene; In another embodiment, two non-adjacent R dd Together they form C 1-3 Alkylene; In another embodiment, two non-adjacent R dd Together they form C 1-2 Alkylene; In another embodiment, two non-adjacent R dd Together form -CH2CH2-; In another embodiment, two non-adjacent R dd Together form -CH2CH2-; In another embodiment, two non-adjacent R dd Together they form C 1-4 Alkylene, or R' dd With non-adjacent R dd Together they form C 1-4 Alkylene, or two R' dd Together they form C 1-4 Alkylene; in another embodiment, two Rdd The alkylene group formed together is optionally substituted by one or more of the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 Aryl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl, preferably optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another embodiment, two non-adjacent R dd Together they form -CH2CH2-, making The structure is as follows: In another embodiment, two non-adjacent R dd The formed cyclic group is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 In another embodiment, two non-adjacent R dd The ring group formed is unsubstituted; in another embodiment, two non-adjacent R dd No ring is formed.

[0272] In one embodiment, CR dd R dd Forming a 3- to 7-membered carbocyclylene group, such as cyclopropylene; in another embodiment, CR dd R dd To form a 3- to 7-membered heterocyclylene group, for example For example In another embodiment, CR dd R dd The formed ring group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R", preferably optionally substituted with 1 -OR', preferably optionally substituted with 1 -OH; in another embodiment, CR dd R dd The ring group formed is unsubstituted; in another embodiment, CR dd R dd No ring is formed.

[0273] In a more specific embodiment, CR dd R dd Form a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene; in another more specific embodiment, CRdd R dd To form cyclopropylene, In another more specific embodiment, CR dd R dd To form cyclopropylene or In another more specific embodiment, CR dd R dd To form a cyclopropylene group.

[0274] In one embodiment, two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered carbocyclylene group; in another embodiment, the two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene group; in another embodiment, the two adjacent R dd and the atoms to which they are attached together form a phenylene group; in another embodiment, the two ortho R dd and the atoms to which they are attached together form a 5- to 6-membered heteroarylene group; in another embodiment, the two adjacent R dd and the atoms to which they are attached together to form a ring optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -NR'R"; in another embodiment, the two ortho R dd and the atoms to which they are attached together to form a ring optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, C 1-6 Alkyl and C 1-6 In another embodiment, the two ortho R dd and the atoms to which they are attached together to form a ring are unsubstituted; in another embodiment, the two adjacent R dd and the atoms to which they are connected do not form a ring.

[0275] In a more specific embodiment, two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene or a 5- to 6-membered heteroarylene; in another more specific embodiment, the two ortho-positioned R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene; in another more specific embodiment, the two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene group.

[0276] In one embodiment, R' dd is H; in another embodiment, R'dd C 1-6 Alkyl; in another embodiment, R' dd C 1-6 Haloalkyl; in another embodiment, R' dd is -L"-OR'; in another embodiment, R' dd is -L"-NR'R"; in another embodiment, R' dd is -L"-3 to 7 membered carbocyclyl; in another embodiment, R' dd is -L"-3 to 7-membered heterocyclic group.

[0277] In a more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7 membered carbocyclyl and -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl and -L"-3 to 7 membered carbocyclyl; in another more specific embodiment, R' dd Independently selected from H, Me, -CH2-cyclopropyl.

[0278] In one embodiment, R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene group, for example In another embodiment, R' dd With adjacent R dd and the atoms to which they are attached together form a 5- to 6-membered heteroarylene group, for example In another embodiment, R' dd With adjacent R dd and the atoms to which they are attached together to form a ring optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; in another embodiment, R' dd With adjacent R ddand the atoms to which they are attached together to form a ring optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; in another embodiment, R' dd With adjacent R dd and the atoms to which they are attached together to form a ring are unsubstituted; in another embodiment, R' dd With adjacent R dd and the atoms to which they are connected do not form a ring.

[0279] In a more specific embodiment, R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene; in another more specific embodiment, R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene; in another more specific embodiment, R' dd With adjacent R dd and the atoms they connect to form In another more specific embodiment, R' dd With adjacent R dd and the atoms they connect to form

[0280] In a more specific embodiment, R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L"-S(O)2NR'R", -L"-S(O)NR'R", -L"-OC(O)R', -L"-OC(O)NR'R", -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR' or -L"-NR'R"; in another more specific embodiment, R dd Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR' or -L"-NR'R"; in another more specific embodiment, Rdd Independently selected from H, D, Me, N(CH3)2 or C(CH3)2OH.

[0281] In a more specific embodiment, R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R" or -L"-3 to 7 membered carbocyclyl; in another more specific embodiment, R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR' or -L"-NR'R"; in another more specific embodiment, R dd Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl or -L"-OR'; in another more specific embodiment, R dd independently selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, or -NHMe, preferably H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe or -NHMe; in another more specific embodiment, R dd Independently selected from H, Me or -C(CH3)2OH.

[0282] In a more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6Haloalkyl, -C 1-6 Alkylene-OR', -C 1-6 Alkylene-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; in another more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene-OR', -C 1-4 Alkylene-NR'R" or -L"-3 to 7 membered carbocyclyl; in another more specific embodiment, R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl or -L"-3 to 7 membered carbocyclyl; in another more specific embodiment, R' dd Independently selected from H, Me, -CH2-cyclopropyl.

[0283] In a more specific embodiment, two non-adjacent R dd Together they form C 1-4 Alkylene, or R' dd With non-adjacent R dd Together they form C 1-4 Alkylene, or two R' dd Together they form C 1-4 Alkylene, wherein the C 1-4 The alkylene group is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0284] L and L'

[0285] In one embodiment, L is a covalent bond; in another embodiment, L is -O-; in another embodiment, L is -S-; in another embodiment, L is -NR'-, such as -NH-; in another embodiment, L is -S(O)2-; in another embodiment, L is -C(O)-; in another embodiment, L is -C(O)O-; in another embodiment, L is -C(O)NR'-; in another embodiment, L is -OC(O)-; in another embodiment, L is -OC(O)NR'-; in another embodiment, L is -N(R')C(O)O-; in another embodiment, L is -N(R')C(O)-; in another embodiment, L is -N(R')S(O)2; in another embodiment, L is C 1-8 Alkylene, preferably C 1-6 Alkylene, more preferably C 1-4 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0286] In one embodiment, L' is a covalent bond; in another embodiment, L' is -O-; in another embodiment, L' is -S-; in another embodiment, L' is -NR'-; in another embodiment, L' is -S(O)2-; in another embodiment, L' is -C(O)-; in another embodiment, L' is -C(O)O-; in another embodiment, L' is -C(O)NR'-; in another embodiment, L' is -OC(O)-; in another embodiment, L' is -OC(O)NR'-; in another embodiment, L' is -N(R')C(O)O-; in another embodiment, L' is -N(R')C(O)-; in another embodiment, L' is -N(R')S(O)2; in another embodiment, L' is C 1-8 Alkylene, preferably C 1-6 Alkylene, more preferably C 1-4 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0287] In another embodiment, L' is C 1-8 Alkylene, preferably C 1-6 Alkylene, more preferably C 1-4 Alkylene, wherein 1, 2, 3 or 4 methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -O-, -C(O)-, -OC(O)- or -C(O)O-, preferably optionally and independently replaced by -N(R')C(O)- or -O-.

[0288] In a more specific embodiment, L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2- or -C(O)-; or L or L' is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-; in another more specific embodiment, L or L' is independently selected from a covalent bond, O or C 1-6 In another more specific embodiment, L or L' is independently selected from a covalent bond, O or C 1-4 In a more specific embodiment, L or L' is independently selected from a covalent bond or C 1-6 In another more specific embodiment, L or L' is independently selected from a covalent bond or C 1-4 Alkylene; In another more specific embodiment, L is independently selected from a covalent bond, -O-, -S-, -NR'- or C 1-6 Alkylene; in another more specific embodiment, L is independently selected from a covalent bond, -NR'- or C 1-4 Alkylene; in another more specific embodiment, L is independently selected from a covalent bond or -NR'-; in another more specific embodiment, L is independently selected from a covalent bond, -NH- or -CH(CH3)-; in another more specific embodiment, L is independently selected from a covalent bond or -NH-; in another more specific embodiment, L' is independently selected from a covalent bond or C 1-2 Alkylene; in another more specific embodiment, L' is independently selected from a covalent bond or a methylene group; in another more specific embodiment, L and L' are each optionally substituted with 1, 2, 3 or 4 groups selected from the following: C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group, preferably optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6Alkyl or C 1-6 Haloalkyl

[0289] R' and R"

[0290] In one embodiment, R' is H; in another embodiment, R' is C 1-8 Alkyl; in another embodiment, R' is C 1-8 Alkoxy; in another embodiment, R' is C 1-8 Haloalkyl; in another embodiment, R' is -L"-C6- 10 In another embodiment, R' is -L"-3 to 14-membered carbocyclyl; in another embodiment, R' is -L"-3 to 14-membered heterocyclyl; in another embodiment, R' is -L"-5 to 14-membered heteroaryl; in another embodiment, R' is C 1-6 Alkyl; in another embodiment, R' is C 1-6 haloalkyl; in another embodiment, R' is Me; in another embodiment, R' is Et; in another embodiment, R' is CHF2; in another embodiment, R' is cyclopropyl.

[0291] In one embodiment, R" is H; in another embodiment, R" is C 1-8 Alkyl; in another embodiment, R" is C 1-8 Alkoxy; in another embodiment, R" is C 1-8 Haloalkyl; in another embodiment, R" is -L"-C6- 10 In another embodiment, R" is -L"-3 to 14-membered carbocyclyl; in another embodiment, R" is -L"-3 to 14-membered heterocyclyl; in another embodiment, R" is -L"-5 to 14-membered heteroaryl; in another embodiment, R" is C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R" is C 1-6 Halogenated alkyl, preferably C 1-4 haloalkyl; in another embodiment, R" is Me; in another embodiment, R" is Et; in another embodiment, R" is CHF2; in another embodiment, R" is cyclopropyl.

[0292] In a more specific embodiment, R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d-3 to 7 membered heterocyclyl; In another more specific embodiment, R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; in another more specific embodiment, R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R' and R" are each independently selected from C 1-6 Alkyl or C 1-6 In another more specific embodiment, R" is H or Me, preferably Me.

[0293] In a more specific embodiment, R" is selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R" is C 1-4 haloalkyl; in another more specific embodiment, R" is selected from H, methyl and CHF2; in another more specific embodiment, R" is CHF2.

[0294] L”

[0295] In one embodiment, L" is a covalent bond; in another embodiment, L" is -O-; in another embodiment, L" is -S-; in another embodiment, L" is C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; in another embodiment, L" is optionally substituted by one or more R, preferably optionally substituted by 1, 2, 3 or 4 R; in another embodiment, L" is -C(R)2-, preferably In another embodiment, L" is unsubstituted.

[0296] In a more specific embodiment, L" is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted with 1, 2, 3 or 4 R; in another more specific embodiment, L" is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted with 1, 2, 3 or 4 R; in another more specific embodiment, L" is independently selected from a covalent bond, C 1-4 Alkylene or -C(R)2-; In another more specific embodiment, L" is independently selected from a covalent bond or C 1-4 Alkylene.

[0297] In a more specific embodiment, L" is independently selected from a covalent bond, C 1-4 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R together with the C atom to which they are commonly attached form a 3- to 7-membered carbocyclyl, preferably a 3- to 5-membered carbocyclyl, preferably

[0298] R

[0299] In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R is C 1-8 Halogenated alkyl, preferably C 1-6 haloalkyl; in another embodiment, R is -L d -3 to 10-membered carbocyclic group, preferably -L d -3 to 7 membered carbocyclyl; in another embodiment, R is -L d -3 to 10-membered heterocyclic group, preferably -L d -3 to 7 membered heterocyclic group;

[0300] In one embodiment, the two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene, preferably a 3- to 10-membered heterocyclylene, preferably a 3- to 7-membered carbocyclylene, preferably a 3- to 7-membered heterocyclylene, preferably a 3- to 5-membered carbocyclylene, preferably a 3- to 5-membered heterocyclylene, preferably a

[0301] In a more specific embodiment, R is independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclyl; In another more specific embodiment, R is independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0302] In a more specific embodiment, the two R together with the C atom to which they are commonly attached form a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, preferably a 3- to 7-membered carbocyclylene, preferably a 3- to 5-membered carbocyclylene, preferably

[0303] L d

[0304] In one embodiment, L d is a covalent bond; in another embodiment, L d C 1-8 Alkylene; in another embodiment, L d C 1-6 Alkylene; in another embodiment, L d C 1-4 Alkylene.

[0305] In a more specific embodiment, L d Independently selected from a covalent bond or C 1-6 Alkylene; in another more specific embodiment, L d Independently selected from a covalent bond or C 1-4 Alkylene.

[0306] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of Ring A can be combined with V, W, Q, Y, R A 、R B 、R C , R' C 、R 1a 、R 1b , Z1, Z6, R E 、R e 、R d1 、R d 、R dd , L, L', R', R" and L" or any combination thereof. The present invention is intended to include combinations of all these technical solutions, which are not listed one by one due to space limitations.

[0307] In a more specific embodiment, the present invention provides a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0308] V is selected from the group consisting of covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0309] W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0310] Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time;

[0311] or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0312] R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0313] R B Selected from H, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0314] R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0315] One of Z1 and Z6 is CR E , the other is CR d1 or N;

[0316] R E Selected from -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C6- 10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution;

[0317] R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl;

[0318] R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0319] Ring A is selected from C6- 10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring;

[0320] R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0321] Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0322] R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0323] Or two R dd Together they form C 1-8 Alkylene, optionally substituted with one or more of the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl, or -L"-5 to 10-membered heteroaryl;

[0324] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0325] R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl;

[0326] L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0327] R is independently selected from H, D, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -3 to 10-membered carbocyclic group or -L d -3 to 10-membered heterocyclic group;

[0328] or two R together with the C atom to which they are commonly attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene;

[0329] L d Independently selected from a covalent bond or C 1-8 alkylene;

[0330] f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0331] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0332] In a more specific embodiment, the present invention provides a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0333] V is selected from the group consisting of covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0334] W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C ';

[0335] Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time;

[0336] or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0337] R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0338] R BSelected from H, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0339] R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0340] One of Z1 and Z6 is CR E , the other is CR d1 or N;

[0341] R E Selected from -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C6- 10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution;

[0342] R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl;

[0343] R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6- 10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl;

[0344] Ring A is selected from C6- 10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring;

[0345] R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0346] Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0347] R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C6- 10aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl;

[0348] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0349] R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl, -L"-C6- 10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl;

[0350] L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0351] f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0352] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0353] The structure of ring A in formula (I) should be understood as two adjacent atoms on ring A being connected to Q and Y respectively, and the two adjacent atoms may be carbon atoms or heteroatoms such as N.

[0354] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein V is selected from a covalent bond, CR C or CR C RC '; is preferably selected from a covalent bond, CH, CH2, CD, CHD or CD2, more preferably a covalent bond.

[0355] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein W is CR C or CR C R C '; preferably CR C R C ', more preferably CH2, CD, CHD or CD2.

[0356] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound of formula (I) is one of the following formulas:

[0357] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein Q and Y are independently selected from a covalent bond, O, S, NR A , S(O), S(O)2, C(O) or CR 1a R 1b ; and Q and Y are not covalent bonds at the same time.

[0358] Preferably, Q is selected from O, S or NR A , preferably S or NR A , preferably NR A , more preferably NH.

[0359] Preferably, Y is selected from a covalent bond, O, S or CR 1a R 1b , preferably selected from a covalent bond, O or CR 1a R 1b , preferably selected from a covalent bond, O, CH2, CF2 or C(CH3)2, more preferably C(CH3)2.

[0360] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R A Selected from H, C 1-6 Alkyl, C 1-6haloalkyl, -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl; preferably selected from H, C 1-6 Alkyl or C 1-6 preferably H.

[0361] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R B Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl or -L-3 to 10-membered heterocyclyl; preferably selected from H, C 1-6 Alkyl or C 1-6 preferably H.

[0362] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R C and R' C Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; preferably independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; more preferably independently H or D.

[0363] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; preferably independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 preferably independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 preferably independently selected from H, D, halogen, C1-3 Alkyl or C 1-3 Haloalkyl; preferably independently selected from H, D, F or Me; more preferably Me.

[0364] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyridinyl, dihydropyridooxazinyl, indolyl, triazolopyridinyl, tetrahydroimidazopyrazinyl, dihydropyrrolopyridinyl, thienopyridinyl, benzimidazolyl, dihydroimidazooxazinyl, tetrahydropyrazolopyridinyl, tetrahydropyrrolopyridinyl, dihydropyrazolooxazinyl, dihydropyrroloimidazolyl, oxazolopyridinyl, pyrazoloazepanyl, pyrazoloazepanyl, imidazoazepanyl, imidazoazepanyl, pyrazolodiazepanyl, pyrazolodiazepanyl and thienopyridinyl, which are optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R e group substitution;

[0365] Optionally, R E and its substituent R e Together they form a group selected from:

[0366] In some embodiments of the present invention, R E and its substituent R e Together they form a group selected from:

[0367] Wherein, g=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0368] Preferably, g=0, 1, 2, 3, 4, 5 or 6, preferably g=0, 1, 2, 3 or 4, preferably g=0, 1 or 2.

