HPK1 inhibitors, methods for preparing same, and uses thereof

Abstract

The present application is in the field of medicine and provides HPK1 inhibitors, their preparation methods, and uses thereof. In particular, the present application discloses a compound of formula (I'), its preparation method, pharmaceutical compositions containing said compound, and its use in preparing medicaments for preventing and / or treating HPK1-mediated related diseases. [C1] TIFF2025531383001107.tif33156

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS 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, which are incorporated herein by reference in their entireties.

[0002] <Technical field> The present disclosure is in the field of medicine, and specifically relates to compounds of formula (I'), methods for their preparation, pharmaceutical compositions comprising said compounds, and their use in the manufacture of medicaments for the prevention and / or treatment of HPK1-mediated related diseases. [Background technology]

[0003] HPK1 (hematopoietic progenitor kinase 1), also known as MAP4K1, is a serine / threonine kinase and a member of the MAP4K family. HPK1 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 and playing an important role in immune regulation. HPK1 is also an emerging target for tumor immunotherapy.

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

[0005] Given that HPK1 plays a key role in the development and progression of tumors and immune-related diseases (e.g., solid tumors, hematological malignancies, autoimmune diseases, inflammation), and that there are no commercially available drugs against this target, developing HPK1 inhibitors with high activity, high selectivity, and good druggability is particularly important. Summary of the Invention [Problem to be solved by the invention]

[0006] One object of the present disclosure is to provide a class of HPK1 inhibitor compounds and a preparation method thereof. Another object of the present disclosure is to provide the use of a class of HPK1 inhibitors in tumor immunotherapy. The compounds of the present disclosure have good inhibitory activity against HPK1, kinase selectivity and good druggability, and can be used to prevent and / or treat HPK1-mediated related diseases. [Means for solving the problem]

[0007] The present disclosure provides compounds of formula (I'), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof. [ka]

[0008] wherein each group is as defined herein.

[0009] Some embodiments of the present disclosure relate to salts of the above compounds, alternatively the hydrochloride salts.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0011] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for treating and / or preventing an HPK1-mediated disorder, disease, or condition.

[0012] In some embodiments, the present disclosure provides a method for treating and / or preventing an HPK1-mediated disorder, disease, or condition with a compound of the present disclosure or a pharmaceutical composition thereof, the method comprising administering a compound of the present disclosure or a pharmaceutical composition thereof to a subject.

[0013] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in the treatment and / or prevention of an HPK-mediated disorder, disease, or condition.

[0014] In some embodiments, the present disclosure is for use in the treatment and / or prevention of a proliferative disorder.

[0015] In some embodiments, the proliferative disorder is associated with one or more activating mutations in HPK1.

[0016] In some embodiments, the proliferative disorder is cancer.

[0017] In some embodiments, the HPK1-mediated disorder, disease or condition is a chronic viral infection.

[0018] In some embodiments, the present disclosure relates to the use of a compound of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for increasing the efficacy of vaccination.

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

[0020] In some embodiments, the present disclosure relates to a method of increasing the efficacy of vaccination with a compound of the present disclosure or a pharmaceutical composition thereof, the method comprising administering the compound or pharmaceutical composition to a subject.

[0021] Definitions and Explanations

[0022] Unless otherwise specified, the following terms and phrases as used herein are intended to have the following meanings: The absence of a special definition for certain terms or phrases should not be considered unclear or ambiguous, but rather should be understood in their ordinary sense. When trade names appear herein, it is intended to refer to the corresponding product or its active ingredients.

[0023] definition

[0024] chemical definition

[0025] Definitions of certain functional groups and chemical terms are described in more detail below.

[0026] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~8 "Alkyl" refers to 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 It is intended to include alkyl.

[0027] "C 1~8 "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 1 to 8 carbon atoms. In some embodiments, C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl and C 1~2 Alkyl is an alternative example. 1~6 Examples of alkyl include methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). 1~6 The term "alkyl" also includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), i-Bu(-CHCH(CH)), and t-Bu(-C(CH)).

[0028] "C 2~8 "Alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2~6 Alkenyl and C 2~4 Alkenyl is an alternative example. In some embodiments, C 2~6 Alkenyl is an alternative example. In some embodiments, C 2~4 Alkenyl is an alternative example. 2~6 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2~6 The term "alkenyl" also includes heteroalkenyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] "C 2~8 "Alkynyl" refers to the radical of 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 an alternative example. In some embodiments, C 2~4 Alkynyl is an alternative example. 2~6 Examples of alkynyl 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. 2~6The term "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 are substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] "C 1~8 "Alkylene" is C 1~8 refers to a divalent group formed by removing another hydrogen from an alkyl, and can be substituted or unsubstituted. In some embodiments, C 1~6 Alkylene, C 1~4 Alkylene, C 2~4 Alkylene and C 1~3 Alkylene is an alternative example. In some embodiments, C 1~2 Alkylene is an alternative example. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Examples of substituted alkylene groups, such as those 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)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0031] "C 0~8 Alkylene is a chemical bond and the above "C 1~8 "C" refers to "alkylene" 0~6 Alkylene is a chemical bond and the above "C 1~6 "C" refers to "alkylene" 0~4Alkylene is a chemical bond and the above "C 1~4 "C" refers to "alkylene" 0~3 Alkylene is a chemical bond and the above "C 1~3 It refers to alkylene.