[0369] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R e are independently selected from H, D, halogen, -CN, oxo, C 1-6 Alkyl, C1-6 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl; preferably independently selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl or C 1-6 preferably independently selected from H, D, halogen, -CN, -OR', C 1-6 Alkyl or C 1-6 Haloalkyl; preferably independently selected from H, D, Me, F, Cl, -CN or -OCH3;.

[0370] Optionally, R E Together with the substituent R thereon e Together they form a group selected from:

[0371] Preferably selected from: More preferably selected from:

[0372] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein Z6 is CR E , Z1 is CR d1 or N, or Z1 is CR E , Z6 is N; preferably Z6 is CR E , Z1 is CR d1 or N; preferably Z6 is CR E , Z1 is CR d1 More preferably, Z6 is CR E , Z1 is CH or CD.

[0373] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R d1 Selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 more preferably H or D.

[0374] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein ring A is selected from a benzene ring, a furan ring, a furazan ring, an imidazolidine ring, an imidazoline ring, an imidazole ring, an isothiazole ring, an isoxazole ring, a morpholine ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, an oxazolidine ring, an oxazole ring, an oxetane ring , azetidine ring, pyrimidine ring, piperazine ring, piperidine ring, pyran ring, pyrazine ring, pyrazolidine ring, pyrazoline ring, pyrazole ring, pyridazine ring, pyridine ring, pyrrolidine ring, pyrroline ring, 2H-pyrrole ring, pyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiazole ring, thiophene ring, triazine ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, xanthene ring, tetrahydroquinoline ring, tetrahydroisoquinoline ring and hexahydropyrazinoquinoline ring; preferably selected from a benzene ring, a pyridine ring, a pyrazole ring or an imidazole ring; more preferably a benzene ring.

[0375] Optionally, ring A together with the substituents R thereon d Together they form a group selected from:

[0376] Preferably selected from: Wherein f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0377] Optionally, f=0, 1, 2, 3, 4, 5 or 6, preferably f=0, 1, 2, 3 or 4, preferably f=0, 1 or 2.

[0378] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Independently selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0379] Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace.

[0380] Optionally, R d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace.

[0381] Optionally, R d Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R" or -L'-4 to 6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The haloalkyl or 4 to 6 membered heterocyclic group is optionally substituted by 1 or 2 R dd replace.

[0382] In some embodiments of the present invention, R d Independently selected from H, D, Preferably independently selected from H, D,

[0383] In some embodiments of the present invention, ring A together with the substituents R thereon dTogether they form a group selected from:

[0384] Preferably Preferably More preferably

[0385] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R d Independently selected from H, F, -OH, -OCH3,

[0386] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L"-S(O)2NR'R", -L"-S(O)NR'R", -L"-OC(O)R', -L"-OC(O)NR'R", -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl; preferably independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-SR' or -L"-NR'R"; preferably independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR' or -L"-NR'R", is preferably independently selected from H, D, Me, N(CH3)2 or C(CH3)2OH.

[0387] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein ring A together with the substituent R thereon d Together they form a group selected from:

[0388] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein L and L' are independently selected from a chemical bond, -O-, -S-, -NR'-, -S(O)2- or -C(O)-; or L or L' is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-.

[0389] Preferably, L or L' is independently selected from a covalent bond, O or C 1-6 Alkylene, preferably independently selected from covalent bonds, O or C 1-4 Alkylene.

[0390] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein L" is selected from a covalent bond, -O- or -S-; or L" is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -S-, -S(O)- or -S(O)2-; preferably selected from a covalent bond or C 1-6 Alkylene; more preferably a covalent bond or C 1-4 Alkylene.

[0391] In a more specific embodiment, the present invention provides a compound of formula (I') or formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which has the following structural formula:

[0392] in,

[0393] Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic;

[0394] X1 for CR e6 , N, O, S or NR' e6 ;

[0395] X2 is C or N;

[0396] X3 is C or N;

[0397] X4 for CR e4 , CR e4 R' e4 or N;

[0398] X5 for CR e5 , N, O, S or NR' e5 ;

[0399] X6 is C or N;

[0400] X7 for CR e1 or N;

[0401] X8 for CR e2 or N;

[0402] X9 for CR e3 or N;

[0403] X 10 Selected from CR e7 , O, S, N or NR' e7 ;

[0404] X 11 Selected from CR e8 , O, S, N or NR' e8 ;

[0405] R e1 、R e2 、R e3 、R e4 、R e5 and R e6 Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C6- 10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl;

[0406] R' e1 , R' e2 , R' e3 , R' e4 Independently selected from none, H, D, halogen, -CN, C 1-8 Alkyl or C 1-8Haloalkyl; or CR e1 R' e1 Forming -C(O)-, or CR e2 R' e2 Forming -C(O)-, or CR e3 R' e3 Forming -C(O)-, or CR e4 R' e4 Formation of -C(O)-;

[0407] R' e5 and R' e6 Independently selected from H, C 1-8 Alkyl or C 1-8 alkyl halide;

[0408] R e7 and R e8 Independently selected from H, D, halogen, CN, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 10-membered carbocyclyl, or -L'-3 to 10-membered heterocyclyl;

[0409] R' e7 and R' e8 Independently selected from H, D, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-3 to 10-membered carbocyclyl, or -L'-3 to 10-membered heterocyclyl;

[0410] or X 10 and X 11 The substituents on the 3-5 Alkylene, which optionally contains a double bond, the C 3-5 The alkylene group is optionally substituted by 1, 2, 3 or 4 R e substituted, and one or more methylene units are optionally and independently replaced by NR"-, -N(R")C(O)-, -C(O)N(R")-, -N(R")S(O)2-, -S(O)2N(R")-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0411] E is selected from CR e12 or N;

[0412] J is selected from CR e13 or N;

[0413] R e9 、R e10 、R e11 、R e12and R e13 Selected from H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 10-membered carbocyclyl, -L'-3 to 10-membered heterocyclyl or -Y5-C 0-8 Alkylene-R6;

[0414] Y5 is selected from O, S or NR5;

[0415] R5 is selected from H, C 1-8 Alkyl or C 1-8 alkyl halide;

[0416] R6 is selected from 3 to 10 membered carbocyclyl or 3 to 10 membered heterocyclyl;

[0417] or R e9 、R e13 and the carbon atoms to which they are connected together form a 5-10 membered carbocyclic group, a 5-10 membered heterocyclic group, a C6- 10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[0418] or R e9 、R e10 and the carbon atoms to which they are connected together form a 5-10 membered carbocyclic group, a 5-10 membered heterocyclic group, a C6- 10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[0419] Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace;

[0420] Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace;

[0421] Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace;

[0422] Z5 is selected from covalent bond, CR d5 or N;

[0423] R d2 、R d3 、R d4 and R d5 independently selected from H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R", or R d2 、R d3 、R d4 and R d5 Independently selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0424] or R d2 and R d3 Together with the atoms to which they are attached, or R d3 and R d4 Together with the atoms to which they are attached, or R d4 and R d5 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic heterocyclyl, a 6- to 10-membered bridged bicyclic heterocyclyl, a 6- to 10-membered spiro bicyclic heterocyclyl, or a 6- to 10-membered fused bicyclic heterocyclyl, wherein the 3- to 7-membered monocyclic heterocyclyl, the 6- to 10-membered bridged bicyclic heterocyclyl, the 6- to 10-membered spiro bicyclic heterocyclyl, or the 6- to 10-membered fused bicyclic heterocyclyl is optionally substituted by 1, 2, 3, 4, or 5 R dd replace;

[0425] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0426] Other groups are as defined herein;

[0427] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0428] In a more specific embodiment, the present invention provides a compound of formula (II-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0429] V is selected from covalent bond, CR C or CR C R C ';

[0430] Q and Y are independently selected from a covalent bond, O, S, NR A , S(O), S(O)2, C(O) or CR 1a R1b ; and Q and Y are not covalent bonds at the same time;

[0431] R A Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl, or -L"-3 to 10-membered heterocyclyl;

[0432] R B Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl, or -L-3 to 10-membered heterocyclyl;

[0433] R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl, or -L-3 to 10-membered heterocyclyl;

[0434] Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic;

[0435] X2 is C or N;

[0436] X3 is C or N;

[0437] X4 for CR e4 , CR e4 R' e4 or N;

[0438] R e1 、R e2 、R e3 、R e4 and R e5 Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-3 to 10 membered carbocyclyl, or -L'-3 to 10 membered heterocyclyl;

[0439] R' e1 , R' e2 , R' e3 and R' e4 Independently selected from H, D, halogen, -CN, C 1-6 Alkyl or C 1-6 Haloalkyl; or CR e1 R' e1 Forming -C(O)-, or CR e2 R' e2 Forming -C(O)-, or CR e3 R' e3 Forming -C(O)-, or CR e4 R' e4 Formation of -C(O)-;

[0440] Z1 is CR d1 or N;

[0441] Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace;

[0442] Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace;

[0443] Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace;

[0444] Z5 is selected from covalent bond, CR d5 or N;

[0445] R d1 Selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl, or -L-3 to 10-membered heterocyclyl;

[0446] R d2 、R d3 、R d4 and R d5 independently selected from H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R", or R d2 、R d3 、R d4 and R d5 Independently selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0447] or R d2 and R d3 Together with the atoms to which they are attached, or R d3 and R d4 Together with the atoms to which they are attached, or R d4 and R d5 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic heterocyclyl, a 6- to 10-membered bridged bicyclic heterocyclyl, a 6- to 10-membered spiro bicyclic heterocyclyl, or a 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl, or 6- to 10-membered fused bicyclic heterocyclyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 R dd replace;

[0448] R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L"-S(O)2NR'R", -L"-S(O)NR'R", -L"-OC(O)R', -L"-OC(O)NR'R", -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl;

[0449] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2- or -C(O)-; or L or L' is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-;

[0450] R' and R" are independently selected from H, C 1-6 Alkyl, C1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocyclyl;

[0451] L" is selected from a covalent bond, -O- or -S-; or L" is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-;

[0452] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0453] In a more specific embodiment, the present invention provides a compound of formula (II-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0454] V is selected from covalent bond, CR C or CR C R' C ;

[0455] Q is selected from O, S or NR A ;

[0456] Y is selected from a covalent bond, O, S or CR 1a R 1b ;

[0457] R A and R B Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0458] R C , R' C Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0459] R 1a and R 1b Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0460] Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic;

[0461] X2 is C or N;

[0462] X3 is C or N;

[0463] X4 for CR e4 , CR e4 R' e4 or N;

[0464] R e1 Selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl or C 1-6 alkyl halide;

[0465] R e2 、R e3 、R e4 、R e5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0466] R' e1 , R' e2 , R' e3 , R' e4 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0467] Z1 is CR d1 or N;

[0468] Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace;

[0469] Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace;

[0470] Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace;

[0471] Z5 is selected from covalent bond, CR d5 or N;

[0472] R d1 and R d5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0473] R d2 、R d3 and R d4 Independently selected from H, D, halogen, C 1-6 Alkyl, C1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace;

[0474] R dd Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR', -L"-SR' or -L"-NR'R";

[0475] R' and R" are independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclyl;

[0476] L' is selected from a covalent bond, O or C 1-6 alkylene;

[0477] L" is selected from a covalent bond or C 1-6 alkylene;

[0478] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0479] In a more specific embodiment, the present invention provides a compound of formula (II-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0480] V is selected from a covalent bond, CH, CH2, CD, CHD or CD2, preferably a covalent bond;

[0481] Q is selected from S or NR A , preferably NR A ;

[0482] Y is selected from a covalent bond, O or CR 1a R 1b , preferably selected from a covalent bond, O, CH2, CF2 or C(CH3)2, more preferably C(CH3)2;

[0483] R A and R B is H;

[0484] R 1a and R 1bIndependently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably independently selected from H, D, F or Me;

[0485] Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic;

[0486] X2 is C or N;

[0487] X3 is C or N; preferably, one of X2 and X3 is C and the other is N;

[0488] X4 selected from CR e4 , CR e4 R' e4 or N;

[0489] R e1 is selected from H, D, halogen, -CN or -OR', preferably H, D, F, Cl, -CN or -OCH3;

[0490] R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H, D or Me;

[0491] R e3 、R e4 、R e5 independently selected from H or D;

[0492] R' e1 , R' e2 , R' e3 , R' e4 independently selected from H or D;

[0493] Z1 is CR d1 or N;

[0494] Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace;

[0495] Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace;

[0496] Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace;

[0497] Z5 is selected from covalent bond, CRd5 or N; preferably, the ring where Z2, Z3, Z4 and Z5 are located is selected from a benzene ring, a pyridine ring, a pyrazole ring or an imidazole ring;

[0498] R d1 and R d5 independently H or D;

[0499] R d2 、R d3 and R d4 Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R" or -L'-4 to 6 membered heterocyclic group, said C 1-6 Alkyl, C 1-6 The haloalkyl or 4 to 6 membered heterocyclic group is optionally substituted by 1 or 2 R dd Substituted; preferably R d2 、R d3 and R d4 Independently selected from H, D, More preferably, R d2 Selected from H, D, R d3 Selected from H, D, R d4 Selected from H, D, or

[0500] R dd Independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR' or -L"-NR'R", preferably independently selected from H, D, Me, N(CH3)2 or C(CH3)2OH;

[0501] L' is selected from a covalent bond, O or C 1-6 Alkylene, preferably a covalent bond, O or C 1-4 alkylene;

[0502] L" is selected from a covalent bond or C 1-6 Alkylene, preferably a covalent bond or C 1-4 alkylene;

[0503] R' and R" are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0504] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0505] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0506] Selected from Preferably selected from

[0507] The ring where Z2, Z3, Z4 and Z5 are located together with the substituents thereon constitute the following group:

[0508] Preferably Preferably More preferably

[0509] In a more specific embodiment, the present invention provides a compound of formula (III) or formula (IV) or formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0510] X2 is C or N;

[0511] X3 is C or N;

[0512] X4 for CR e4 or N;

[0513] R e1 Selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl, C 1-6 alkyl halide;

[0514] R e2 、R e3 、R e4 、R e5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0515] R 1a and R 1b are independently H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0516] Z1 is CR d1 or N, preferably CR d1 ;

[0517] Z2 is CR d2 or N, preferably CR d2 ;

[0518] Z4 for CR d4 or N, preferably CR d4 ;

[0519] Z5 is CR d5 or N, preferably CR d5 ;

[0520] R d2 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 R dd replace;

[0521] R d1 、R d4 or R d5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0522] R dd Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR', -L"-SR' or -L"-NR'R";

[0523] L' is selected from a covalent bond, -O- or C 1-6 alkylene;

[0524] L" is selected from a covalent bond or C 1-6 alkylene;

[0525] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0526] R' and R" are independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclyl;

[0527] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0528] In a more specific embodiment, the present invention provides a compound of formula (III) or formula (IV) or formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0529] X2 is C or N;

[0530] X3 is C or N;

[0531] X4 for CR e4 or N;

[0532] R e1 Selected from H, D, halogen, -CN, -OR', C 1-6 Alkyl or C 1-6 alkyl halide;

[0533] R e2 、R e3 、R e4 、R e5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0534] R 1a and R 1b Independently C 1-6 Alkyl or C 1-6 alkyl halide;

[0535] Z1 is CR d1 or N, preferably CR d1 ;

[0536] Z2 is CR d2 or N, preferably CR d2 ;

[0537] Z4 for CR d4 or N, preferably CR d4 ;

[0538] Z5 is CR d5 or N, preferably CR d5 ; Preferably, the ring where Z2, Z4 and Z5 are located is selected from a benzene ring or a pyridine ring, preferably a benzene ring;

[0539] R d1 、R d2 、R d4 or R d5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0540] R dd Selected from H, D, halogen, C1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR' or -L"-NR'R";

[0541] L" is selected from a covalent bond or C 1-6 alkylene;

[0542] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0543] R' and R" are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0544] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0545] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0546] X2 is C or N;

[0547] X3 is C or N;

[0548] X4 for CR e4 or N;

[0549] R e1 is selected from H, D, halogen or OR', preferably H, D or halogen;

[0550] R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H or D.