[0032] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0033] "C 1~8 Haloalkyl refers to any of the above "C" groups substituted with one or more halogens. 1~8 In some embodiments, C 1~6 Haloalkyl, C 1~4 Haloalkyl, C 1~3 Haloalkyl and C 1~2 Haloalkyl is a further alternative. Exemplary haloalkyl groups include, but are not limited to, -CF, -CHF, -CHFCHF, -CHCHF, -CFCF, -CCl, -CHCl, -CHCl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Haloalkyl can be optionally substituted at any available point of attachment with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] "C 6~10 "Aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared π electrons in a cyclic arrangement). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10Aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl groups also include ring systems in which the above-mentioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, the point of attachment of which is on the aryl ring, in which case the number of carbon atoms still represents the number of carbon atoms in the aryl ring system. Aryl may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] "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, and optionally containing 1, 2, or 3 double or triple bonds, such as monocyclic carbocyclyl, bridged carbocyclyl, spirocarbocyclyl, and fused carbocyclyl. More specifically, "3- to 14-membered carbocyclyl" or "3- to 14-membered cycloalkyl" 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 a further alternative, and C 5~7 Cycloalkyl and C 5~6 In some embodiments, C is cycloalkyl. 3~7 Cycloalkyl and C 3~6 Cycloalkyl is a further alternative, and C 5~6Cycloalkyl. Cycloalkyl also includes ring systems in which the cycloalkyl ring described above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl system. Examples of carboalkyl groups 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. The cycloalkyl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] "3- to 14-membered heterocyclyl" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. Optionally, nitrogen atoms therein are oxidized to form N-oxides, and sulfur atoms are oxidized to form sulfones or sulfoxides. 3- to 14-membered heterocyclyl includes monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclyl. More specifically, 3- to 14-membered heterocyclyl includes any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic ring, or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring. Further alternatively, 3- to 14-membered heterocyclyl includes 3- to 8-membered or 3- to 7-membered monocyclic heterocyclyl, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl, and 6- to 10-membered fused bicyclic heterocyclyl. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting.In some embodiments, 4- to 12-membered heterocyclyl is an alternative, which is a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1-5 ring heteroatoms selected from nitrogen, oxygen, and sulfur; in some embodiments, 3- to 10-membered heterocyclyl is an alternative, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-5 ring heteroatoms selected from nitrogen, oxygen, and sulfur; in some embodiments, 3- to 8-membered heterocyclyl or 3- to 7-membered heterocyclyl is an alternative, which is a 3- to 8-membered or 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms selected from nitrogen, oxygen, and sulfur; and 3- to 6-membered heterocyclyl. An alternative example is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur; a 4- to 8-membered heterocyclyl is an alternative example, a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heterocyclyl is a further alternative, a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur; and a 4- to 5-membered heterocyclyl is a further alternative, a 4- to 5-membered non-aromatic ring system having ring carbon atoms and 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl has one oxygen ring heteroatom and one nitrogen ring heteroatom. In some embodiments, the heterocyclyl has one oxygen ring heteroatom. Heterocyclyl also includes ring systems in which the heterocyclyl ring is fused to one or more cycloalkyl groups, the point of attachment of which is on the cycloalkyl ring, or in which the heterocyclyl ring is fused to one or more aryl or heteroaryl groups, the point of attachment of which is on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members of the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl.Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidinyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, thiepanyl, azepinyl, oxepinyl, and thiepinyl. Exemplary 7-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, diazepanyl, oxathiepanyl, and thiazepanyl. Exemplary 5-membered heterocyclyl groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.The heterocyclyl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] "5- to 14-membered heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (e.g., having 6, 10, or 14 shared π electrons in a cyclic arrangement), each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring. In such cases, the number of carbon atoms still refers to the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 10-membered heteroaryl group is an alternative example, which is a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are further alternatives, which are radicals of 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups 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 heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridyl.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, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] Divalent radicals formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined above are collectively referred to as "-ylene" or "-ylidene." Ring-forming groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl are collectively referred to as "cyclyl."

[0039] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl as defined herein may be substituted groups.

[0040] Exemplary substituents on carbon atoms include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(Rbb )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 、-SO2OR aa 、-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 of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd or substituted with a group,

[0041] Alternatively, two geminal hydrogens on a carbon atom may be ═O, ═S, or ═NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is replaced by a group,

[0042] R aa are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R aa two of the groups are joined to form a heterocyclyl or heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group,

[0043] R bb each independently represents 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 groups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group,

[0044] R cc are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group,

[0045] R dd each independently represents a 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(=NRff )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(R ee )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, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be linked to form =O or =S;

[0046] R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group,

[0047] R ff are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ffgroups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group,

[0048] R gg each independently represents a 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)(C 1~6 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 1~6alkyl), -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)SC 1~6 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 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 3~7 Heterocyclyl or C 5~10 Heteroaryl or two geminal R gg The substituents may be linked to form =O or =S, where X - is the counterion.

[0049] Exemplary substituents on a nitrogen atom include 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, including but not limited to alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bonded to a nitrogen atom cc groups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as described above.

[0050] Other definitions

[0051] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate and amino acid addition salts of compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for contact with patient tissues and do not cause undue toxicity, irritation, allergy, or the like, that are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. The term also includes, to the extent possible, zwitterionic forms of compounds of the present disclosure.

[0052] 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, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0053] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the necessary base to form the salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then isolating the free acid. The free acid forms differ somewhat from their respective salt forms in physical properties, such as solubility in polar solvents. However, for purposes of this disclosure, each salt is still equivalent to its respective free acid.

[0054] Salts can be prepared from inorganic acids and include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, and iodide. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucoheptanoate, lactobionate, laurylsulfonate, and isethionate. Salts can also be prepared from organic acids, including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, naphthoate, besylate, tosylate, 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, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also included are salts of amino acids, such as arginine salts, gluconate salts, galacturonate salts, and the like (see, e.g., Berge, S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19).

[0055] "Subjects" to which administration is contemplated include, but are not limited to, humans (e.g., 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 the elderly)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, 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" may be used interchangeably herein.

[0056] "Disease," "disorder," and "condition" may be used interchangeably herein.

[0057] Unless otherwise specified, as used herein, the term "treatment" includes an effect on a subject suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or that delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"). The term also includes an effect that occurs before the subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0058] Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating 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 the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in treating a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0059] Unless otherwise specified, a "prophylactically effective amount" of a compound used herein is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of 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.

[0060] "Combination" and related terms refer to simultaneous or sequential administration of a compound of the present disclosure and another therapeutic agent. For example, a compound of the present disclosure can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosages, or simultaneously with the other therapeutic agent in a single unit dosage.

[0061] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, such as racemic mixtures and mixtures enriched in one or more stereoisomers. Individual isomers can be separated from the mixture by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, alternative isomers can be prepared by asymmetric synthesis.

[0062] The compounds of the present disclosure may exist in tautomeric forms.Tautomers are functional isomers that occur when atoms in a molecule rapidly move between two positions.Tautomers are special functional isomers.A pair of tautomers can be converted into each other, but the relatively stable isomer is usually the predominant form.The most important examples are enol and keto tautomers.

[0063] The term "solvate" refers to a compound or its salt form associated with a solvent, usually by solvolysis. This physical association may involve hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, further including both stoichiometric and non-stoichiometric solvates. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0064] The term "hydrate" refers to a compound associated with water. Generally, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, including monohydrates (x is 1), lower hydrates (x is a number greater than 0 but less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0065] The term "metabolite" refers to a product produced during metabolism in the body of a substance, including a compound of the present disclosure, and includes intermediate and final metabolic products.

[0066] The compounds of the present disclosure may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Thus, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0067] The present disclosure also includes compounds labeled with isotopes (isotopic variants) equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms whose atomic mass or mass number differs from that of atoms common in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 CI. Compounds of the present disclosure, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the above isotopes and / or other isotopes of other atoms are all within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, for example, those that contain radioactive isotopes (e.g., 3 H and 14 C) can be used to measure drug and / or substrate distribution within tissues. 3 H, tritium, and 14The C isotope carbon-14 is a further alternative because it is easy to prepare and detect. 2 Substitution of heavier isotopes, such as deuterium, for H, may be an alternative in some cases, as it may confer therapeutic benefits due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formula (I) of the present disclosure, and prodrugs thereof, may generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in the following schemes, and / or procedures disclosed in the Examples and Preparations.

[0068] Furthermore, prodrugs are also included within the context of the present disclosure. As used herein, the term "prodrug" refers to a compound that is converted into an active form that has medical effects in vivo, for example, by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, 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.

[0069] A prodrug is any covalently bonded compound of the present disclosure that releases the parent compound in vivo when the prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups so that the modification can be cleaved by routine manipulation or degraded in vivo to yield the parent compound. Prodrugs include, for example, compounds of the present disclosure in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that cleaves to form a hydroxyl, amino, or sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include, but are not limited to, acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives of the hydroxyl, sulfhydryl, or amino functional group of a compound of Formula (I). Furthermore, in the case of carboxylic acid (—COOH), esters such as methyl esters and ethyl esters can be employed. The esters themselves may be active in themselves and / or hydrolyzable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include groups that can be readily decomposed in the human body to release the parent acid or its salt.

[0070] The present disclosure also provides pharmaceutical formulations 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 which are within the scope of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0071] As used herein, the term "compounds of the present disclosure" refers to compounds of the following formula (I'), formula (I), formula (II), etc., or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

[0072] In this disclosure, compounds are named using standard nomenclature.For compounds with asymmetric centers, unless otherwise specified, it should be understood that all optical isomers and their mixtures are included.In addition, unless otherwise specified, all isomeric compounds and carbon-carbon double bonds included in this disclosure can exist in Z and E forms.For compounds that can exist in different tautomeric forms, the compounds described are not limited to any specific tautomer, and are intended to include all tautomeric forms.

[0073] In one embodiment, the present disclosure relates to a compound of formula (I'), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof. [ka]

[0074] V is a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0075] W is NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0076] Is Z7 a C;

[0077] Alternatively, V is not connected to W, Z7 is C or N, and W is H, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H and C 1-6 alkyl; V is absent, H, D, halogen, C 1-8 Alkyl and C 1-8 haloalkyl, alternatively selected from absent, H, D and halogen;

[0078] Q and Y are independently a covalent bond, -O-, -S-, or -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)- and -N(R A )S(O)2-; Q and Y cannot simultaneously be a covalent bond;

[0079] Alternatively, Q and Y may independently be each independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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 C optionally replaced by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- 1-8 is alkylene;

[0080] R A is H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0081] R B is H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0082] R C , R' C , R 1a and R 1b are independently H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0083] One of Z1 and Z6 is CR E and the other is CR d1 or N;

[0084] R E -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl, wherein 6-10 Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e optionally substituted with a group;

[0085] R e are independently 1, 2 or 3 R es optionally substituted with H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8Alkynyl, -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 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0086] Or, two geminal R e can be one, two or three R's along with the atoms to which they are attached. es forming an optionally substituted 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl;

[0087] R es are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L'-OR' and -L'-NR'R'';

[0088] R d1 H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0089] Ring A is C 6-10 selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring;

[0090] R d are independently H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R d are 1, 2, 3, 4, 5, 6, 7 or 8 R dd C optionally substituted with 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0091] Or, two adjacent R d together with the atoms to which they are attached, 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd may be substituted with;