[0551] R e3 、R e4 and R e5 independently H or D;

[0552] R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me;

[0553] Z1, Z2, Z4 and Z5 are CH or CD;

[0554] R dd Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR';

[0555] L" is selected from a covalent bond or C 1-6 alkylene;

[0556] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0557] R' is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0558] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0559] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0560] X2 is C or N;

[0561] X3 is C or N; preferably, one of X2 and X3 is C and the other is N;

[0562] X4 for CR e4 or N;

[0563] R e1 Selected from H, F, Cl or OCH3, preferably H, F or Cl;

[0564] R e2 Selected from H or Me, preferably H;

[0565] R e3 、R e4 and R e5 is H; preferably, Selected from Preferably selected from More preferably selected from

[0566] R 1a and R 1b for Me;

[0567] Z1, Z2, Z4 and Z5 are CH;

[0568] R dd is H or -L"-OH, preferably H or C(CH3)2OH;

[0569] L" is selected from a covalent bond or C 1-4 alkylene;

[0570] n=0 or 1; preferably for

[0571] In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0572] X2 is C or N;

[0573] X3 is C or N;

[0574] X4 for CR e4 or N;

[0575] R e1 is selected from H, D, halogen, CN or OR', preferably selected from H, D, F, CN or OR';

[0576] R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0577] R e3 、R e4 and R e5 independently H or D;

[0578] R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me;

[0579] Z1 is selected from CH, CD or N, preferably CH or CD;

[0580] Z2, Z4 and Z5 are independently selected from CH, CD or N;

[0581] R dd Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR';

[0582] L" is selected from a covalent bond or C 1-6 alkylene;

[0583] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0584] R' is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0585] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0586] In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0587] X2 is C or N;

[0588] X3 is C or N; preferably, one of X2 and X3 is C and the other is N;

[0589] X4 for CR e4 or N;

[0590] R e1 Selected from H, F, Cl, CN or OCH3, preferably selected from H, F, CN or OCH3;

[0591] R e2 selected from H or Me;

[0592] R e3 、R e4 and R e5 is H; preferably, Selected from Preferably selected from More preferably selected from More preferably selected from

[0593] R 1a and R 1b for Me;

[0594] Z1 is CH;

[0595] Z2, Z4 and Z5 are independently CH or N; preferably Z2 and Z4 are independently CH or N, and Z5 is CH; preferably Z2 is CH or N, and Z4 and Z5 are CH;

[0596] R dd is H or -L"-OH, preferably H or C(CH3)2OH;

[0597] L" is selected from a covalent bond or C 1-4 alkylene;

[0598] n=0 or 1; preferably for

[0599] In a more specific embodiment, the present invention provides a compound of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0600] X2 is C or N;

[0601] X3 is C or N;

[0602] X4 for CR e4 or N, preferably CR e4 ;

[0603] R e1 is selected from H, D, halogen or OR', preferably OR';

[0604] R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H or D;

[0605] R e3 、R e4 and R e5 independently H or D;

[0606] R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me;

[0607] Z1 is N, CH or CD, preferably CH or CD;

[0608] Z2, Z4 and Z5 are independently CH or CD;

[0609] R dd Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR', preferably H or D;

[0610] L" is selected from a covalent bond or C 1-6 alkylene;

[0611] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0612] R' is selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide;

[0613] The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

[0614] In a more specific embodiment, the present invention provides a compound of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0615] X2 is C or N;

[0616] X3 is C or N; preferably, one of X2 and X3 is C and the other is N;

[0617] X4 for CR e4 or N, preferably CR e4 ;

[0618] R e1 Selected from H, F, Cl or OCH3, preferably OCH3;

[0619] R e2 is H;

[0620] R e3 、R e4 and R e5 is H; preferably, Selected from Preferably

[0621] R 1a and R 1b for Me;

[0622] Z1 is CH or N;

[0623] Z2, Z4 and Z5 are CH;

[0624] R dd is H;

[0625] n=0.

[0626] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0627] in,

[0628] R E Selected from -L-3 to 10-membered carbocyclyl, -L-3 to 10-membered heterocyclyl, -LC 6-10 Aryl or -L-5 to 10 membered heteroaryl, preferably -LC 6-10 aryl or -L-5 to 10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R e replace;

[0629] R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl;

[0630] Y is selected from O, S or CR 1a R 1b ;

[0631] R 1a and R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0632] Q, V, R B and Z1 are each as defined herein;

[0633] Z2 is selected from CR d2 or N;

[0634] Z3 is selected from CR d3 or N;

[0635] Z4 selected from CR d4 or N;

[0636] Z5 is selected from covalent bond, CR d5 or N, preferably CR d5 or N;

[0637] R d3 and R d4 One of them is -NR' d6 C(O)R d6 , -L'-3 to 7 membered carbocyclic group or -L'-3 to 7 membered heterocyclic group, another d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl;

[0638] R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd replace;

[0639] R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6Haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl;

[0640] Or two non-adjacent R dd Together they form C 1-6 Alkylene, preferably forming C 1-4 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0641] R d6 Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl or -L"-Y3-C 1-6 Alkylene-R4;

[0642] Y3 is selected from O, S or NR3;

[0643] R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0644] R4 is selected from -OR', -SR' or -NR'R";

[0645] L is independently selected from a covalent bond, -O-, -S-, -NR'- or C 1-6 alkylene;

[0646] L' is independently selected from a covalent bond or C 1-6 alkylene;

[0647] L and L' are each optionally substituted with 1, 2, 3 or 4 groups selected from: C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group;

[0648] L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d-3 to 7-membered heterocyclyl, or two R together with the C atom to which they are attached form a 3 to 7-membered carbocyclylene or a 3 to 7-membered heterocyclylene;

[0649] L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene;

[0650] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group;

[0651] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0652] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0653] R E is -L-5 to 10-membered heteroaryl, preferably 5 to 10-membered heteroaryl; preferably, R E wherein the heteroaryl is selected from pyridyl, pyridinone, pyrazolyl, imidazolyl, oxazolyl, triazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrazinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, triazolopyridinyl, imidazoazacyclopentyl, imidazocyclohexyl, imidazoazacyclohexyl, imidazoazepine, dihydroimidazooxazinyl, imidazopyrazinone, imidazodiazepine, imidazopiperazinone, pyrazoloazacyclohexyl, pyrazolodiazepine, dihydropyrazolooxazinyl, triazoloazacyclohexyl, dihydropyridooxazinyl, pyrrolopyridinyl, oxazolopyridinyl, which is optionally substituted by 1, 2, 3, 4 or 5 R e replace;

[0654] R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR' or -NR'R";

[0655] Y is O or CR 1a R 1b , preferably CR 1a R 1b ;

[0656] R 1a and R 1b Independently selected from C 1-6 Alkyl or C 1-6 Haloalkyl, preferably selected from Me or Et;

[0657] Q, V, R B and Z1 are each as defined herein;

[0658] Z2 is selected from CR d2 or N;

[0659] Z3 is selected from CR d3 or N;

[0660] Z4 selected from CR d4 or N;

[0661] Z5 is selected from CR d5 or N;

[0662] R d3 and R d4 One of them is -NR' d6 C(O)R d6 or -L'-3 to 7 membered heterocyclic group, preferably -L'-3 to 7 membered heterocyclic group, another d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0663] R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd replace;

[0664] R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl;

[0665] Or two non-adjacent R dd Together they form C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C1-6 alkyl halide;

[0666] R d6 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, -L"-3 to 7-membered heterocyclyl, or -L"-Y3-C 1-4 Alkylene-R4;

[0667] Y3 is selected from O or NR3, preferably O;

[0668] R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H, C 1-3 Alkyl or C 1-3 alkyl halide;

[0669] R4 is selected from -OR' or -NR'R", preferably -OR';

[0670] L is independently selected from a covalent bond, -NR'- or C 1-4 Alkylene, preferably a covalent bond or -NR'-; preferably, L is a covalent bond, -NH- or -CH(CH3)-, preferably a covalent bond or -NH-;

[0671] L' is independently selected from a covalent bond or C 1-4 alkylene;

[0672] L and L' are each optionally substituted with 1, 2, 3 or 4 groups selected from: C 1-6 Alkyl or C 1-6 alkyl halide;

[0673] L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene group, preferably a 3- to 5-membered carbocyclylene group;

[0674] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group, preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0675] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (II') above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0676] R E As defined herein;

[0677] R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR' or -NR'R", which is optionally substituted by 1, 2 or 3 R es replace;

[0678] Or two R e and the atoms to which they are attached together form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, preferably a 3- to 7-membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R es replace;

[0679] R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0680] Q, V, R B , Z1 and Z7 are each as defined herein;

[0681] Z2 is selected from CR d2 or N;

[0682] Z3 is selected from CR d3 or N;

[0683] Z4 selected from CR d4 or N;

[0684] Z5 is selected from covalent bond, CR d5or N, preferably CR d5 or N;

[0685] R d3 and R d4 One of them is -NR' d6 C(O)R d6 、-C(O)NR d7 R' d7 , -L'-3 to 7 membered carbocyclic group or -L'-3 to 7 membered heterocyclic group, preferably -NR' d6 C(O)R d6 、-C(O)NR d7 R' d7 or -L'-3 to 7 membered heterocyclic group, another with R d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, OR' and NR'R";

[0686] R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd replace;

[0687] R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl, preferably selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl;

[0688] or CR dd R dd To form a 3 to 7 membered carbocyclylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -NR'R", preferably optionally substituted with 1 -OR';

[0689] Or two non-adjacent R dd Together they form C 1-6 Alkylene, preferably forming C 1-4 Alkylene, preferably forming C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0690] Or two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0691] R d7 and R' d7 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0692] The remaining variables are as defined herein;

[0693] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0694] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0695] in,

[0696] R E As defined herein;

[0697] X1 for CR e6 , N, O, S or NR' e6 ;

[0698] X2 is C or N;

[0699] X3 is C or N;

[0700] X4 for CR e4 or N;

[0701] X5 for CR e5 , N, O, S or NR' e5 ;

[0702] X6 is C or N;

[0703] X7 for CR e1 or N;

[0704] X8 for CR e2 or N;

[0705] X9 for CR e3 or N;

[0706] R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl;

[0707] R e3 、R e4 、R e5 and R e6 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0708] R' e5 and R' e6 Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0709] R 1a and R 1b are independently H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0710] Z1 is selected from CR d1 or N;

[0711] Z2 is selected from CR d2 or N;

[0712] Z4 selected from CR d4 or N;

[0713] Z5 is selected from CR d5 or N;

[0714] R d1 Selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0715] R d2 、R d4and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl;

[0716] R d3 Selected from or -NR' d6 C(O)R d6 ;

[0717] a and b are independently 0, 1, 2 or 3, preferably a+b≤5;

[0718] L' is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl or C 1-6 alkyl halide;

[0719] Y1 and Y2 are independently selected from CR dd R dd , O, S or NR' dd , or when Y1 is connected to L', Y1 is CR dd or N;

[0720] R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl;

[0721] Or two non-adjacent R dd Together they form C 1-4 Alkylene, or R' dd With non-adjacent R dd Together they form C 1-4 Alkylene, or two R' dd Together they form C 1-4 Alkylene, wherein the C 1-4 The alkylene group is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0722] R' dd Independently selected from H, C 1-6 Alkyl, C 1-6haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl;

[0723] n = 0, 1, 2, 3 or 4;

[0724] R d6 Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl or -L"-Y3-C 1-6 Alkylene-R4;

[0725] L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7-membered heterocyclyl, or two R together with the C atom to which they are attached form a 3 to 7-membered carbocyclylene or a 3 to 7-membered heterocyclylene;

[0726] L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene;

[0727] Y3 is selected from O, S or NR3;

[0728] R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0729] R4 is selected from -OR', -SR' or -NR'R";

[0730] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group;

[0731] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0732] It should be understood that when Y1 or Y2 is CR dd R dd , one of the R dd When it is oxo, the other Rdd Should not exist.

[0733] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0734] Among them, R E As defined herein;

[0735] X1 for CR e6 , N or NR' e6 , preferably N;

[0736] X2 is C or N;

[0737] X3 is C or N;

[0738] X4 for CR e4 or N;

[0739] X5 for CR e5 , N or NR' e5 , preferably CR e5 or N;

[0740] X6 is C or N, preferably C;

[0741] X7 for CR e1 or N;

[0742] X8 for CR e2 or N;

[0743] X9 for CR e3 or N;

[0744] R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", 3 to 7 membered carbocyclic group or 3 to 7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' or -NR'R";

[0745] R e3 、R e4 、R e5 and R e6 are independently H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0746] R' e5 and R'e6 Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0747] R 1a and R 1b Independently C 1-6 Alkyl or C 1-6 alkyl halide;

[0748] Z1 is selected from CR d1 or N, preferably CR d1 ;

[0749] Z2 is selected from CR d2 or N;

[0750] Z4 selected from CR d4 or N;

[0751] Z5 is selected from CR d5 or N, preferably CR d5 ;

[0752] R d1 、R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0753] R d3 Selected from or -NR' d6 C(O)R d6 ;

[0754] a and b are independently 0, 1 or 2; preferably a+b≤3;

[0755] L' is independently selected from a covalent bond or C 1-4 alkylene;

[0756] Y1 is CR dd R dd or NR' dd ; or when Y1 is connected to L', Y1 is CH, CD or N;

[0757] Y2 is CR dd R dd , O or NR' dd ; Preferably, at least one of Y1 and Y2 is a heteroatom group;

[0758] R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl;

[0759] Or two non-adjacent R dd Together they form C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0760] R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR', -C 1-6 Alkylene-NR'R", -L"-3 to 7 membered carbocyclic group or -L"-3 to 7 membered heterocyclic group, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, or -L"-3 to 7-membered heterocyclyl;

[0761] n = 0, 1, 2, 3 or 4;

[0762] R d6 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, -L"-3 to 7-membered heterocyclyl, or -L"-Y3-C 1-4 Alkylene-R4, preferably not -L"-Y3-C 1-4 Alkylene-R4;

[0763] L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl, or two R groups together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene group;

[0764] Y3 is selected from O or NR3;

[0765] R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0766] R4 is selected from -OR' or -NR'R";

[0767] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group.

[0768] In some embodiments of the present invention, at most 5 of X1-X9 are heteroatoms, preferably at most 4 are heteroatoms, and preferably at most 3 are heteroatoms.

[0769] In some embodiments of the present invention, one of X2 and X3 is N and the other is C.

[0770] In some embodiments of the present invention, at most only one of X4 and X7-X9 is N.

[0771] In some embodiments of the present invention, at most two of Z2, Z4 and Z5 are N, and preferably at most one N.

[0772] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E As defined herein;

[0773] X1 is N;

[0774] X2 is C or N;

[0775] X3 is C or N;

[0776] X4 for CR e4 or N, preferably N;

[0777] X5 for CR e5 or N, preferably CR e5 ;

[0778] X6 is C;

[0779] X7 for CR e1 or N, preferably CR e1 ;

[0780] X8 for CR e2 or N, preferably N;

[0781] X9 for CR e3 or N, preferably CR e3 ;

[0782] R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -O-3 to 7 membered carbocyclic group or 3 to 7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C1-6 haloalkyl or -OR';

[0783] R e3 、R e4 and R e5 independently H or D;

[0784] R' e5 Selected from H, C 1-3 Alkyl or C 1-3 alkyl halide;

[0785] R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 alkyl halide;

[0786] Z1 is selected from CR d1 or N, preferably CR d1 ;

[0787] Z2 is selected from CR d2 or N;

[0788] Z4 selected from CR d4 or N;

[0789] Z5 is selected from CR d5 or N, preferably CR d5 ;

[0790] R d1 H or D;

[0791] R d2 、R d4 and R d5 Independently selected from H, D, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl, preferably R d2 and R d5 Independently selected from H, D or halogen, preferably R d5 is H or D;

[0792] R d3 Selected from or -NR' d6 C(O)R d6 Preferably, for Preferably

[0793] a and b are independently 0, 1 or 2, preferably a and b are 1;

[0794] L' is independently selected from a covalent bond or C 1-2 Alkylene, preferably selected from a covalent bond or a methylene group;

[0795] Y1 is NR' dd , preferably NH; or when Y1 is connected to L', Y1 is CH, CD or N;

[0796] Y2 is CR dd R dd , O or NR' dd ;

[0797] R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R" or -L"-3 to 7 membered carbocyclic group, preferably selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR' or -L"-NR'R", preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR';

[0798] Or two non-adjacent R dd Together they form C 1-2 alkylene;

[0799] R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene-OR', -C 1-4 Alkylene-NR'R" or -L"-3 to 7 membered carbocyclic group, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl or -L"-3 to 7-membered carbocyclic group;

[0800] n = 0, 1, 2, 3 or 4;

[0801] R d6 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl or -L"-OC 1-4 Alkylene -OR', preferably not -L"-OC 1-4 Alkylene-OR';

[0802] R' d6 Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0803] L" is independently selected from a covalent bond, C 1-4 Alkylene or -C(R)2-, preferably selected from covalent bonds or C 1-4Alkylene, wherein the two R together with the C atom to which they are attached form a 3- to 5-membered carbocyclylene group, preferably

[0804] R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0805] In some specific embodiments of the present invention, when Y1 is N, Y2 is O, L' is a covalent bond, and R dd Not oxygenated.

[0806] In some specific embodiments of the present invention, when R e2 For-OC 1-6 When alkyl, R e2 is -OMe, preferably, when R e2 For-OC 1-6 When alkyl halide, R e2 It is -O-halomethyl.

[0807] In some specific embodiments of the present invention, R d2 and R d4 At least one of them is H or D, preferably at least one of them is H.

[0808] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E As defined herein;

[0809] X1 is N;

[0810] X2 is C or N;

[0811] X3 is C or N;

[0812] X4 for CR e4 or N, preferably N;

[0813] X5 for CR e5 or N, preferably CR e5 ;

[0814] X6 is C;

[0815] X7 for CR e1 or N, preferably CR e1 ;

[0816] X8 for CR e2 or N, preferably N;

[0817] X9 for CR e3or N, preferably CR e3 ;

[0818] R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl or Preferably selected from H, F, Cl, CN, Me, CHF2, OCH3 or OEt, preferably R e2 Not for OEt;

[0819] R e3 、R e4 and R e5 is H;

[0820] R' e5 for Me;

[0821] R 1a and R 1b independently Me or Et;

[0822] Z1 is selected from CR d1 or N, preferably CR d1 ;

[0823] Z2 is selected from CR d2 or N;

[0824] Z4 selected from CR d4 or N;

[0825] Z5 is selected from CR d5 or N, preferably CR d5 ;

[0826] R d1 is H;

[0827] R d2 、R d4 and R d5 Independently selected from H, F, Me or CHF2, preferably R d2 and R d5 Independently selected from H or F, preferably R d5 is H;

[0828] R d3 Selected from or -NR' d6 C(O)R d6 , preferably

[0829] a is 1 or 2, b is 1;

[0830] L' is independently selected from a covalent bond or a methylene group, preferably a covalent bond;

[0831] Y1 is NH, CH or N, preferably CH or N, preferably N;

[0832] Y2 is CR dd R dd , O or NR' dd , preferably O;

[0833] R dd independently selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, or -NHMe, preferably H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe or -NHMe;

[0834] Or two non-adjacent R dd Together to form -CH2CH2-, preferably The structure is as follows:

[0835] R' dd Independently selected from H, Me, -CH2-cyclopropyl;

[0836] n = 0, 1, or 2;

[0837] R d6 Selected from -CH2-cyclopropyl or -CH2-O-CH2CH2-OH, preferably -CH2-cyclopropyl;

[0838] R' d6 For H.

[0839] In some specific embodiments of the present invention, R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably

[0840] In some specific embodiments of the present invention, R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from:

[0841] In some specific embodiments of the present invention, Selected from: Preferably selected from: Preferably not Preferably selected from:

[0842] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0843] in,

[0844] R E As defined herein;

[0845] X5 for CR e5 , N, O, S or NR' e5 , preferably CR e5 , O, N or NR' e5 , preferably CR e5 or N;

[0846] X7 for CR e1 or N;

[0847] X8 for CR e2 or N;

[0848] R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R es replace;

[0849] Res Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0850] R e5 Selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0851] Z1 is selected from CR d1 or N, preferably CR d1 ;

[0852] Z2 is selected from CR d2 or N;

[0853] Z4 selected from CR d4 or N;

[0854] Z5 is selected from CR d5 or N, preferably CR d5 ;

[0855] R d1 Selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0856] R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -NR'R"; preferably R d2 and R d5 Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0857] R d3 Selected from -NR' d6 C(O)R d6 and -C(O)NR d7 R' d7 ;

[0858] a and b are independently 0, 1, 2 or 3, preferably 0, 1 or 2; preferably a+b≤5, preferably a+b≤3;

[0859] L' is independently covalently bonded to C 1-6 Alkylene, preferably selected from covalent bonds and C 1-4 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl or C 1-6 alkyl halide;

[0860] Y1 is CR dd R dd or NR' dd ; or when Y1 is connected to L', Y1 is CR dd or N;

[0861] Y2 is selected from CR dd R dd 、O、S、S(O),NR' dd and S(O)2, preferably selected from CR dd R dd 、O、NR' dd and S(O)2; preferably, at least one of Y1 and Y2 is a heteroatom group;

[0862] R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl;

[0863] or CR dd R dd To form a 3 to 7 membered carbocyclylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0864] Or two non-adjacent R dd Together they form C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0865] R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl;

[0866] or R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R";

[0867] R d7 and R' d7 Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0868] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7-membered carbocyclyl and -L d -3 to 7 membered heterocyclic group, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl;

[0869] L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene;

[0870] The remaining variables are as defined in this article;

[0871] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0872] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E As defined herein;

[0873] X5 for CR e5or N, preferably CR e5 ;

[0874] X7 for CR e1 or N, preferably CR e1 ;

[0875] X8 for CR e2 or N, preferably N;

[0876] R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", -O-3 to 7 membered carbocyclyl, -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, preferably not -NR'R", preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -O-3 to 7 membered carbocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 R es Substituted; preferably R e1 is not a heterocyclic group;

[0877] R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR' are preferably selected from H, D, F, Me and OH;

[0878] R e5 Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H or D;

[0879] Z1 is selected from CR d1 or N, preferably CR d1 ;

[0880] Z2 is selected from CR d2 or N;

[0881] Z4 selected from CR d4 or N;

[0882] Z5 is selected from CR d5 or N, preferably CR d5 ;

[0883] R d1 is H or D;

[0884] R d2 、Rd4 and R d5 Independently selected from H, D, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and -OR', preferably R d2 and R d5 Independently selected from H, D and halogen; preferably R d2 、R d4 and R d5 is H or D;

[0885] R d3 Selected from and -NR' d6 C(O)R d6 Preferably, for Preferably

[0886] a and b are independently 0, 1 or 2, preferably a and b are 1;

[0887] L' is independently selected from a covalent bond or C 1-2 Alkylene, preferably selected from a covalent bond or a methylene group;

[0888] Y1 is NR' dd ; or when Y1 is connected to L', Y1 is CR dd or N;

[0889] Y2 is selected from CR dd R dd 、O、NR' dd and S(O)2;

[0890] R dd Independently selected from H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R" or -L"-3 to 7 membered carbocyclic group, preferably selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR' or NR'R", preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR';

[0891] or CR dd R dd forming a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, which is optionally substituted with one -OR', preferably optionally substituted with one OH;

[0892] Or two non-adjacent R dd Together they form C 1-2alkylene;

[0893] R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl and -L"-3 to 7 membered carbocyclyl;

[0894] or R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0895] L" is independently selected from a covalent bond, C 1-4 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R together with the C atom to which they are commonly attached form a 3- to 7-membered carbocyclyl, preferably a 3- to 5-membered carbocyclyl, preferably

[0896] R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0897] The remaining variables are as defined in this article;

[0898] Preferably, when Y1 is N, Y2 is O, L' is a covalent bond, and R dd Not for oxygen generation;

[0899] Preferably, when R e2 For-OC 1-6 When alkyl, R e2 is -OMe, preferably, when R e2 For-OC 1-6 When alkyl halide, R e2 is -O-halomethyl;

[0900] Preferably,

[0901] R e1 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", -O-3 to 7-membered carbocyclyl, -O-3 to 7-membered heterocyclyl, 3 to 7-membered carbocyclyl and 3 to 7-membered heterocyclyl, preferably other than -NR'R" and 3 to 7-membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6Alkyl, C 1-6 Haloalkyl, -OR', -O-3 to 7 membered carbocyclyl and 3 to 7 membered carbocyclyl, which are optionally substituted by 1, 2 or 3 R es replace;

[0902] R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OMe, -O-halomethyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 R es replace;

[0903] Preferably, when R e2 When it is a heterocyclic group, R es independently selected from H, D, halogen (F), C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably selected from H, D, F and Me, and is preferably halogen (F).

[0904] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E As defined herein;

[0905] X5 for CR e5 or N, preferably CR e5 ;

[0906] X7 for CR e1 or N, preferably CR e1 ;

[0907] X8 for CR e2 or N, preferably N;

[0908] R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OH, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably not Preferably selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, cyclopropyl, Preferred R e1 Not for Preferred R e2 Not for OEt;

[0909] R e5 is selected from H, D, F, Br and Me, preferably H;

[0910] Z1 is selected from CR d1 or N, preferably CR d1 ;

[0911] Z2 is selected from CR d2 or N;

[0912] Z4 selected from CR d4 or N;

[0913] Z5 is selected from CR d5 or N, preferably CR d5 ;

[0914] R d1 is H;

[0915] R d2 、R d4 and R d5 Independently selected from H, F, CN, Me, CHF2 and OCH3, preferably R d2 and R d5 are independently selected from H and F; preferably, R d2 、R d4 and R d5 is H;

[0916] R d3 Selected from and -NR' d6 C(O)R d6 , preferably

[0917] a is 0, 1 or 2, preferably 0 or 1, b is 0 or 1;

[0918] L' is independently selected from a covalent bond or a methylene group, preferably a covalent bond;

[0919] Y1 is NH; or when Y1 is connected to L', Y1 is selected from CH, C(OH) and N, preferably selected from CH and N, preferably N;

[0920] Y2 is selected from CR dd R dd 、O、NR' dd and S(O)2, preferably selected from CR dd R dd , O and NR' dd , preferably O;

[0921] R dd independently selected from H, F, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, and -NHMe, preferably selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, and -NHMe, preferably selected from H, OH, Me, -C(CH3)2OH, -CH2OMe and

[0922] or CR dd R dd To form cyclopropylene, Preferably forming a cyclopropylene or Preferably, a cyclopropylene group is formed;

[0923] Or two non-adjacent R dd Together they form -CH2CH2-;

[0924] R' dd Independently selected from H, Me, -CH2-cyclopropyl;

[0925] or R' dd With adjacent R dd and the atoms they connect to form Preferred Formation

[0926] The remaining variables are as defined herein.

[0927] Preferably,

[0928] R e1 Selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, and cyclopropyl, preferably selected from H, F, CN, Me, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and cyclopropyl;

[0929] R e2 Selected from H, F, Cl, CN, Me, CHF2, OCH3, OEt, OCHF2, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, CHF2, OCH3, OCHF2, cyclopropyl,

[0930] Preferably,

[0931] R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably

[0932] Preferably,

[0933] R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from:

[0934] Preferably, Selected from: Preferably selected from: Preferably selected from:

[0935] In a more specific embodiment, the present invention provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0936] in,

[0937] X1 selected from CR e6 , O, S, N or NR' e6 ;

[0938] X5 for CR e5 , N, O, S or NR' e5 ;

[0939] X6 is C or N;

[0940] X 10 Selected from CR e7 , O, S, N or NR' e7 ;

[0941] X 11 Selected from CR e8 , O, S, N or NR' e8 ;

[0942] R e7 and R e8 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl;

[0943] R' e7 and R' e8 Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 7-membered carbocyclyl, or -L'-3 to 7-membered heterocyclyl;

[0944] or X 10 and X 11 The substituents on the 3-5 Alkylene, which optionally contains a double bond, the C 3-5 The alkylene group is optionally substituted by 1, 2, 3 or 4 R e substituted, and wherein 1, 2 or 3 methylene units are optionally and independently replaced by -NR"-, -N(R")C(O)-, -C(O)N(R")-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S- or -S(O)-;

[0945] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group;

[0946] L' is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl or C 1-6 alkyl halide;

[0947] L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene;

[0948] R e As defined herein, preferably R e Not alkenyl or alkynyl;

[0949] R e5 , R' e5 、R e6 and R' e6 Each as defined herein;

[0950] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined herein;

[0951] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0952] In a more specific embodiment, the present invention provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0953] X1 selected from CR e6 , N or NR' e6 , preferably N;

[0954] X5 for CR e5 , N or NR' e5 ;

[0955] X6 is C or N, preferably C;

[0956] X 10 Selected from CR e7 , N or NR' e7 ;

[0957] X11 Selected from CR e8 , O, N or NR' e8 ;

[0958] R e7 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl;

[0959] R' e7 Selected from H, D, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group;

[0960] R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0961] R' e8 Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0962] or X 10 and X 11 The substituents on the 3-5 Alkylene, preferably forming -(CH2)4-, which optionally contains a double bond, the C 3-5 Alkylene or -(CH2)4- is optionally substituted by 1, 2, 3 or 4 R e substituted, and wherein 1, 2 or 3 methylene units are optionally and independently replaced by -NR"-, -C(O)N(R")-, -C(O)- or -O-, preferably wherein 1 methylene unit is optionally and independently replaced by -O-;

[0963] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group;

[0964] R e As defined herein, preferably R e Not alkenyl or alkynyl;

[0965] R e5 , R' e5 、R e6 and R' e6 Each as defined herein;

[0966] R 1a 、R 1b , Z1, Z2, Z4, Z5 and Rd3 Each is as defined herein.

[0967] In some specific embodiments of the present invention, X1, X5, X6, X 10 and X 11 There are at most 3 heteroatoms.

[0968] In a more specific embodiment, the present invention provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0969] X1 is N;

[0970] X5 for CR e5 , N or NR' e5 , preferably CR e5 or N, more preferably CR e5 ;

[0971] X6 is C or N, preferably C;

[0972] X 10 CR e7 or NR' e7 ;

[0973] X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ;

[0974] R e7 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, or -O-3- to 7-membered heterocyclyl;

[0975] R' e7 Selected from C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group, preferably a 3- to 7-membered carbocyclic group;

[0976] R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide;

[0977] R' e8 Selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[0978] or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably

[0979] R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0980] R e1 、R e2 、R e5 and R' e5 Each is as defined herein; preferably, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR', -O-3 to 7 membered carbocyclic group, preferably selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl or -OR';

[0981] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each is as defined herein.

[0982] In some embodiments of the present invention, when R e7 or R' e7 When it is a heterocyclic group, it is a 3- to 7-membered oxazoheterocyclic group, preferably a 4- to 6-membered oxazoheterocyclic group, and preferably a 5-membered oxazoheterocyclic group.

[0983] In a more specific embodiment, the present invention provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[0984] X1 is N;

[0985] X5 for CR e5 , N or NR' e5 , preferably CR e5 or N, more preferably CR e5 ;

[0986] X6 is C or N, preferably C;

[0987] X 10 Selected from CRe7 or NR' e7 ;

[0988] X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ;

[0989] R e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl,

[0990] R' e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or morpholinyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl or tetrahydropyranyl, preferably selected from Me, Et, cyclopropyl or tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl or Preferably cyclopropyl;

[0991] R e8 is selected from H, Me or Et, preferably H or Me, preferably Me;

[0992] R' e8 is Me or Et, preferably Me;

[0993] or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably

[0994] R e1 and R e2independently selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl or Preferably selected from H, F, CN, Me, OMe, OEt, OCHF2 or -O-cyclopropyl, preferably selected from H, F, CN, Me, OCH3, OEt, OCHF2 or -O-cyclopropyl, preferably selected from H, Me, OCH3 or OEt;

[0995] R e5 is H;

[0996] R' e5 for Me;

[0997] R" is H or methyl;

[0998] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each is as defined herein.

[0999] In some embodiments of the present invention, X 10 and X 11 The substituents on the above together form a structure selected from the following: Preferably selected from: Preferably selected from: Preferably selected from:

[1000] In some specific embodiments of the present invention, Selected from Preferably selected from: Preferably selected from:

[1001] In some embodiments of the present invention, R dd Independently selected from H, Me or -C(CH3)2OH, or two non-adjacent R dd Together to form -CH2CH2-, preferably The structure is as follows:

[1002] Preferably, R d3 Selected from: Preferably selected from: Preferably

[1003] In a more specific embodiment, the present invention provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[1004] in,

[1005] X 10 CR e7 or NR' e7 ;

[1006] X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ;

[1007] R e7 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 7 membered carbocyclyl, 3 to 7 membered heterocyclyl and -O-3 to 7 membered heterocyclyl; preferably selected from C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 7-membered carbocyclyl, tetrahydrofuranyl, morpholinyl, and -O-3- to 7-membered heterocyclyl; preferably 3- to 7-membered carbocyclyl;

[1008] R' e7 Selected from C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group, preferably a 3- to 7-membered carbocyclic group;

[1009] R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide;

[1010] R' e8 Selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[1011] or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably

[1012] R e1 and R e2 Each is as defined herein, R' e1 and R' e2 Each is as defined herein; preferably, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR', -O-3 to 7 membered carbocyclyl and -O-3 to 7 membered heterocyclyl, preferably not halogen, preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -O-3 to 7 membered carbocyclic group; preferably R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR', preferably R e2 H, D or C 1-6 alkyl halide;

[1013] R' e1 and R' e2 Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, halogen and C 1-6 alkyl;

[1014] or CR e1 R' e1 forming a 3- to 7-membered carbocyclic group and a 3- to 7-membered heterocyclic group, preferably forming a 3- to 7-membered heterocyclic group;

[1015] R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably R" is C 1-4 alkyl halide;

[1016] The remaining variables are as defined in this article;

[1017] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[1018] In a more specific embodiment, the present invention provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[1019] X 10 Selected from CR e7 or NR' e7 ;

[1020] X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ;

[1021] R e7 Selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably cyclopropyl;

[1022] R' e7 is selected from Me, Et and cyclopropyl, preferably cyclopropyl;

[1023] R e8 is selected from H, Me or Et, preferably H or Me, preferably Me;

[1024] R' e8 is Me or Et, preferably Me;

[1025] or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably

[1026] R e1 and R e2 independently selected from H, F, CN, Me, CHF2, OH, OMe, OEt, OCHF2, -O-cyclopropyl and Preferably selected from H, CN, Me, CHF2, OH, OCH3, OEt, -O-cyclopropyl and Preferably selected from H, Me, CHF2, OCH3, OEt and -O-cyclopropyl; preferably R e2 is selected from H, F, CN, Me, CHF2, OH and OMe, preferably R e2 is H or CHF2;

[1027] R' e1 and R' e2 independently selected from H, F and Me;

[1028] or CR e1 R' e1 form

[1029] R" is selected from H, methyl and CHF2, preferably CHF2;

[1030] The remaining variables are as defined herein.

[1031] Preferably,

[1032] X 10 and X 11 The substituents on the above together form a structure selected from the following: Preferably selected from: Preferably selected from:

[1033] Preferably, Selected from Preferably selected from: Preferably selected from:

[1034] Preferably, Y1 is CH or N, and Y2 is selected from CR dd R dd and O;

[1035] R dd are independently selected from H, OH, Me, -CH2OMe and -C(CH3)2OH, or two non-adjacent R dd Together they form -CH2CH2-;

[1036] Preferably, R d3 Selected from: Preferably selected from: Preferably

[1037] In a more specific embodiment, the present invention provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[1038] in,

[1039] E is selected from CR e12 or N;

[1040] J is selected from CR e13 or N;

[1041] R e9 、R e10 、R e11 、Re12 and R e13 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, -L'-3 to 7 membered heterocyclyl or -Y5-C 0-6 Alkylene-R6;

[1042] Y5 is selected from O, S or NR5;

[1043] R5 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[1044] R6 is selected from 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl;

[1045] or R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[1046] or R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[1047] R e As defined herein, preferably R e Not alkenyl or alkynyl;

[1048] L' is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group;

[1049] L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene;

[1050] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -Ld -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group;

[1051] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined herein;

[1052] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[1053] In a more specific embodiment, the present invention provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[1054] E is selected from CR e12 or N;

[1055] J is selected from CR e13 or N;

[1056] R e9 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl, 3 to 7 membered heterocyclyl or -Y5-C 0-6 Alkylene-R6, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR' or -NR'R";

[1057] Y5 is selected from O or NR5;

[1058] R5 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[1059] R6 is selected from 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl;

[1060] R e10 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[1061] R e11 、R e12 and R e13 H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[1062] or R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[1063] or R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[1064] R e As defined herein, preferably R e Not alkenyl or alkynyl;

[1065] R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group;

[1066] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each is as defined herein.