[0092] R dd are independently 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 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0093] Or, CR dd R dd H, D, halogen, C 1-6 Alkyl, C 1-6 forming a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene optionally substituted by 1, 2, or 3 groups selected from haloalkyl, —OR′, and —NR′R″;

[0094] Alternatively, two non-adjacent R dd are both substituted with the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 C optionally substituted with one or more of aryl, -L''-3 to 10-membered carbocyclyl, -L''-3 to 10-membered heterocyclyl, and -L''-5 to 10-membered heteroaryl 1-8 Does it form an alkylene;

[0095] Or, two adjacent R dd along with the atoms to which they are attached, H, D, halogens, CN, C 1-6 Alkyl, C 1-6 forming a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene, or a 5- to 6-membered heteroarylene optionally substituted by 1, 2, 3, or 4 substituents selected from haloalkyl, -OR', and -NR'R'';

[0096] 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)-, and -N(R')S(O)2-; or L or 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)-, and -N(R')S(O)2-; or or multiple methylene units may be 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- 1-8 is alkylene;

[0097] R' and R'' are independently 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, and -L''-5- to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl;

[0098] L" is selected from a covalent bond, -O-, and -S-; or L" is a C optionally substituted with one or more R. 1-8 alkylene, and 1-8 One or more methylene units in the alkylene may be independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0099] R is independently H, D, C 1-8 Alkyl, C 1-8 Haloalkyl, -L d -3 to 10-membered carbocyclyl and -L d - selected from 3- to 10-membered heterocyclyl;

[0100] or two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene;

[0101] L d are independently a covalent bond and C 1-8 alkylene;

[0102] f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0103] wherein each of the above groups may be deuterated up to fully deuterated.

[0104] In one embodiment, the disclosure relates to a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof. [ka]

[0105] V is a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0106] W is NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0107] Q and Y are independently a covalent bond, -O-, -S-, or -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)- and -N(R A)S(O)2-; Q and Y cannot simultaneously be a covalent bond;

[0108] Alternatively, Q and Y may independently be each independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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 C optionally replaced by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- 1-8 is alkylene;

[0109] R A is H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0110] R B is H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0111] R C , R' C , R 1a and R 1b are independently H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0112] One of Z1 and Z6 is CR E and the other is CR d1 or N;

[0113] R E -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl, wherein 6-10 Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e optionally substituted with a group;

[0114] R e are independently H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, 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 selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl;

[0115] R d1 H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0116] Ring A is C 6-10 selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring;

[0117] R d are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R d are 1, 2, 3, 4, 5, 6, 7 or 8 R dd C optionally substituted with 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0118] Or, two adjacent R d together with the atoms to which they are attached, 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd may be substituted with;

[0119] R dd are independently H, D, halogen, -CN, -NO2, oxo, C1-8 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 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0120] Or two R's dd are both substituted with the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 C optionally substituted with one or more of aryl, -L''-3 to 10-membered carbocyclyl, -L''-3 to 10-membered heterocyclyl, and -L''-5 to 10-membered heteroaryl 1-8 Forming alkylene;

[0121] 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)-, and -N(R')S(O)2-; or L or 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)-, and -N(R')S(O)2-; or or multiple methylene units may be 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- 1-8 is alkylene;

[0122] R' and R'' are independently H, C 1-8Alkyl, 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, and -L''-5- to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl;

[0123] L″ is selected from a covalent bond, —O—, and —S—; or L″ is C optionally substituted with one or more R. 1-8 alkylene, and 1-8 One or more methylene units in the alkylene may be independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0124] R is independently H, D, C 1-8 Alkyl, C 1-8 Haloalkyl, -L d -3 to 10-membered carbocyclyl and -L d - selected from 3- to 10-membered heterocyclyl;

[0125] or two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene;

[0126] L d are independently a covalent bond and C 1-8 alkylene;

[0127] f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0128] wherein each of the above groups may be deuterated up to fully deuterated.

[0129] In another embodiment, the present disclosure relates to a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof. [ka]

[0130] V is a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0131] W is NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0132] Q and Y are independently a covalent bond, -O-, -S-, or -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)- and -N(R A )S(O)2-; Q and Y cannot simultaneously be a covalent bond;

[0133] Alternatively, Q and Y may independently be each independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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 C optionally replaced by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- 1-8 is alkylene;

[0134] R A is H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0135] R B is H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0136] R C , R' C , R 1a and R 1b are independently H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0137] One of Z1 and Z6 is CR E and the other is CR d1 or N;

[0138] R E -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl, wherein 6-10Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e optionally substituted with a group;

[0139] R e are independently 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 selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl;

[0140] R d1 H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0141] Ring A is C 6-10 selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring;

[0142] R d are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R dare 1, 2, 3, 4, 5, 6, 7 or 8 R dd C optionally substituted with 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0143] Or, two adjacent R d together with the atoms to which they are attached, 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd may be substituted with;

[0144] R dd are independently 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 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0145] 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)-, and -N(R')S(O)2-; or L or 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)-, and -N(R')S(O)2-; or or multiple methylene units may be 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- 1-8 is alkylene;

[0146] R' and R'' are independently 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, and -L''-5- to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl;

[0147] L" is selected from a covalent bond, -O-, and -S-; or L" is a C group in which one or more methylene units may be independently replaced with -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. 1-8 is alkylene;

[0148] f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0149] wherein each of the above groups may be deuterated up to fully deuterated.

[0150] V

[0151] 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 ' is.

[0152] In a more specific embodiment, V is a covalent bond, CR C and CR C R C In one more specific embodiment, V is selected from a covalent bond, CH, CH2, CD, CHD, and CD2; in one more specific embodiment, V is a covalent bond.