[1067] In some specific embodiments of the present invention, at least one of E and J is N; preferably, only one of E and J is N.

[1068] In a more specific embodiment, the present invention provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[1069] E is selected from CR e12 or N;

[1070] J is selected from CR e13 or N;

[1071] R e9 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl, -NR'R", 3 to 7 membered heterocyclic group or -OC 0-4 Alkylene-3-7 membered heterocyclic group, preferably selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl or -NR'R";

[1072] Re10 Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[1073] R e11 、R e12 and R e13 is H or D;

[1074] or R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered heterocyclic group, preferably a dihydrooxazinyl group, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[1075] or R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a dihydrooxazinyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace;

[1076] R e As defined herein, preferably R e Not alkenyl or alkynyl; preferably R e Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR' and -NR'R", preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR' are preferably selected from Me and OMe;

[1077] R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[1078] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each is as defined herein.

[1079] In some embodiments of the present invention, R e Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, preferably H or Me.

[1080] In a more specific embodiment, the present invention provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

[1081] E is selected from CR e12 or N;

[1082] J is selected from CR e13 or N;

[1083] R e9 Selected from H, -NHMe, Preferably selected from H, -NHMe or

[1084] R e10 selected from H or Me;

[1085] R e11 、R e12 and R e13 is H;

[1086] or R e9 、R e13 and the carbon atoms they are connected to form

[1087] or R e9 、R e10 and the carbon atoms they are connected to form Preferred Formation Preferred Formation Preferred Formation

[1088] R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each is as defined herein.

[1089] In some specific embodiments of the present invention, Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably

[1090] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from:

[1091] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from:

[1092] In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[1093] In one embodiment, the present invention relates to the use of a compound of the present invention or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the prevention and / or treatment of an HPK1-mediated disorder, disease or condition.

[1094] In one embodiment, the present invention relates to a compound of the present invention or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition comprising the same, for use in preventing and / or treating an HPK1-mediated disorder, disease or condition.

[1095] In one embodiment, the present invention relates to a method for preventing and / or treating an HPK1-mediated disorder, disease or condition, comprising administering to a subject a compound of the present invention or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or a pharmaceutical composition comprising the same.

[1096] Furthermore, the disorder, disease or condition is a proliferative disorder.

[1097] Furthermore, the proliferative disorder is cancer.

[1098] Furthermore, the proliferative disorder is associated with one or more activating mutations in HPK1.

[1099] In one embodiment, the disorder, disease or condition is a chronic viral infection.

[1100] In one embodiment, the present invention relates to the use of a compound of the present invention or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or a pharmaceutical composition comprising the same, for the preparation of a medicament for increasing the efficacy of vaccination.

[1101] In one embodiment, the present invention relates to a compound or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition comprising the same, for use in increasing the efficacy of vaccination.

[1102] In one embodiment, the present invention relates to a method of increasing the efficacy of vaccination, comprising administering to a subject a compound of the present invention or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or a pharmaceutical composition comprising the same.

[1103] Pharmaceutical compositions and kits

[1104] In one aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[1105] Pharmaceutically acceptable carriers, adjuvants, or vehicles used in the present invention refer to non-toxic carriers, adjuvants, or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, 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, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[1106] Suitable formulations for administering the compounds of the present invention will be readily apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (particularly solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injection)), elixirs, syrups, cachets, emulsions, inhalants, or dispersible powders. If necessary, the indicated dose may be administered several times daily.

[1107] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[1108] use

[1109] The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the present invention is HPK1.

[1110] The compounds disclosed herein can be used to inhibit the activity of the HPK1 enzyme. HPK1 is a member of the germinal center kinase subfamily of Ste20-related serine / threonine kinases. HPK1 phosphorylates and activates MAP3K proteins (including MEKK1, MLK3, and TAK1), leading to the activation of MAPK Jnk, which in turn exerts MAP4K function.

[1111] In one embodiment, the presently disclosed subject matter relates to a method of inhibiting HPK1, comprising contacting HPK1 with an effective amount of a compound or pharmaceutical composition of the present invention.

[1112] In some embodiments, the subject matter disclosed in the invention relates to a method for enhancing the immune response of a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition of the invention. In some aspects of this embodiment, the T cells of the subject have at least one of the following compared to before the administration of the compound or pharmaceutical composition: enhanced activation, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival rate, and enhanced cytolytic activity. In some aspects of this embodiment, T cell activation is characterized by an increased occurrence rate of γ-IFN+CD8T cells or an enhanced production of IL-2 or granzyme B by T cells relative to before the administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the number of T cells is increased compared to before the administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the T cells are antigen-specific CD8T cells. In some aspects of this embodiment, the antigen-presenting cells of the subject have enhanced maturation and activation compared to before the administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the antigen-presenting cells are dendritic cells. In some aspects of this embodiment, the maturation of antigen-presenting cells is characterized by an increased occurrence rate of CD83+ dendritic cells. In some aspects of this embodiment, antigen presenting cell activation is characterized by increased expression of CD80 and CD86 on dendritic cells.

[1113] The compounds disclosed herein bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the compounds disclosed herein reduce, inhibit, or otherwise diminish HPK1-mediated phosphorylation of SLP76 and / or Gads.

[1114] The compounds disclosed herein may or may not be specific HPK1 antagonists. Specific HPK1 antagonists reduce the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinases). In some embodiments, the compounds disclosed herein specifically inhibit the serine / threonine kinase activity of HPK1. In some such embodiments, the HPK1 antagonist has an IC of 100 for HPK1. 50 is the IC of an HPK1 antagonist against another serine / threonine kinase or another type of kinase (e.g., tyrosine kinase) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less.

[1115] The compounds disclosed herein can be used in methods for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a compound of the invention. "Contacting" means bringing the compound into sufficient proximity with an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., a T cell, B cell, dendritic cell) to allow the compound to bind to HPK1 and inhibit its activity. Contacting the compound with HPK1 can be performed in vitro or in vivo by administering the compound to a subject.

[1116] Whether HPK1 has been inhibited can be determined using any method known in the art for measuring the kinase activity of an HPK, including in vitro kinase assays, immunoblotting with antibodies specific for phosphorylation targets of HPK1 (such as SLP76 and Gads), or measurement of downstream biological effects of HPK1 kinase activity, such as recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation.

[1117] The compounds disclosed herein can be used to treat HPK1-dependent disorders. As used herein, an "HPK1-dependent disorder" is a pathological condition in which HPK1 activity is required for the cause or maintenance of the pathological condition. In some embodiments, the HPK1-dependent disorder is cancer.

[1118] The compounds disclosed herein can also be used to enhance the immune response of a subject in need thereof. Such methods comprise administering an effective amount of a compound of the present invention.

[1119] As used herein, "enhancing immune response" refers to the improvement of any immunogenic response to an antigen. Non-limiting examples of improvements to the immunogenic response of an antigen include enhanced dendritic cell maturation or migration, enhanced T cell (e.g., CD4 T cells, CD8 T cells) activation, enhanced T cell (e.g., CD4 T cells, CD8 T cells) proliferation, enhanced B cell proliferation, increased T cell and / or B cell survival rate, improved antigen presentation via antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increased production of cytokines (e.g., interleukin-2) via T cells, increased resistance to immunosuppression induced by prostaglandin E2 and enhanced CD8 T cell activation and / or cytolytic activity.

[1120] In some embodiments, the subject has enhanced maturation and activation of antigen-presenting cells relative to prior to administration of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof. In some embodiments, the antigen-presenting cells are dendritic cells. In some embodiments, antigen-presenting cell maturation is characterized by an increased occurrence of CD83+ dendritic cells. In some embodiments, antigen-presenting cell activation is characterized by increased expression of CD80 and CD86 on dendritic cells.

[1121] The compounds of the present invention disclosed herein, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, and pharmaceutically acceptable agents, are suitable for treating T cell dysfunction disorders. A "T cell dysfunction disorder" is a T cell disorder or disorder characterized by a reduced response to antigenic stimulation. In a specific embodiment, the T cell dysfunction disorder is a disorder specifically associated with increased kinase activity of HPK1. In another embodiment, the T cell dysfunction disorder is a disorder in which T cells lack the ability or ability to secrete cytokines, proliferate, or perform cytolytic activity. In a specific aspect, the reduced response can result in ineffective control of pathogens or tumors that present immunogens. Examples of T cell dysfunction disorders characterized by T cell dysfunction include acute infections of unknown origin, chronic infections, and tumor immunity.

[1122] Therefore, the compounds disclosed herein are useful in treating diseases where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.

[1123] The term "dysfunction" in the context of immune dysfunction is a state of reduced immune response to antigenic stimulation. The term includes common elements in which exhaustion and / or loss of ability to recognize antigens can occur, but the subsequent immune response is ineffective in controlling infection or tumor growth.

[1124] As used herein, the term "dysfunctional" also includes being resistant or unresponsive to antigen recognition, specifically, having a reduced ability to translate antigen recognition into downstream T cell effector functions such as proliferation, cytokine production (e.g., IL-2, γ-IFN), and / or target cell killing.

[1125] The term "incompetence" refers to a state of being unable to respond to antigenic stimulation caused by incomplete or insufficient signaling delivered via the T cell receptor (e.g., intracellular Ca +2In the absence of costimulation, T cell aphasia can also result from antigenic stimulation, causing cells to become resistant to subsequent antigenic activation even in the presence of costimulation. The anergic state can often be resolved by the presence of interleukin-2. Aphaic T cells do not undergo clonal expansion and / or acquire effector functions.

[1126] The term "exhaustion" refers to T cell exhaustion, a state of T cell dysfunction caused by persistent TCR signaling, such as occurs during a variety of chronic infections and cancers. It differs from capacity loss in that it is not caused by incomplete or insufficient signaling, but by persistent signaling. It is defined by adverse effector function, persistent expression of inhibitory receptors, and a transcriptional state that is different from functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can be caused by exogenous negative regulatory pathways (such as immunoregulatory cytokines) as well as cellular endogenous negative regulatory (co-stimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[1127] "Immunogenicity" refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the elimination of tumor cells through an immune response.

[1128] In some embodiments, the subject matter disclosed herein relates to a method for treating an HPK1-dependent condition, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the present invention. In some aspects of this embodiment, the HPK1-dependent condition is cancer. In some aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, a hematologic malignancy, and renal cell carcinoma. In some aspects of this embodiment, the cancer has an increased amount of T cell infiltration. In some aspects of this embodiment, the cancer cells of the subject selectively have increased expression of MHC class I antigens compared to prior to administration of the compound or composition.

[1129] In some embodiments, the subject matter disclosed herein relates to a method for treating chronic viral infections. In some embodime...

Claims

1. A compound of formula (I'), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: V is selected from the group consisting of a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C '; W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C '; Z7 is C; Or V and W are not connected, Z7 is C or N, and W is selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H and C 1-6 Alkyl, V is selected from the group consisting of: absent, H, D, halogen, C 1-8 Alkyl and C 1-8 haloalkyl, preferably selected from the group consisting of absent, H, D and halogen; Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time; or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution; R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; R B Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; One of Z1 and Z6 is CR E , the other is CR d1 or N; R E Selected from -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C 6-10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution; R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C 6-10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R es replace; Or two R e and the atoms to which they are attached together form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R es replace; R es Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR' and -L'-NR'R"; R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; Ring A is selected from C 6-10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring; R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or CR dd R dd To form a 3 to 7 membered carbocyclylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; Or two non-adjacent R dd Together they form C 1-8 Alkylene, optionally substituted with one or more of the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl, or -L"-5 to 10-membered heteroaryl; Or two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene, or a 5- to 6-membered heteroarylene, which is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl; L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R is independently selected from H, D, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -3 to 10-membered carbocyclic group or -L d -3 to 10-membered heterocyclic group; or two R together with the C atom to which they are commonly attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene; L d Independently selected from a covalent bond or C 1-8 alkylene; f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

2. A compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: V is selected from the group consisting of a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C '; W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C '; Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time; or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution; R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; R B Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; One of Z1 and Z6 is CR E , the other is CR d1 or N; R E Selected from -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C 6-10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution; R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C 6-10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl; R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; Ring A is selected from C 6-10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring; R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenation Alkyl, -L'-C 6-10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; Or two R dd Together they form C 1-8 Alkylene, optionally substituted with one or more of the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl, or -L"-5 to 10-membered heteroaryl; L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl; L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R is independently selected from H, D, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -3 to 10-membered carbocyclic group or -L d -3 to 10-membered heterocyclic group; or two R together with the C atom to which they are commonly attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene; L d Independently selected from a covalent bond or C 1-8 alkylene; f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

3. A compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: V is selected from the group consisting of covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C or CR C R C '; W is selected from NR', S(O), S(O)2, C(O), CR C or CR C R C '; Q and Y are independently selected from a covalent bond, -O-, -S-, -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR A -、-OC(O)-、-OC(O)NR A -、-N(R A )C(O)O-、-N(R A )C(O)-or-N(R A )S(O)2-; and Q and Y are not covalent bonds at the same time; or Q and Y are independently C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -CR 1a R 1b -、-N(R A )-、-N(R A )C(O)-、-C(O)N(R A )-、-N(R A )S(O)2-、-S(O)2N(R A )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- substitution; R A Selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; R B Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; One of Z1 and Z6 is CR E , the other is CR d1 or N; R E Selected from -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl, wherein C 6-10 Aryl, 3 to 14 membered carbocyclyl, 3 to 14 membered heterocyclyl, or 5 to 14 membered heteroaryl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e group substitution; R e are independently selected from H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C 6-10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl; R d1 Selected from H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, or -L-5 to 14-membered heteroaryl; Ring A is selected from C 6-10 aromatic ring, 3- to 14-membered carbocyclic ring, 3- to 14-membered heterocyclic ring, or 5- to 14-membered heteroaromatic ring; R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR'R”, -L”-OC(O)R’, -L”-OC(O)NR'R”, -L”-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- or -N(R')S(O)2-; or L or L' is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R' and R" are independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L"-C 6-10 aryl, -L"-3 to 14-membered carbocyclyl, -L"-3 to 14-membered heterocyclyl, or -L"-5 to 14-membered heteroaryl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 14-membered heterocyclyl; L" is selected from a covalent bond, -O- or -S-; or L" is C 1-8 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

4. The compound of formula (I') or formula (I) according to any one of claims 1 to 3, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: V is selected from covalent bond, CR C or CR C R C '; is preferably selected from a covalent bond, CH, CH2, CD, CHD or CD2, more preferably a covalent bond.

5. The compound of formula (I') or formula (I) according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: W is CR C or CR C R C '; preferably CR C R C ', more preferably CH2, CD, CHD or CD2.

6. The compound of formula (I') or formula (I) according to any one of claims 1 to 5, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: The compound of formula (I) is one of the following:

7. The compound of formula (I') or formula (I) according to any one of claims 1 to 6, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: Q and Y are independently selected from a covalent bond, O, S, NR A , S(O), S(O)2, C(O) or CR 1a R 1b ; and Q and Y are not covalent bonds at the same time; Preferably, Q is selected from O, S or NR A , preferably S or NR A , preferably NR A , more preferably NH; Preferably, Y is selected from a covalent bond, O, S or CR 1a R 1b , preferably selected from a covalent bond, O or CR 1a R 1b , preferably selected from a covalent bond, O, CH2, CF2 or C(CH3)2, more preferably C(CH3)2.

8. The compound of formula (I') or formula (I) according to any one of claims 1 to 7, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R A Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl; preferably selected from H, C 1-6 Alkyl or C 1-6 preferably H.

9. The compound of formula (I') or formula (I) according to any one of claims 1 to 8, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R B Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl or -L-3 to 10-membered heterocyclyl; preferably selected from H, C 1-6 Alkyl or C 1-6 preferably H.

10. The compound of formula (I') or formula (I) according to any one of claims 1 to 9, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R C and R' C Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; preferably independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; more preferably independently H or D.

11. The compound of formula (I') or formula (I) according to any one of claims 1 to 10, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; preferably independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 preferably independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 preferably independently selected from H, D, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl; preferably independently selected from H, D, F or Me; more preferably Me.

12. The compound of formula (I') or formula (I) according to any one of claims 1 to 11, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R E Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyridinyl, dihydropyridooxazinyl, indolyl, triazolopyridinyl, tetrahydroimidazopyrazinyl, dihydropyrrolopyridinyl, thienopyridinyl, benzimidazolyl, dihydroimidazooxazinyl, tetrahydropyrazolopyridinyl, tetrahydropyrrolopyridinyl, dihydropyrazolooxazinyl, dihydropyrroloimidazolyl, oxazolopyridinyl, pyrazoloazepanyl, pyrazoloazepanyl, imidazoazepanyl, imidazoazepanyl, pyrazolodiazepanyl, pyrazolodiazepanyl and thienopyridinyl, which are optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R e group substitution; Preferably, R E and its substituent R e Together they form a group selected from: Preferably selected from wherein g = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, g=0, 1, 2, 3, 4, 5 or 6, preferably g=0, 1, 2, 3 or 4, preferably g=0, 1 or 2.

13. The compound of formula (I') or formula (I) according to any one of claims 1 to 12, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R e are independently selected from H, D, halogen, -CN, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl; preferably independently selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl or C 1-6 preferably independently selected from H, D, halogen, -CN, -OR', C 1-6 Alkyl or C 1-6 Haloalkyl; preferably independently selected from H, D, Me, F, Cl, -CN or -OCH3; Preferably, R E Together with the substituent R thereon e Together they form a group selected from: Preferably selected from: More preferably selected from:

14. The compound of formula (I') or formula (I) according to any one of claims 1 to 13, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein Z6 is CR E , Z1 is CR d1 or N, or Z1 is CR E , Z6 is N; preferably Z6 is CR E , Z1 is CR d1 or N; preferably Z6 is CR E , Z1 is CR d1 More preferably, Z6 is CR E , Z1 is CH or CD.

15. The compound of formula (I') or formula (I) according to any one of claims 1 to 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R d1 Selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10 membered carbocyclyl or -L-3 to 10 membered heterocyclyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 more preferably H or D.

16. A compound of formula (I') or formula (I) according to any one of claims 1 to 15, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: Ring A is selected from the group consisting of a benzene ring, a furan ring, a furazan ring, an imidazolidine ring, an imidazoline ring, an imidazole ring, an isothiazole ring, an isoxazole ring, a morpholine ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, an oxazolidine ring, an oxazole ring, an oxetane ring, an azetidine ring, a pyrimidine ring, a piperazine ring, a piperidine ring, a pyran ring, a pyrazolidine ring, a pyrazoline ring, a pyrazole ring, ring, pyridazine ring, pyridine ring, pyrrolidine ring, pyrroline ring, 2H-pyrrole ring, pyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiazole ring, thiophene ring, triazine ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, xanthene ring, tetrahydroquinoline ring, tetrahydroisoquinoline ring and hexahydropyrazinoquinoline ring; preferably selected from benzene ring, pyridine ring, pyrazole ring or imidazole ring; more preferably benzene ring; Preferably, ring A together with the substituents R thereon d Together they form a group selected from: Preferably selected from: where f = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, f=0, 1, 2, 3, 4, 5 or 6, preferably f=0, 1, 2, 3 or 4, preferably f=0, 1 or 2.

17. A compound of formula (I') or formula (I) according to any one of claims 1 to 16, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R d independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R"; or R d Independently selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; Or two adjacent R d The 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, taken together with the atoms to which they are attached, forms a 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl or 6- to 10-membered fused bicyclic heterocyclyl optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; Preferably, R d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; Preferably, R d Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R" or -L'-4 to 6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The haloalkyl or 4 to 6 membered heterocyclic group is optionally substituted by 1 or 2 R dd replace; Preferably, R d Independently selected from H, D, Preferably independently selected from H, D, Preferably, ring A together with the substituents R thereon d Together they form a group selected from: Preferably Preferably More preferably 18. A compound of formula (I') or formula (I) according to any one of claims 1 to 17, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R d Independently selected from H, F, -OH, -OCH3, 19. The compound of formula (I') or formula (I) according to any one of claims 1 to 17, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L"-S(O)2NR'R", -L"-S(O)NR'R", -L"-OC(O)R', -L"-OC(O)NR'R", -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl; preferably independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-SR' or -L"-NR'R"; preferably independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR' or -L"-NR'R", is preferably independently selected from H, D, Me, N(CH3)2 or C(CH3)2OH.

20. A compound of formula (I') or formula (I) according to any one of claims 1 to 19, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, Ring A together with the substituent R thereon d Together they form a group selected from:

21. A compound of formula (I') or formula (I) according to any one of claims 1 to 20, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: L and L' are independently selected from a chemical bond, -O-, -S-, -NR'-, -S(O)2- or -C(O)-; or L or L' is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-; Preferably, L or L' is independently selected from a covalent bond, O or C 1-6 Alkylene, preferably independently selected from covalent bonds, O or C 1-4 Alkylene.

22. The compound of formula (I') or formula (I) according to any one of claims 1 to 21, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: L" is selected from a covalent bond, -O- or -S-; or L" is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -S-, -S(O)- or -S(O)2-; preferably selected from a covalent bond or C 1-6 Alkylene; more preferably a covalent bond or C 1-4 Alkylene.

23. A compound of formula (I') or formula (I) according to any one of claims 1 to 22, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, having the following structural formula: in, Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic; X1 for CR e6 , N, O, S or NR' e6 ; X2 is C or N; X3 is C or N; X4 for CR e4 , CR e4 R' e4 or N; X5 for CR e5 , N, O, S or NR' e5 ; X6 is C or N; X7 for CR e1 or N; X8 for CR e2 or N; X9 for CR e3 or N; X 10 Selected from CR e7 , O, S, N or NR' e7 ; X 11 Selected from CR e8 , O, S, N or NR' e8 ; R e1 、R e2 、R e3 、R e4 、R e5 and R e6 Independently selected from H, D, halogen, -CN, C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-OR', -L'-NR'R”, -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R”, -L'-S(O)2R', -L'-S(O)2NR'R”, -L'-OC(O)R', -L'-OC(O)NR'R”, -L'-C 6-10 aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, or -L'-5 to 14-membered heteroaryl; R' e1 , R' e2 , R' e3 , R' e4 Independently selected from none, H, D, halogen, -CN, C 1-8 Alkyl or C 1-8 Haloalkyl; or CR e1 R' e1 Forming -C(O)-, or CR e2 R' e2 Forming -C(O)-, or CR e3 R' e3 Forming -C(O)-, or CR e4 R' e4 Formation of -C(O)-; R' e5 and R' e6 Independently selected from H, C 1-8 Alkyl or C 1-8 alkyl halide; R e7 and R e8 Independently selected from H, D, halogen, CN, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 10-membered carbocyclyl, or -L'-3 to 10-membered heterocyclyl; R' e7 and R' e8 Independently selected from H, D, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-3 to 10-membered carbocyclyl, or -L'-3 to 10-membered heterocyclyl; or X 10 and X 11 The substituents on the 3-5 Alkylene, which optionally contains a double bond, the C 3-5 The alkylene group is optionally substituted by 1, 2, 3 or 4 R e substituted, and one or more methylene units are optionally and independently replaced by NR"-, -N(R")C(O)-, -C(O)N(R")-, -N(R")S(O)2-, -S(O)2N(R")-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; E is selected from CR e12 or N; J is selected from CR e13 or N; R e9 、R e10 、R e11 、R e12 and R e13 Selected from H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 10-membered carbocyclyl, -L'-3 to 10-membered heterocyclyl or -Y5-C 0-8 Alkylene-R6; Y5 is selected from O, S or NR5; R5 is selected from H, C 1-8 Alkyl or C 1-8 alkyl halide; R6 is selected from 3 to 10 membered carbocyclyl or 3 to 10 membered heterocyclyl; or R e9 、R e13 and the carbon atoms to which they are connected together form a 5-10 membered carbocyclic group, a 5-10 membered heterocyclic group, a C6- 10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace; or R e9 、R e10 and the carbon atoms to which they are connected together form a 5-10 membered carbocyclic group, a 5-10 membered heterocyclic group, a C6- 10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace; Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace; Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace; Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace; Z5 is selected from covalent bond, CR d5 or N; R d2 、R d3 、R d4 and R d5 independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R", or R d2 、R d3 、R d4 and R d5 Independently selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, -L'-C6- 10 aryl, -L'-3 to 14 membered carbocyclyl, -L'-3 to 14 membered heterocyclyl, or -L'-5 to 14 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; or R d2 and R d3 Together with the atoms to which they are attached, or R d3 and R d4 Together with the atoms to which they are attached, or R d4 and R d5 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic heterocyclyl, a 6- to 10-membered bridged bicyclic heterocyclyl, a 6- to 10-membered spiro bicyclic heterocyclyl, or a 6- to 10-membered fused bicyclic heterocyclyl, wherein the 3- to 7-membered monocyclic heterocyclyl, the 6- to 10-membered bridged bicyclic heterocyclyl, the 6- to 10-membered spiro bicyclic heterocyclyl, or the 6- to 10-membered fused bicyclic heterocyclyl is optionally substituted by 1, 2, 3, 4, or 5 R dd replace; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; Other groups are as defined in claims 1 to 20; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

24. The compound of formula (II-1) according to claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein V is selected from covalent bond, CR C or CR C R C '; Q and Y are independently selected from a covalent bond, O, S, NR A , S(O), S(O)2, C(O) or CR 1a R 1b ; and Q and Y are not covalent bonds at the same time; R A Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl, or -L"-3 to 10-membered heterocyclyl; R B Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl, or -L-3 to 10-membered heterocyclyl; R C , R' C 、R 1a and R 1b Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl, or -L-3 to 10-membered heterocyclyl; Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic; X2 is C or N; X3 is C or N; X4 for CR e4 , CR e4 R' e4 or N; R e1 、R e2 、R e3 、R e4 and R e5 Independently selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-3 to 10 membered carbocyclyl, or -L'-3 to 10 membered heterocyclyl; R' e1 , R' e2 , R' e3 and R' e4 Independently selected from H, D, halogen, -CN, C 1-6 Alkyl or C 1-6 Haloalkyl; or CR e1 R' e1 Forming -C(O)-, or CR e2 R' e2 Forming -C(O)-, or CR e3 R' e3 Forming -C(O)-, or CR e4 R' e4 Formation of -C(O)-; Z1 is CR d1 or N; Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace; Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace; Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace; Z5 is selected from covalent bond, CR d5 or N; R d1 Selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-3 to 10-membered carbocyclyl, or -L-3 to 10-membered heterocyclyl; R d2 、R d3 、R d4 and R d5 independently selected from H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' or -L'-C(O)NR'R", or R d2 、R d3 、R d4 and R d5 Independently selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 10 membered carbocyclyl or -L'-3 to 10 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; or R d2 and R d3 Together with the atoms to which they are attached, or R d3 and R d4 Together with the atoms to which they are attached, or R d4 and R d5 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic heterocyclyl, a 6- to 10-membered bridged bicyclic heterocyclyl, a 6- to 10-membered spiro bicyclic heterocyclyl, or a 6- to 10-membered fused bicyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl, or 6- to 10-membered fused bicyclic heterocyclyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 R dd replace; R dd Independently selected from H, D, halogen, -CN, -NO2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L"-S(O)2NR'R", -L"-S(O)NR'R", -L"-OC(O)R', -L"-OC(O)NR'R", -L"-3 to 10-membered carbocyclyl or -L"-3 to 10-membered heterocyclyl; L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2- or -C(O)-; or L or L' is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-; R' and R" are independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl, -L"-3 to 10-membered heterocyclyl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocyclyl; L" is selected from a covalent bond, -O- or -S-; or L" is C 1-6 Alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

25. The compound of formula (II-1) according to claim 24, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein V is selected from covalent bond, CR C or CR C R' C ; Q is selected from O, S or NR A ; Y is selected from a covalent bond, O, S or CR 1a R 1b ; R A and R B Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R C , R' C Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a and R 1b Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic; X2 is C or N; X3 is C or N; X4 for CR e4 , CR e4 R' e4 or N; R e1 Selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl or C 1-6 alkyl halide; R e2 、R e3 、R e4 、R e5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R' e1 , R' e2 , R' e3 , R' e4 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CR d1 or N; Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace; Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace; Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace; Z5 is selected from covalent bond, CR d5 or N; R d1 and R d5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R d2 、R d3 and R d4 Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R dd replace; R dd Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR', -L"-SR' or -L"-NR'R"; R' and R" are independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclyl; L' is selected from a covalent bond, O or C 1-6 alkylene; L" is selected from a covalent bond or C 1-6 alkylene; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

26. The compound of formula (II-1) according to claim 25, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein V is selected from a covalent bond, CH, CH2, CD, CHD or CD2, preferably a covalent bond; Q is selected from S or NR A , preferably NR A ; Y is selected from a covalent bond, O or CR 1a R 1b , preferably selected from a covalent bond, O, CH2, CF2 or C(CH3)2, more preferably C(CH3)2; R A and R B is H; R 1a and R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably independently selected from H, D, F or Me; Indicates that a double bond may or may not exist. When it exists, it indicates that the ring is aromatic and R' e1 , R' e2 , R' e3 , R' e4 Absent, its absence indicates that the ring in which it is located is not aromatic; X2 is C or N; X3 is C or N; preferably, one of X2 and X3 is C and the other is N; X4 selected from CR e4 , CR e4 R' e4 or N; R e1 is selected from H, D, halogen, -CN or -OR', preferably H, D, F, Cl, -CN or -OCH3; R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H, D or Me; R e3 、R e4 、R e5 independently selected from H or D; R' e1 , R' e2 , R' e3 , R' e4 independently selected from H or D; Z1 is CR d1 or N; Z2 is a C atom or a N atom, which is optionally replaced by R d2 replace; Z3 is a C atom or a N atom, which is optionally replaced by R d3 replace; Z4 is a C atom or a N atom, which is optionally replaced by R d4 replace; Z5 is selected from covalent bond, CR d5 or N; preferably, the ring where Z2, Z3, Z4 and Z5 are located is selected from a benzene ring, a pyridine ring, a pyrazole ring or an imidazole ring; R d1 and R d5 independently H or D; R d2 、R d3 and R d4 Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R" or -L'-4 to 6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The haloalkyl or 4- to 6-membered heterocyclic group is optionally substituted by 1 or 2 R dd Substituted; preferably R d2 、R d3 and R d4 Independently selected from H, D, More preferably, R d2 Selected from H, D, R d3 Selected from H, D, R d4 Selected from H, D, or R dd Independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR' or -L"-NR'R", preferably independently selected from H, D, Me, N(CH3)2 or C(CH3)2OH; L' is selected from a covalent bond, O or C 1-6 Alkylene, preferably a covalent bond, O or C 1-4 alkylene; L" is selected from a covalent bond or C 1-6 Alkylene, preferably a covalent bond or C 1-4 alkylene; R' and R" are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

27. The compound of formula (II-1) according to any one of claims 23 to 26, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein Selected from Preferably selected from The ring where Z2, Z3, Z4 and Z5 are located together with the substituents thereon constitute the following group: Preferably Preferably More preferably 28. The compound of formula (III) or formula (IV) or formula (V) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: X2 is C or N; X3 is C or N; X4 for CR e4 or N; R e1 Selected from H, D, halogen, -CN, -OR', -SR', -NR'R", C 1-6 Alkyl, C 1-6 alkyl halide; R e2 、R e3 、R e4 、R e5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a and R 1b are independently H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CR d1 or N, preferably CR d1 ; Z2 is CR d2 or N, preferably CR d2 ; Z4 for CR d4 or N, preferably CR d4 ; Z5 is CR d5 or N, preferably CR d5 ; R d2 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 R dd replace; R d1 、R d4 or R d5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R dd Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR', -L"-SR' or -L"-NR'R"; L' is selected from a covalent bond, -O- or C 1-6 alkylene; L" is selected from a covalent bond or C 1-6 alkylene; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; R' and R" are independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; or R' and R" together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclyl; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

29. The compound of formula (III) or formula (IV) or formula (V) of claim 28, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: X2 is C or N; X3 is C or N; X4 for CR e4 or N; R e1 Selected from H, D, halogen, -CN, -OR', C 1-6 Alkyl or C 1-6 alkyl halide; R e2 、R e3 、R e4 、R e5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a and R 1b Independently C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CR d1 or N, preferably CR d1 ; Z2 is CR d2 or N, preferably CR d2 ; Z4 for CR d4 or N, preferably CR d4 ; Z5 is CR d5 or N, preferably CR d5 ; Preferably, the ring where Z2, Z4 and Z5 are located is selected from a benzene ring or a pyridine ring, preferably a benzene ring; R d1 、R d2 、R d4 or R d5 Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R dd Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR' or -L"-NR'R"; L" is selected from a covalent bond or C 1-6 alkylene; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; R' and R" are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

30. The compound of formula (III) of claim 29, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X2 is C or N; X3 is C or N; X4 for CR e4 or N; R e1 is selected from H, D, halogen or OR', preferably H, D or halogen; R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H or D. R e3 、R e4 and R e5 independently H or D; R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me; Z1, Z2, Z4 and Z5 are CH or CD; R dd Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR'; L" is selected from a covalent bond or C 1-6 alkylene; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; R' is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

31. The compound of formula (III) of claim 30, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X2 is C or N; X3 is C or N; preferably, one of X2 and X3 is C and the other is N; X4 for CR e4 or N; R e1 Selected from H, F, Cl or OCH3, preferably H, F or Cl; R e2 Selected from H or Me, preferably H; R e3 、R e4 and R e5 is H; preferably, Selected from Preferably selected from More preferably selected from R 1a and R 1b for Me; Z1, Z2, Z4 and Z5 are CH; R dd is H or -L"-OH, preferably H or C(CH3)2OH; L" is selected from a covalent bond or C 1-4 alkylene; n=0 or 1; preferably for 32. The compound of formula (IV) of claim 29, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X2 is C or N; X3 is C or N; X4 for CR e4 or N; R e1 is selected from H, D, halogen, CN or OR', preferably selected from H, D, F, CN or OR'; R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R e3 、R e4 and R e5 independently H or D; R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me; Z1 is selected from CH, CD or N, preferably CH or CD; Z2, Z4 and Z5 are independently selected from CH, CD or N; R dd Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR'; L" is selected from a covalent bond or C 1-6 alkylene; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; R' is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

33. The compound of formula (IV) of claim 32, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X2 is C or N; X3 is C or N; preferably, one of X2 and X3 is C and the other is N; X4 for CR e4 or N; R e1 Selected from H, F, Cl, CN or OCH3, preferably selected from H, F, CN or OCH3; R e2 selected from H or Me; R e3 、R e4 and R e5 is H; preferably, Selected from Preferably selected from More preferably selected from More preferably selected from R 1a and R 1b for Me; Z1 is CH; Z2, Z4 and Z5 are independently CH or N; preferably Z2 and Z4 are independently CH or N, and Z5 is CH; preferably Z2 is CH or N, Z4 and Z5 are CH; R dd is H or -L"-OH, preferably H or C(CH3)2OH; L" is selected from a covalent bond or C 1-4 alkylene; n=0 or 1; preferably for 34. The compound of formula (V) of claim 29, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X2 is C or N; X3 is C or N; X4 for CR e4 or N, preferably CR e4 ; R e1 is selected from H, D, halogen or OR', preferably OR'; R e2 Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H or D; R e3 、R e4 and R e5 independently H or D; R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me; Z1 is N, CH or CD, preferably CH or CD; Z2, Z4 and Z5 are independently CH or CD; R dd Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR', preferably H or D; L" is selected from a covalent bond or C 1-6 alkylene; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; R' is selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radical definitions are optionally deuterated, up to fully deuterated.