[0153] 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 halogen, for example, F; in another embodiment, V is C 1-8 Alkyl, alternatively C 1-6 alkyl; in another embodiment, V is C 1-8 Haloalkyl, alternatively C 1-6 It is haloalkyl.

[0154] In a more specific embodiment, V is absent, H, D, halogen, C 1-8 Alkyl and C 1-8 haloalkyl; in another more particular embodiment, V is selected from absent, H, D, and halogen.

[0155] Z7

[0156] In one embodiment, Z7 is C.

[0157] In one embodiment, V is not connected to W, V is absent, and Z7 is N.

[0158] W

[0159] 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 ' is.

[0160] 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.

[0161] In one embodiment, V is not connected to W; in one embodiment, W is H; in another embodiment, W is C 1-6 alkyl, for example methyl; in another embodiment, W is C 1-6 It is haloalkyl.

[0162] In a more specific embodiment, W is selected from the group consisting of H and C. 1-6 alkyl.

[0163] Q and Y

[0164] 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 -S(O)-; 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 Is it;

[0165] Or, Q is C 1-8 alkylene, and in one embodiment, the C 1-8 One or more methylene units in the alkylene may independently be -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-;

[0166] 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)-; in another embodiment, Y is -C(O)-; in another embodiment, Y is -C(O)O-; in another embodiment, Y is -C(O)NRA -; 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 Is it;

[0167] Or, Y is C 1-8 alkylene, and in one embodiment, the C 1-8 One or more methylene units in the alkylene may independently be -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-;

[0168] Q and Y cannot simultaneously be a covalent bond.

[0169] In a more specific embodiment, Q and Y are independently a covalent bond, O, S, NR A , S(O), S(O)2, C(O) and CR 1a R 1b and Q and Y cannot simultaneously be a covalent bond.

[0170] In another more specific embodiment, Q is O, S, or NR A In another more specific embodiment, Q is selected from S or NR A and in another more specific embodiment, Q is NR A , for example, NH.

[0171] In another more specific embodiment, Y is selected from the group consisting of a covalent bond, O, S, and CR. 1a R 1b In another more specific embodiment, Y is selected from a covalent bond, O, and CR 1a R 1b In another more specific embodiment, Y is selected from a covalent bond, O, CH2, CF2, and C(CH3)2; in another more specific embodiment, Y is C(CH3)2; in another more specific embodiment, Y is [ka] is.

[0172] R A

[0173] In one embodiment, R A is H; in another embodiment, R A is C 1-8 alkyl; in another embodiment, R A is C 1-8 alkoxy; in another embodiment, R A is C 1-8 haloalkyl; in another embodiment, R A Ha-L''-C 6-10 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 is C 1-6 alkyl; in another embodiment, R A is 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 heterocyclyl.

[0174] In a more specific embodiment, R A is H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-3 to 10-membered carbocyclyl, and -L"-3 to 10-membered heterocyclyl; in another more specific embodiment, R A is H, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R A is H.

[0175] R B

[0176] In one embodiment, R B is H; in another embodiment, R B is C 1-8 alkyl; in another embodiment, R B is C 2-8 alkenyl; in another embodiment, R B is C 2-8 alkynyl; in another embodiment, R B is C 1-8 haloalkyl; in another embodiment, R B is -L-OR'; in another embodiment, R B is -L-NR'R''; in another embodiment, R B is -LC(O)NR'R''; in another embodiment, R B Ha-LC 6-10 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 is C 1-6 alkyl; in another embodiment, R B is C 1-6haloalkyl; in another embodiment, R B is -L-3 to 10-membered carbocyclyl; in another embodiment, R B is -L-3 to 10-membered heterocyclyl.

[0177] In a more specific embodiment, R B is H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -L-3 to 10-membered carbocyclyl, and -L-3 to 10-membered heterocyclyl; in another more specific embodiment, R B is H, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R B is H.

[0178] R C and R' C

[0179] 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 is C 1-8 alkyl; in another embodiment, R C is C 2-8 alkenyl; in another embodiment, R C is C 2-8 alkynyl; in another embodiment, R C is 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 Ha-LC6-10 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 is C 1-6 alkyl; in another embodiment, R C is C 1-6 haloalkyl; in another embodiment, R C is -L-3 to 10-membered carbocyclyl; in another embodiment, R C is -L-3 to 10-membered heterocyclyl.

[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 is C 1-8 alkyl; in another embodiment, R' C is C 2-8 alkenyl; in another embodiment, R' C is C 2-8 alkynyl; in another embodiment, R' C is 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 Ha-LC 6-10 aryl; in another embodiment, R' C is -L-3 to 14 membered carbocyclyl; in another embodiment, R' Cis -L-3 to 14 membered heterocyclyl; in another embodiment, R' C is -L-5 to 14 membered heteroaryl; in another embodiment, R' C is C 1-6 alkyl; in another embodiment, R' C is C 1-6 haloalkyl; in another embodiment, R' C is -L-3 to 10-membered carbocyclyl; in another embodiment, R' C is -L-3 to 10-membered heterocyclyl.

[0181] In a more specific embodiment, R C and R' C are independently 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, and -L-3 to 10-membered heterocyclyl; in another more specific embodiment, R C and R' C are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R C and R' C are independently H or D.

[0182] R 1a and R 1b

[0183] 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 is C 1-8 alkyl; in another embodiment, R 1a is C 2-8alkenyl; in another embodiment, R 1a is C 2-8 alkynyl; in another embodiment, R 1a is 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 Ha-LC 6-10 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 1a is -L-5 to 14 membered heteroaryl; in another embodiment, R 1a is C 1-6 alkyl; in another embodiment, R 1a is 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 is Et.