35. The compound of formula (V) of claim 34, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X2 is C or N; X3 is C or N; preferably, one of X2 and X3 is C and the other is N; X4 for CR e4 or N, preferably CR e4 ; R e1 Selected from H, F, Cl or OCH3, preferably OCH3; R e2 is H; R e3 、R e4 and R e5 is H; preferably, Selected from Preferably R 1a and R 1b for Me; Z1 is CH or N; Z2, Z4 and Z5 are CH; R dd is H; n＝0。 36. The compound of formula (II) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R E Selected from -L-3 to 10-membered carbocyclyl, -L-3 to 10-membered heterocyclyl, -LC 6-10 Aryl or -L-5 to 10 membered heteroaryl, preferably -LC 6-10 aryl or -L-5 to 10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R e replace; R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl; Y is selected from O, S or CR 1a R 1b ; R 1a and R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Q, V, R B and Z1 are each as defined in any one of claims 23 to 25; Z2 is selected from CR d2 or N; Z3 is selected from CR d3 or N; Z4 selected from CR d4 or N; Z5 is selected from covalent bond, CR d5 or N, preferably CR d5 or N; R d3 and R d4 One of them is -NR' d6 C(O)R d6 , -L'-3 to 7 membered carbocyclic group or -L'-3 to 7 membered heterocyclic group, another d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl; R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd replace; R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl; Or two non-adjacent R dd Together they form C 1-6 Alkylene, preferably forming C 1-4 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R d6 Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl or -L"-Y3-C 1-6 Alkylene-R4; Y3 is selected from O, S or NR3; R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R4 is selected from -OR', -SR' or -NR'R"; L is independently selected from a covalent bond, -O-, -S-, -NR'- or C 1-6 alkylene; L' is independently selected from a covalent bond or C 1-6 alkylene; L and L' are each optionally substituted with 1, 2, 3 or 4 groups selected from: C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group; L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7-membered heterocyclyl, or two R together with the C atom to which they are attached form a 3 to 7-membered carbocyclylene or a 3 to 7-membered heterocyclylene; L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

37. The compound of formula (II) of claim 36, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E is -L-5 to 10-membered heteroaryl, preferably 5 to 10-membered heteroaryl; preferably, R E wherein the heteroaryl is selected from pyridyl, pyridinone, pyrazolyl, imidazolyl, oxazolyl, triazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrazinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, triazolopyridinyl, imidazoazacyclopentyl, imidazocyclohexyl, imidazoazacyclohexyl, imidazoazepine, dihydroimidazooxazinyl, imidazopyrazinone, imidazodiazepine, imidazopiperazinone, pyrazoloazacyclohexyl, pyrazolodiazepine, dihydropyrazolooxazinyl, triazoloazacyclohexyl, dihydropyridooxazinyl, pyrrolopyridinyl, oxazolopyridinyl, which is optionally substituted by 1, 2, 3, 4 or 5 R e replace; R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR' or -NR'R"; Y is O or CR 1a R 1b , preferably CR 1a R 1b ; R 1a and R 1b Independently selected from C 1-6 Alkyl or C 1-6 Haloalkyl, preferably selected from Me or Et; Q, V, R B and Z1 are each as defined in any one of claims 23 to 25; Z2 is selected from CR d2 or N; Z3 is selected from CR d3 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N; R d3 and R d4 One of them is -NR' d6 C(O)R d6 or -L'-3 to 7 membered heterocyclic group, preferably -L'-3 to 7 membered heterocyclic group, another d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd replace; R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl; Or two non-adjacent R dd Together they form C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R d6 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, -L"-3 to 7-membered heterocyclyl, or -L"-Y3-C 1-4 Alkylene-R4; Y3 is selected from O or NR3, preferably O; R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H, C 1-3 Alkyl or C 1-3 alkyl halide; R4 is selected from -OR' or -NR'R", preferably -OR'; L is independently selected from a covalent bond, -NR'- or C 1-4 Alkylene, preferably a covalent bond or -NR'-; preferably, L is a covalent bond, -NH- or -CH(CH3)-, preferably a covalent bond or -NH-; L' is independently selected from a covalent bond or C 1-4 alkylene; L and L' are each optionally substituted with 1, 2, 3 or 4 groups selected from: C 1-6 Alkyl or C 1-6 alkyl halide; L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene group, preferably a 3- to 5-membered carbocyclylene group; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group, preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

38. The compound of formula (II) or formula (II') of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R E as defined in claim 36 or 37; R e Independently selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR' or -NR'R", which is optionally substituted by 1, 2 or 3 R es replace; Or two R e and the atoms to which they are attached together form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, preferably a 3- to 7-membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R es replace; R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; Q, V, R B , Z1 and Z7 are each as defined in any one of claims 1 and 23-25; Z2 is selected from CR d2 or N; Z3 is selected from CR d3 or N; Z4 selected from CR d4 or N; Z5 is selected from covalent bond, CR d5 or N, preferably CR d5 or N; R d3 and R d4 One of them is -NR' d6 C(O)R d6 、-C(O)NR d7 R' d7 , -L'-3 to 7 membered carbocyclic group or -L'-3 to 7 membered heterocyclic group, preferably -NR' d6 C(O)R d6 、-C(O)NR d7 R' d7 or -L'-3 to 7 membered heterocyclic group, another with R d2 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, OR' and NR'R"; R d2 、R d3 、R d4 and R d5 Optionally 1, 2, 3 or 4 R dd replace; R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl, preferably selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl; or CR dd R dd To form a 3 to 7 membered carbocyclylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -NR'R", preferably optionally substituted with 1 -OR'; Or two non-adjacent R dd Together they form C 1-6 Alkylene, preferably forming C 1-4 Alkylene, preferably forming C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; Or two adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; R d7 and R' d7 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide; The remaining variables are as defined in claim 36 or 37; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

39. The compound of formula (VI) or formula (VI-1) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R E As defined in any one of claims 36 to 38; X1 for CR e6 , N, O, S or NR' e6 ; X2 is C or N; X3 is C or N; X4 for CR e4 or N; X5 for CR e5 , N, O, S or NR' e5 ; X6 is C or N; X7 for CR e1 or N; X8 for CR e2 or N; X9 for CR e3 or N; R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl; R e3 、R e4 、R e5 and R e6 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R' e5 and R' e6 Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a and R 1b are independently H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is selected from CR d1 or N; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N; R d1 Selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, or -L'-3 to 7 membered heterocyclyl; R d3 Selected from or -NR' d6 C(O)R d6 ; a and b are independently 0, 1, 2 or 3, preferably a+b≤5; L' is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl or C 1-6 alkyl halide; Y1 and Y2 are independently selected from CR dd R dd , O, S or NR' dd , or when Y1 is connected to L', Y1 is CR dd or N; R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl; Or two non-adjacent R dd Together they form C 1-4 Alkylene, or R' dd With non-adjacent R dd Together they form C 1-4 Alkylene, or two R' dd Together they form C 1-4 Alkylene, wherein the C 1-4 The alkylene group is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl; n = 0, 1, 2, 3 or 4; R d6 Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, -L"-3 to 7 membered heterocyclyl or -L"-Y3-C 1-6 Alkylene-R4; L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group, or two R and their common C The atoms together form a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene; L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene; Y3 is selected from O, S or NR3; R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R4 is selected from -OR', -SR' or -NR'R"; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

40. The compound of formula (VI) or formula (VI-1) of claim 39, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R E As defined in any one of claims 36 to 38; X1 for CR e6 , N or NR' e6 , preferably N; X2 is C or N; X3 is C or N; X4 for CR e4 or N; X5 for CR e5 , N or NR' e5 , preferably CR e5 or N; X6 is C or N, preferably C; X7 for CR e1 or N; X8 for CR e2 or N; X9 for CR e3 or N; R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", 3 to 7 membered carbocyclic group or 3 to 7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' or -NR'R"; R e3 、R e4 、R e5 and R e6 are independently H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R' e5 and R' e6 Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a and R 1b Independently C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is selected from CR d1 or N, preferably CR d1 ; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N, preferably CR d5 ; R d1 、R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R d3 Selected from or -NR' d6 C(O)R d6 ; a and b are independently 0, 1 or 2; preferably a+b≤3; L' is independently selected from a covalent bond or C 1-4 alkylene; Y1 is CR dd R dd or NR' dd ; or when Y1 is connected to L', Y1 is CH, CD or N; Y2 is CR dd R dd , O or NR' dd ; Preferably, at least one of Y1 and Y2 is a heteroatom group; R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl; Or two non-adjacent R dd Together they form C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR', -C 1-6 Alkylene-NR'R", -L"-3 to 7 membered carbocyclic group or -L"-3 to 7 membered heterocyclic group, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, or -L"-3 to 7-membered heterocyclyl; n = 0, 1, 2, 3 or 4; R d6 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, -L"-3 to 7-membered heterocyclyl, or -L"-Y3-C 1-4 Alkylene-R4, preferably not -L"-Y3-C 1-4 Alkylene-R4; L" is independently selected from a covalent bond or C 1-6 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl, or two R groups together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene group; Y3 is selected from O or NR3; R' d6 and R3 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R4 is selected from -OR' or -NR'R"; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group; Preferably, at most 5 of X1-X9 are heteroatoms, preferably at most 4 are heteroatoms, preferably at most 3 are heteroatoms; preferably, one of X2 and X3 is N and the other is C; Preferably, at most one of X4 and X7-X9 is N; Preferably, at most 2 of Z2, Z4 and Z5 are N, and preferably at most 1 N.

41. The compound of formula (VI) or formula (VI-1) of claim 39 or 40, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R E As defined in any one of claims 36 to 38; X1 is N; X2 is C or N; X3 is C or N; X4 for CR e4 or N, preferably N; X5 for CR e5 or N, preferably CR e5 ; X6 is C; X7 for CR e1 or N, preferably CR e1 ; X8 for CR e2 or N, preferably N; X9 for CR e3 or N, preferably CR e3 ; R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -O-3 to 7 membered carbocyclic group or 3 to 7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl or -OR'; R e3 、R e4 and R e5 independently H or D; R' e5 Selected from H, C 1-3 Alkyl or C 1-3 alkyl halide; R 1a and R 1b Independently C 1-3 Alkyl or C 1-3 alkyl halide; Z1 is selected from CR d1 or N, preferably CR d1 ; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N, preferably CR d5 ; R d1 is H or D; R d2 、R d4 and R d5 Independently selected from H, D, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl, preferably R d2 and R d5 Independently selected from H, D or halogen, preferably R d5 H or D; R d3 Selected from or -NR' d6 C(O)R d6 ; preferably, for Preferably a and b are independently 0, 1 or 2, preferably a and b are 1; L' is independently selected from a covalent bond or C 1-2 Alkylene, preferably selected from a covalent bond or a methylene group; Y1 is NR' dd , preferably NH; or when Y1 is connected to L', Y1 is CH, CD or N; Y2 is CR dd R dd , O or NR' dd ; R dd Independently selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R" or -L"-3 to 7 membered carbocyclic group, preferably selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR' or -L"-NR'R", preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR'; Or two non-adjacent R dd Together they form C 1-2 alkylene; R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene-OR', -C 1-4 Alkylene-NR'R" or -L"-3 to 7 membered carbocyclic group, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl or -L"-3 to 7-membered carbocyclic group; n = 0, 1, 2, 3 or 4; R d6 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl or -L"-OC 1-4 Alkylene -OR', preferably not -L"-OC 1-4 Alkylene-OR'; R' d6 Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; L" is independently selected from a covalent bond, C 1-4 Alkylene or -C(R)2-, preferably selected from covalent bonds or C 1-4 Alkylene, wherein the two R in -C(R)2- together with the C atom to which they are commonly attached form a 3- to 5-membered carbocyclic group, preferably R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, when Y1 is N, Y2 is O, L' is a covalent bond, and R dd Not for oxygen generation; Preferably, when R e2 For-OC 1-6 When alkyl, R e2 is -OMe, preferably, when R e2 For-OC 1-6 When alkyl halide, R e2 For-O- halomethyl; Preferably, R d2 and R d4 At least one of them is H or D, preferably at least one of them is H.

42. A compound of formula (VI) or formula (VI-1) according to any one of claims 39 to 41, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R E As defined in any one of claims 36 to 38; X1 is N; X2 is C or N; X3 is C or N; X4 for CR e4 or N, preferably N; X5 for CR e5 or N, preferably CR e5 ; X6 is C; X7 for CR e1 or N, preferably CR e1 ; X8 for CR e2 or N, preferably N; X9 for CR e3 or N, preferably CR e3 ; R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl or Preferably selected from H, F, Cl, CN, Me, CHF2, OCH3 or OEt, preferably R e2 Not for OEt; R e3 、R e4 and R e5 is H; R' e5 for Me; R 1a and R 1b are independently Me or Et; Z1 is selected from CR d1 or N, preferably CR d1 ; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N, preferably CR d5 ; R d1 is H; R d2 、R d4 and R d5 Independently selected from H, F, Me or CHF2, preferably R d2 and R d5 Independently selected from H or F, preferably R d5 is H; R d3 Selected from or -NR' d6 C(O)R d6 , preferably a is 1 or 2, b is 1; L' is independently selected from a covalent bond or a methylene group, preferably a covalent bond; Y1 is NH, CH or N, preferably CH or N, preferably N; Y2 is CR dd R dd , O or NR' dd , preferably O; R dd independently selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, or -NHMe, excellent is selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe or -NHMe; Or two non-adjacent R dd Together to form -CH2CH2-, preferably The structure is as follows: R' dd Independently selected from H, Me, -CH2-cyclopropyl; n = 0, 1, or 2; R d6 Selected from -CH2-cyclopropyl or -CH2-O-CH2CH2-OH, preferably -CH2-cyclopropyl; R' d6 is H; Preferably, R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably Preferably, R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably, Selected from: Preferably selected from: Preferably not Preferably selected from:

43. The compound of formula (VI) or formula (VI-1) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R E As defined in any one of claims 36 to 38; X5 for CR e5 , N, O, S or NR' e5 , preferably CR e5 , O, N or NR' e5 , preferably CR e5 or N; X7 for CR e1 or N; X8 for CR e2 or N; R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R es replace; R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; R e5 Selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is selected from CR d1 or N, preferably CR d1 ; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N, preferably CR d5 ; R d1 Selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl or -L'-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -NR'R"; preferably R d2 and R d5 Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; R d3 Selected from -NR’ d6 C(O)R d6 and -C(O)NR d7 R’ d7 ; a and b are independently 0, 1, 2 or 3, preferably 0, 1 or 2; preferably a+b≤5, preferably a+b≤3; L' is independently covalently bonded to C 1-6 Alkylene, preferably selected from covalent bonds and C 1-4 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl or C 1-6 alkyl halide; Y1 is CR dd R dd or NR' dd ; or when Y1 is connected to L', Y1 is CR dd or N; Y2 is selected from CR dd R dd 、O、S、S(O),NR' dd and S(O)2, preferably selected from CR dd R dd 、O、NR' dd and S(O)2; preferably, at least one of Y1 and Y2 is a heteroatom group; R dd Independently selected from H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-SR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl, or -L"-3 to 7 membered heterocyclyl; or CR dd R dd To form a 3 to 7 membered carbocyclylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 groups selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; Or two non-adjacent R dd Together they form C 1-3 Alkylene, optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl or -L"-3 to 7 membered heterocyclyl, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl; or R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, preferably a 3- to 7-membered heterocyclylene, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R"; R d7 and R' d7 Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7-membered carbocyclyl and -L d -3 to 7 membered heterocyclic group, preferably selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene; The remaining variables are as defined in any one of claims 39-42; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

44. The compound of formula (VI) or formula (VI-1) of claim 43, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein R E As defined in any one of claims 36 to 38; X5 for CR e5 or N, preferably CR e5 ; X7 for CR e1 or N, preferably CR e1 ; X8 for CR e2 or N, preferably N; R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -NR'R", -O-3 to 7 membered carbocyclyl, -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, preferably not -NR'R", preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -O-3 to 7 membered carbocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 R es Substituted; preferably R e1 is not a heterocyclic group; R es Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR' are preferably selected from H, D, F, Me and OH; R e5 Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H or D; Z1 is selected from CR d1 or N, preferably CR d1 ; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N, preferably CR d5 ; R d1 H or D; R d2 、R d4 and R d5 Independently selected from H, D, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and -OR', preferably R d2 and R d5 Independently selected from H, D and halogen; preferably R d2 、R d4 and R d5 is H or D; R d3 Selected from and -NR' d6 C(O)R d6 ; preferably, for Preferably a and b are independently 0, 1 or 2, preferably a and b are 1; L' is independently selected from a covalent bond or C 1-2 Alkylene, preferably selected from a covalent bond or a methylene group; Y1 is NR' dd ; or when Y1 is connected to L', Y1 is CR dd or N; Y2 is selected from CR dd R dd 、O、NR' dd and S(O)2; R dd Independently selected from H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR', -L"-NR'R" or -L"-3 to 7 membered carbocyclic group, preferably selected from H, D, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L"-OR' or NR'R", preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or -L"-OR'; or CR dd R dd forming a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, which is optionally substituted with one -OR', preferably optionally substituted with one OH; Or two non-adjacent R dd Together they form C 1-2 alkylene; R' dd Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl and -L"-3 to 7 membered carbocyclyl; or R' dd With adjacent R dd and the atoms to which they are attached together form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, Preferably, a 3- to 7-membered heterocyclylene is formed, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; L" is independently selected from a covalent bond, C 1-4 Alkylene, optionally substituted by 1, 2, 3 or 4 R, R independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R together with the C atom to which they are commonly attached form a 3- to 7-membered carbocyclyl, preferably a 3- to 5-membered carbocyclyl, preferably R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The remaining variables are as defined in any one of claims 39-42; Preferably, when Y1 is N, Y2 is O, L' is a covalent bond, and R dd Not for oxygen generation; Preferably, when R e2 For-OC 1-6 When alkyl, R e2 is -OMe, preferably, when R e2 For-OC 1-6 When alkyl halide, R e2 is -O-halomethyl; Preferably, R e1 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", -O-3 to 7-membered carbocyclyl, -O-3 to 7-membered heterocyclyl, 3 to 7-membered carbocyclyl and 3 to 7-membered heterocyclyl, preferably other than -NR'R" and 3 to 7-membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -O-3 to 7 membered carbocyclyl and 3 to 7 membered carbocyclyl, which are optionally substituted by 1, 2 or 3 R es replace; R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OR', -O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OMe, -O-halomethyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 R es replace; Preferably, when R e2 When it is a heterocyclic group, R es Independently selected from H, D, halogen (F), C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably selected from H, D, F and Me, and is preferably halogen (F).

45. The compound of formula (VI) or formula (VI-1) of claim 43 or 44, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R E As defined in any one of claims 36 to 38; X5 for CR e5 or N, preferably CR e5 ; X7 for CR e1 or N, preferably CR e1 ; X8 for CR e2 or N, preferably N; R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OH, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably not Preferably selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, cyclopropyl, Preferred R e1 Not for Preferred R e2 Not for OEt; R e5 is selected from H, D, F, Br and Me, preferably H; Z1 is selected from CR d1 or N, preferably CR d1 ; Z2 is selected from CR d2 or N; Z4 selected from CR d4 or N; Z5 is selected from CR d5 or N, preferably CR d5 ; R d1 is H; R d2 、R d4 and R d5 Independently selected from H, F, CN, Me, CHF2 and OCH3, preferably R d2 and R d5 are independently selected from H and F; preferably, R d2 、R d4 and R d5 is H; R d3 Selected from and -NR' d6 C(O)R d6 , preferably a is 0, 1 or 2, preferably 0 or 1, b is 0 or 1; L' is independently selected from a covalent bond or a methylene group, preferably a covalent bond; Y1 is NH; or when Y1 is connected to L', Y1 is selected from CH, C(OH) and N, preferably selected from CH and N, preferably N; Y2 is selected from CR dd R dd 、O、NR' dd and S(O)2, preferably selected from CR dd R dd , O and NR' dd , preferably O; R dd independently selected from H, F, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, and -NHMe, preferably selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, and -NHMe, preferably selected from H, OH, Me, -C(CH3)2OH, -CH2OMe and or CR dd R dd To form cyclopropylene, Preferably forming a cyclopropylene or Preferably, a cyclopropylene group is formed; Or two non-adjacent R dd Together they form -CH2CH2-; R' dd Independently selected from H, Me, -CH2-cyclopropyl; or R' dd With adjacent R dd and the atoms they connect to form Preferred Formation The remaining variables are as defined in any one of claims 39-42; Preferably, R e1 Selected from H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, and cyclopropyl, preferably selected from H, F, CN, Me, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and cyclopropyl; R e2 Selected from H, F, Cl, CN, Me, CHF2, OCH3、OEt、OCHF2、 Cyclopropyl, Preferably selected from H, F, Cl, CN, Me, CHF2, OCH3, OCHF2, cyclopropyl, Preferably, R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably Preferably, R d3 Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably, Selected from: Preferably selected from: Preferably selected from:

46. ​​The compound of formula (VI-2) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X1 selected from CR e6 , O, S, N or NR' e6 ; X5 for CR e5 , N, O, S or NR' e5 ; X6 is C or N; X 10 Selected from CR e7 , O, S, N or NR' e7 ; X 11 Selected from CR e8 , O, S, N or NR' e8 ; R e7 and R e8 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl; R' e7 and R' e8 Independently selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-3 to 7-membered carbocyclyl, or -L'-3 to 7-membered heterocyclyl; or X 10 and X 11 The substituents on the 3-5 Alkylene, which optionally contains a double bond, the C 3-5 The alkylene group is optionally substituted by 1, 2, 3 or 4 R e substituted, and wherein 1, 2 or 3 methylene units are optionally and independently replaced by -NR"-, -N(R")C(O)-, -C(O)N(R")-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S- or -S(O)-; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group; L' is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl or C 1-6 alkyl halide; L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene; R e As defined in any one of claims 36 to 38, preferably R e Not alkenyl or alkynyl; R e5 , R' e5 、R e6 and R' e6 Each as defined in any one of claims 39 to 45; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

47. The compound of formula (VI-2) of claim 46, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X1 selected from CR e6 , N or NR' e6 , preferably N; X5 for CR e5 , N or NR' e5 ; X6 is C or N, preferably C; X 10 Selected from CR e7 , N or NR' e7 ; X 11 Selected from CR e8 , O, N or NR' e8 ; R e7 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR', -NR'R", 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl; R' e7 Selected from H, D, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group; R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R' e8 Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; or X 10 and X 11 The substituents on the 3-5 Alkylene, preferably forming -(CH2)4-, which optionally contains a double bond, the C 3-5 Alkylene or -(CH2)4- is optionally substituted by 1, 2, 3 or 4 R e substituted, and wherein 1, 2 or 3 methylene units are optionally and independently replaced by -NR"-, -C(O)N(R")-, -C(O)- or -O-, preferably wherein 1 methylene unit is optionally and independently replaced by -O-; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group; R e As defined in any one of claims 36 to 38, preferably R e Not alkenyl or alkynyl; R e5 , R' e5 、R e6 and R' e6 Each as defined in any one of claims 39 to 45; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; Preferably, X1, X5, X6, X 10 and X 11 There are at most 3 heteroatoms.

48. The compound of formula (VI-2) according to claim 46 or 47, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X1 is N; X5 for CR e5 , N or NR' e5 , preferably CR e5 or N, more preferably CR e5 ; X6 is C or N, preferably C; X 10 CR e7 or NR' e7 ; X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ; R e7 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, or -O-3- to 7-membered heterocyclyl; R' e7 Selected from C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group, preferably a 3- to 7-membered carbocyclic group; Preferably, when R e7 or R' e7 When it is a heterocyclic group, it is a 3- to 7-membered oxo heterocyclic group, preferably a 4- to 6-membered oxo heterocyclic group, preferably a 5-membered oxo heterocyclic group; R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide; R' e8 Selected from C 1-6 Alkyl or C 1-6 alkyl halide; or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R e1 、R e2 、R e5 and R' e5 Each as defined in any one of claims 39 to 45; preferably, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR', -O-3 to 7 membered carbocyclic group, preferably selected from H, D, C 1-6 Alkyl, C 1-6 haloalkyl or -OR'; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45.

49. The compound of formula (VI-2) according to any one of claims 46 to 48, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X1 is N; X5 for CR e5 , N or NR' e5 , preferably CR e5 or N, more preferably CR e5 ; X6 is C or N, preferably C; X 10 Selected from CR e7 or NR' e7 ; X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ; R e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, -O-tetrahydrofuranyl Tetrahydrofuranyl, -O-tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, R' e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or morpholinyl, preferably selected from Me, Et, cyclopropyl, tetrahydrofuranyl or tetrahydropyranyl, preferably selected from Me, Et, cyclopropyl or tetrahydrofuranyl, preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl or Preferably cyclopropyl; R e8 is selected from H, Me or Et, preferably H or Me, preferably Me; R' e8 is Me or Et, preferably Me; or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably R e1 and R e2 independently selected from H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl or Preferably selected from H, F, CN, Me, OMe, OEt, OCHF2 or -O-cyclopropyl, preferably selected from H, F, CN, Me, OCH3, OEt, OCHF2 or -O-cyclopropyl, preferably selected from H, Me, OCH3 or OEt; R e5 is H; R' e5 for Me; R" is H or methyl; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; Preferably, X 10 and X 11 The substituents on the above together form a structure selected from the following: Preferably selected from: Preferably selected from: Preferably selected from: Preferably, Selected from Preferably selected from: Preferably selected from: Preferably, R dd Independently selected from H, Me or -C(CH3)2OH, or two non-adjacent R dd Together to form -CH2CH2-, preferably The structure is as follows: Preferably, R d3 Selected from: Preferably selected from: Preferably 50. The compound of formula (VI-2) of claim 23 or 46, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X 10 CR e7 or NR' e7 ; X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ; R e7 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 7 membered carbocyclyl, 3 to 7 membered heterocyclyl and -O-3 to 7 membered heterocyclyl; preferably selected from C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 7-membered carbocyclyl, tetrahydrofuranyl, morpholinyl, and -O-3- to 7-membered heterocyclyl; preferably 3- to 7-membered carbocyclyl; R' e7 Selected from C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group, preferably a 3- to 7-membered carbocyclic group; R e8 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide; R' e8 Selected from C 1-6 Alkyl or C 1-6 alkyl halide; or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably R e1 and R e2 Each as defined in any one of claims 39 to 45, R' e1 and R' e2 Each as defined in any one of claims 23 to 26; preferably, R e1 and R e2 Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR', -O-3 to 7 membered carbocyclyl and -O-3 to 7 membered heterocyclyl, preferably not halogen, preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR' and -O-3 to 7 membered carbocyclic group; preferably R e2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR', preferably R e2 H, D or C 1-6 alkyl halide; R' e1 and R' e2 Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, halogen and C 1-6 alkyl; or CR e1 R' e1 forming a 3- to 7-membered carbocyclic group and a 3- to 7-membered heterocyclic group, preferably forming a 3- to 7-membered heterocyclic group; R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably R" is C 1-4 alkyl halide; The remaining variables are as defined in any one of claims 46-49; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

51. The compound of formula (VI-2) of claim 50, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein X 10 Selected from CR e7 or NR' e7 ; X 11 Selected from CR e8 , O or NR' e8 , preferably CR e8 or NR' e8 ; R e7 Selected from Me, Et, cyclopropyl, Preferably selected from Me, Et, cyclopropyl, Preferably cyclopropyl; R' e7 is selected from Me, Et and cyclopropyl, preferably cyclopropyl; R e8 is selected from H, Me or Et, preferably H or Me, preferably Me; R' e8 is Me or Et, preferably Me; or X 10 and X 11 The substituents on Preferably not Preferably selected from: Preferably R e1 and R e2 independently selected from H, F, CN, Me, CHF2, OH, OMe, OEt, OCHF2, -O-cyclopropyl and Preferably selected from H, CN, Me, CHF2, OH, OCH3, OEt, -O-cyclopropyl and Preferably selected from H, Me, CHF2, OCH3, OEt and -O-cyclopropyl; preferably R e2 is selected from H, F, CN, Me, CHF2, OH and OMe, preferably R e2 is H or CHF2; R' e1 and R' e2 independently selected from H, F and Me; or CR e1 R' e1 form R" is selected from H, methyl and CHF2, preferably CHF2; The remaining variables are as defined in any one of claims 46-49; Preferably, X 10 and X 11 The substituents on the above together form a structure selected from the following: Preferably selected from: Preferably selected from: Preferably, Selected from Preferably selected from: Preferably selected from: Preferably, Y1 is CH or N, and Y2 is selected from CR dd R dd and O; R dd are independently selected from H, OH, Me, -CH2OMe and -C(CH3)2OH, or two non-adjacent R dd Together they form -CH2CH2-; Preferably, R d3 Selected from: Preferably selected from: Preferably 52. The compound of formula (VI-3) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, E is selected from CR e12 or N; J is selected from CR e13 or N; R e9 、R e10 、R e11 、R e12 and R e13 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -L'-OR', -L'-SR', -L'-NR'R", -L'-3 to 7 membered carbocyclyl, -L'-3 to 7 membered heterocyclyl or -Y5-C 0-6 Alkylene-R6; Y5 is selected from O, S or NR5; R5 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R6 is selected from 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; or R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e replace; or R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e replace; R e As defined in any one of claims 36 to 38, preferably R e Not alkenyl or alkynyl; L' is independently selected from a covalent bond or C 1-6 Alkylene, which is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group; L d Independently selected from a covalent bond or C 1-6 Alkylene, preferably selected from covalent bonds or C 1-4 alkylene; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -3 to 7 membered carbocyclic group or -L d -3 to 7 membered heterocyclic group; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

53. The compound of formula (VI-3) of claim 52, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein E is selected from CR e12 or N; J is selected from CR e13 or N; R e9 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R", 3 to 7 membered carbocyclyl, 3 to 7 membered heterocyclyl or -Y5-C 0-6 Alkylene-R6, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR' or -NR'R"; Y5 is selected from O or NR5; R5 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R6 is selected from 3 to 7 membered carbocyclyl or 3 to 7 membered heterocyclyl; R e10 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R e11 、R e12 and R e13 H, D, C 1-6 Alkyl or C 1-6 alkyl halide; or R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R e replace; or R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 R e replace; R e As defined in any one of claims 36 to 38, preferably R e Not alkenyl or alkynyl; R' and R" are each independently selected from H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3- to 7-membered carbocyclic group, or a 3- to 7-membered heterocyclic group; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; Preferably, at least one of E and J is N; preferably, only one of E and J is N.

54. The compound of formula (VI-3) of claim 52 or 53, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein E is selected from CR e12 or N; J is selected from CR e13 or N; R e9 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl, -NR'R", 3 to 7 membered heterocyclic group or -OC 0-4 Alkylene-3-7 membered heterocyclic group, preferably selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl or -NR'R"; R e10 Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R e11 、R e12 and R e13 is H or D; or R e9 、R e13 and the carbon atoms to which they are attached together form a 5-7 membered heterocyclic group, preferably a dihydrooxazinyl group, which is optionally substituted by 1, 2, 3 or 4 R e replace; or R e9 、R e10 and the carbon atoms to which they are attached together form a 5-7 membered carbocyclyl, a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a dihydrooxazinyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R e replace; R e As defined in any one of claims 36 to 38, preferably R e Not alkenyl or alkynyl; preferably R e Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR' and -NR'R", preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR' are preferably selected from Me and OMe; R' and R" are each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; Preferably, R e Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, preferably H or Me.

55. A compound of formula (VI-3) according to any one of claims 52 to 54, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: E is selected from CR e12 or N; J is selected from CR e13 or N; R e9 Selected from H, -NHMe, Preferably selected from H, -NHMe or R e10 selected from H or Me; R e11 、R e12 and R e13 is H; or R e9 、R e13 and the carbon atoms they are connected to form or R e9 、R e10 and the carbon atoms they are connected to form Preferred Formation Preferred Formation Preferred Formation R 1a 、R 1b , Z1, Z2, Z4, Z5 and R d3 Each as defined in any one of claims 39 to 45; Preferably, Selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably selected from: Preferably 56. A compound of formula (I) according to claim 1, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, selected from:

57. A pharmaceutical composition comprising a compound of any one of claims 1-56 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

58. Use of a compound according to any one of claims 1 to 56 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition according to claim 57, in the preparation of a medicament for preventing and / or treating an HPK1-mediated disorder, disease or condition.

59. A compound according to any one of claims 1 to 56 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition according to claim 57, for use in preventing and / or treating an HPK1-mediated disorder, disease or condition.

60. A method for preventing and / or treating an HPK1-mediated disorder, disease or condition comprising administering to a subject a compound of any one of claims 1 to 56 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition of claim 57.

61. The use of claim 58, the compound of claim 59 or its or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug or pharmaceutical composition or the method of claim 60, wherein the disorder, disease or condition is a proliferative disorder.

62. The use, compound, pharmaceutical composition or method of claim 61, wherein the proliferative disorder is cancer.

63. The use, compound, pharmaceutical composition or method of claim 61, wherein the proliferative disorder is associated with one or more activating mutations in HPK1.

64. The use of claim 58, the compound of claim 59 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or composition thereof or the method of claim 60, wherein the disorder, disease or condition is a chronic viral infection.

65. Use of a compound according to any one of claims 1 to 56 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition according to claim 57, in the preparation of a medicament for increasing the efficacy of vaccination.

66. A compound according to any one of claims 1 to 56 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition according to claim 57, for use in increasing the efficacy of vaccination.

67. A method of increasing the efficacy of vaccination comprising administering to a subject a compound of any one of claims 1-56 or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or the pharmaceutical composition of claim 57.

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