[0184] 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 is C 1-8 alkyl; in another embodiment, R 1b is C 2-8 alkenyl; in another embodiment, R1b is C 2-8 alkynyl; in another embodiment, R 1b is 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 Ha-LC 6-10 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 is C 1-6 alkyl; in another embodiment, R 1b is 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 1b is F; in another embodiment, R 1b is Me; in another embodiment, R 1b is Et.

[0185] In a more specific embodiment, R 1a and R 1b are independently 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, and -L-3 to 10-membered heterocyclyl; in another more specific embodiment, R 1a and R 1b are independently H, D, halogen, CN, C 1-6 Alkyl and C1-6 haloalkyl; in another more specific embodiment, R 1a and R 1b are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R 1a and R 1b are independently H, D, halogen, C 1-3 Alkyl and C 1-3 haloalkyl; in another more specific embodiment, R 1a and R 1b is independently selected from H, D, F, and Me; in another more specific embodiment, R 1a and R 1b is Me.

[0186] In a more specific embodiment, R 1a and R 1b independently, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R 1a and R 1b independently, C 1-3 Alkyl and C 1-3 haloalkyl; in another more specific embodiment, R 1a and R 1b is independently selected from Me and Et.

[0187] Z1 and Z6

[0188] In one embodiment, Z1 is CR E and Z6 is CR d1 In another embodiment, Z1 is CR E and Z6 is N; in another embodiment, Z6 is CR E and Z1 is CR d1 In another embodiment, Z6 is CR E and Z1 is N.

[0189] In a more specific embodiment, Z6 is CR E and Z1 is CH or CD; in another more specific embodiment, Z1 is CR E and Z6 is CH or CD.

[0190] R E

[0191] In one embodiment, R E Ha-LC 6-10 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 pyridyl; 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 pyrrolopyridyl; 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 imidazopyridyl; in another embodiment, R Eis imidazopyridazinyl; in another embodiment, R E is imidazopyrimidinyl; in another embodiment, R E is imidazopyrazinyl; in another embodiment, R E is pyrazolopyridyl; 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 pyridopyridyl; in another embodiment, R E is dihydropyridoxazinyl; in another embodiment, R E is indolyl; in another embodiment, R E is triazolopyridyl; in another embodiment, R E is triazolopyridyl; in another embodiment, R E is tetrahydroimidazopyrazinyl; in another embodiment, R E is dihydropyrrolopyridyl; in another embodiment, R E is thienopyridyl; in another embodiment, R E is benzimidazolyl; in another embodiment, R E is dihydroimidazooxazinyl; in another embodiment, R E is tetrahydropyrazolopyridyl; in another embodiment, R E is tetrahydropyrrolopyridyl; in another embodiment, R E is dihydropyrazolooxazinyl; in another embodiment, R E is dihydropyrrolyl; in another embodiment, R E is oxazolopyridyl; in another embodiment, R E is imidazocyclohexyl; in another embodiment, R E is pyrazoloazepanyl; in another embodiment, R Eis pyrazolopiperidyl; in another embodiment, R E is pyrazolopyrrolidinyl; in another embodiment, R E is imidazoazepanyl; in another embodiment, R E is imidazopiperidyl; in another embodiment, R E is imidazopyrrolidinyl; in another embodiment, R E is imidazopyrazinonyl; in another embodiment, R E is imidazodiazacyclohexyl; in another embodiment, R E is imidazopiperazinonyl; in another embodiment, R E is pyrazolodiazepanyl; in another embodiment, R E is pyrazolodiazacyclohexyl; in another embodiment, R E is pyrazolodiazacyclohexyl; in another embodiment, R E is dihydropyrazolooxazinyl; in another embodiment, R E is triazolopiperidyl; in another embodiment, R E is thienopyridyl; in another embodiment, R E is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R e It may be substituted with a group.

[0192] In a more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] 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.

[0193] In a more specific embodiment, R E and its substituent R e Both [ka] In another more specific embodiment, R E and its substituent R e Both [ka] In another more specific embodiment, R E and its substituent R e Both [ka] In another more specific embodiment, R E and its substituent R e Both [ka] In another more specific embodiment, R E and its substituent R e Both [ka] where X1 is the CR e6 , N, O, S or NR' e6 , alternatively CR e6, N or NR' e6 , alternatively N, alternatively CR e6 , alternatively O, alternatively S, alternatively NR' e6 X2 is C or N, alternatively C, alternatively N; X3 is C or N, alternatively C, alternatively N; X4 is CR e4 or N, alternatively CR e4 , alternatively N; X5 is CR e5 , N, O, S or NR' e5 , alternatively CR e5 , O, N or NR' e5 , alternatively CR e5 , N or NR' e5 , alternatively CR e5 or N, alternatively CR e5 , alternatively N, alternatively O, alternatively S, alternatively NR' e5 X6 is C or N, alternatively C, alternatively N; X7 is CR e1 or N, alternatively CR e1 , alternatively N; X8 is CR e2 or N, alternatively CR e2 , alternatively N; X9 is CR e3 or N, alternatively CR e3 , alternatively N;X 10 is CR e7 , O, S, N and NR' e7 and alternatively selected from CR e7 , N or NR' e7 , alternatively CR e7 or NR' e7 , alternatively CR e7 , alternatively NR' e7 , alternatively O, alternatively S, alternatively N; X 11 is CR e8 , O, S, N or NR' e8 , alternatively CR e8 , O, N or NR' e8 , alternatively CR e8 , O or NR' e8 , alternatively CR e8 or NR' e8, alternatively CR e8 , alternatively NR' e8 , alternatively O, alternatively S, alternatively N; E is CR e12 and N, alternatively CR e12 , alternatively N; J is CR e13 and N, alternatively CR e13 , alternatively N.

[0194] In a more specific embodiment, X 10 and X 11 Each of the substituents C may contain one double bond. 3-5 Forming alkylene, C 3-5 Alkylene can be one, two, three or four R e and the above C 3-5 One or more methylene units in the alkylene may be independently replaced by -NR''-, -N(R'')C(O)-, -C(O)N(R'')-, -N(R'')S(O)-, -S(O)N(R'')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-; alternatively, any of the above C 3-5 One, two, or three methylene units in the alkylene may be 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 10 and X 11 Each of the substituents C may contain one double bond. 3-5 alkylene, alternatively -(CH2)4-, 3-5 Alkylene or -(CH2)4- can be one, two, three or four R e and the above C 3-5 One, two or three methylene units in alkylene or -(CH2)4- may be independently replaced by -NR''-, -C(O)N(R'')-, -C(O)-, or -O-; alternatively, 3-5One methylene unit in alkylene or -(CH2)4- may be independently replaced with -O-; in another more specific embodiment, X 10 and X 11 Each of the substituents in [ka] Alternatively, [ka] Instead of forming [ka] and alternatively forming a structure selected from [ka] Form.

[0195] In another more specific embodiment, X 10 and X 11 Each of the substituents in [ka] Alternatively, [ka] Instead of forming [ka] forming a structure selected from:

[0196] In a more specific embodiment, R e1 , R e2 , R e3 , R e4 , R e5 and R e6 are independently 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'-C 6-10 aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl; in another more specific embodiment, R e1 and R e2 are independently 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, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, —OR′ and —NR′R″; in another more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -O-3 to 7-membered carbocyclyl and 3 to 7-membered heterocyclyl, alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; in another more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, —OR′, and —O-3 to 7-membered carbocyclyl; alternatively, H, D, C 1-6 Alkyl, C1-6 haloalkyl and -OR'; in another more specific embodiment, R e1 and R e2 are independently H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and [ka] and optionally selected from H, F, Cl, CN, Me, CHF2, OCH3 and OEt; and optionally selected from R e2 is not OEt; in another more specific embodiment, R e1 and R e2 is independently selected from H, F, CN, Me, OMe, OEt, OCHF2 and —O-cyclopropyl, alternatively selected from H, F, CN, Me, OCH3, OEt, OCHF2 and —O-cyclopropyl, alternatively selected from H, Me, OCH3 and OEt;

[0197] In a more specific embodiment, R e3 , R e4 , R e5 and R e6 are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R' e5 and R' e6 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; 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 haloalkyl; in another more specific embodiment, R e3 , R e4 and R e5 is independently H or D; in another more specific embodiment, R e3 , Re4 and R e5 is H; in one more specific embodiment, R' e5 and R' e6 are independently H, C 1-8 Alkyl and C 1-8 haloalkyl; in another more specific embodiment, R' e5 and R' e6 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R' e5 is H, C 1-3 Alkyl and C 1-3 haloalkyl; in another more specific embodiment, R' e5 is Me; in another more specific embodiment, R e5 is H.

[0198] In a more specific embodiment, R e5 H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R e5 H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R e5 H, D, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; 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 is H.

[0199] In one embodiment, R e1 / R e2 is H; in another embodiment, R e1 / R e2is 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 is C 1-6 alkyl; in another embodiment, R e1 / R e2 is C 1-6 haloalkyl; in another embodiment, R e1 / R e2 is C 2-6 alkenyl; in another embodiment, R e1 / R e2 is 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 e2 is one, two or three R es In another embodiment, R e1 / R e2 is unsubstituted.

[0200] In one embodiment, R in the above general formula e1 The configuration of [ka] In another embodiment, R e1 The configuration of [ka] In another embodiment, R e2 The configuration of [ka] In another embodiment, R e2 The configuration of [ka] is.

[0201] In a more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; in another more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 are not independently -NR'R''; in another more specific embodiment, Re1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, —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 is not heterocyclyl.

[0202] 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 CHF; in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 is OH; in another embodiment, R e1 / R e2 is OCH; in another embodiment, R e1 / R e2is OEt; in another embodiment, R e1 / R e2 is OCHF; in another embodiment, R e1 / R e2 is -NHCH; in another embodiment, R e1 / R e2 is -O-cyclopropyl; in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 is cyclopropyl; in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] and in another embodiment, R e1 / R e2 teeth [ka] is.

[0203] In a more specific embodiment, R e1 and R e2 are independently H, F, Cl, CN, Me, Et, n-Bu, CHF2, [ka] , OH, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, [ka] , cyclopropyl, [ka] Alternatively, H, F, Cl, CN, Me, Et, n-Bu, CHF2, [ka] , OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, [ka] , cyclopropyl, [ka] and alternatively selected from [ka] Instead, alternatively, H, F, Cl, CN, Me, Et, CHF2, [ka] , OCH3, OEt, OCHF2, -O-cyclopropyl, cyclopropyl, [ka] is selected from.

[0204] In a more specific embodiment, R e1 teeth [ka] rather than; in another more specific embodiment, R e2 is not OEt.

[0205] In a more specific embodiment, R e1 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 e1 is not -NR'R'' or 3- to 7-membered heterocyclyl; in another more specific embodiment, R e1 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 are H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, [ka] , cyclopropyl, [ka] Alternatively, H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, [ka] and cyclopropyl, alternatively selected from H, F, CN, Me, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and cyclopropyl.

[0206] In a more specific embodiment, R e2 H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 are H, F, Cl, CN, Me, CHF2, [ka] , OCH3, OEt, OCHF2, [ka] , cyclopropyl, [ka] Alternatively, H, F, Cl, CN, Me, CHF2, [ka] , OCH3, OCHF2, cyclopropyl, [ka] is selected from.

[0207] In a more specific embodiment, R e1 / R e2When is heterocyclyl, R es are independently H, D, halogen (F), C 1-6 Alkyl and C 1-6 haloalkyl, alternatively selected from H, D, F and Me, alternatively halogen (F).

[0208] In a more specific embodiment, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 is selected from haloalkyl, —OR′, —O-3 to 7-membered carbocyclyl, and —O-3 to 7-membered heterocyclyl, and is alternatively not halogen; alternatively is 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 H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; in another more specific embodiment, R e2 is H, D or C 1-6 is haloalkyl;

[0209] In a more specific embodiment, R e1 and R e2 are independently H, F, CN, Me, CHF2, OH, OMe, OEt, OCHF2, -O-cyclopropyl and [ka] and is selected from H, CN, Me, CHF2, OH, OCH3, OEt, -O-cyclopropyl, and [ka] and alternatively selected from H, Me, CHF2, OCH3, OEt, and -O-cyclopropyl; in another more specific embodiment, R e2is selected from H, F, CN, Me, CHF2, OH, and OMe; in another more specific embodiment, R e2 is H or CHF2.

[0210] In a more specific embodiment, R' e1 and R' e2 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively selected from H, D, halogen and C 1-6 alkyl; in another more specific embodiment, R' e1 and R' e2 is independently selected from H, F and Me.

[0211] In a more specific embodiment, CR e1 R' e1 forms a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, alternatively a 3- to 7-membered heterocyclyl (e.g. [ka] ,for example [ka] ), alternatively forming a 3- to 7-membered heterocyclyl or a 3- to 7-membered carbocyclyl; in another more specific embodiment, CR e1 R' e1 teeth, [ka] In another more specific embodiment, CR e1 R' e1 does not form a ring.

[0212] In a more specific embodiment, R e7 and R e8 are independently H, D, halogen, CN, C 1-8 Alkyl, C 1-8haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 10-membered carbocyclyl, and -L'-3- to 10-membered heterocyclyl; in another more specific embodiment, R' e7 and R' e8 are independently H, D, C 1-8 Alkyl, C 1-8 haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl; in another more specific embodiment, R e7 and R e8 are independently 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, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R' e7 and R' e8 are independently H, D, 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 e7 H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; in another more specific embodiment, R' e7 H, D, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; in another more specific embodiment, R e8 H, D, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R' e8 is H, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R e7 is C 1-6 Alkyl, C1-6 haloalkyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, and —O-3- to 7-membered heterocyclyl; in another more specific embodiment, R′ e7 is C 1-6 Alkyl, C 1-6 is selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, alternatively 3- to 7-membered carbocyclyl; in another more specific embodiment, R e7 or R' e7 When is heterocyclyl, R e7 or R' e7 is a 3- to 7-membered oxacyclyl, alternatively a 4- to 6-membered oxacyclyl, alternatively a 5-membered oxacyclyl; in another more specific embodiment, R e8 H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively C 1-6 Alkyl or C 1-6 haloalkyl; in another more specific embodiment, R' e8 is C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] In another more specific embodiment, R' e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and morpholinyl, alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and tetrahydropyranyl, alternatively selected from Me, Et, cyclopropyl and tetrahydrofuranyl, alternatively selected from Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] and is selected from Me, Et, cyclopropyl, and [ka] and in another more specific embodiment, R e8 is selected from H, Me and Et, alternatively H or Me, alternatively Me; in another more specific embodiment, R' e8 is Me or Et, alternatively Me.

[0213] In a more specific embodiment, R e7 is C 1-6 Alkyl, C 1-6haloalkyl, 3- to 7-membered carbocyclyl, tetrahydrofuranyl, morpholinyl, and —O-3- to 7-membered heterocyclyl; in another more specific embodiment, R e7 is Me, Et, cyclopropyl, [ka] In another more specific embodiment, R e7 is Me, Et, cyclopropyl, [ka] In another more specific embodiment, R e7 is 3- to 7-membered carbocyclyl; in another more specific embodiment, R e7 is cyclopropyl.

[0214] In a more specific embodiment, R' e7 is selected from Me, Et and cyclopropyl; in another more specific embodiment, R' e7 is cyclopropyl.

[0215] In a more specific embodiment, R e9 , R e10 , R e11 , R e12 and R e13 H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Haloalkyl, 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 and -Y5-C 0-8 alkylene-R; in one more specific embodiment, R e9 , R e10 , R e11 , R e12 and R e13 H, D, halogen, CN, C 1-6 Alkyl, C 1-6Haloalkyl, 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 and -Y5-C 0-6 alkylene-R; in one more specific embodiment, R e9 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl and -Y5-C 0-6 alkylene-R6, alternatively H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -OR' and -NR'R''; in a more specific embodiment, R e10 H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in one more specific embodiment, R e11 , R e12 and R e13 H, D, C 1-6 Alkyl or C 1-6 haloalkyl; in one more specific embodiment, R e9 H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 Alkynyl, -NR'R'', 3- to 7-membered heterocyclyl and -OC 0-4 alkylene-3 to 7 membered heterocyclyl, alternatively H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkynyl and -NR'R''; in one more specific embodiment, R e10 H, D, C 1-6 Alkyl and C 1-6 haloalkyl; in one more specific embodiment, Re11 , R e12 and R e13 is H or D; in a more specific embodiment, R e9 -H, -NHMe, [ka] and is selected from H, -NHMe, and [ka] In one more specific embodiment, R e10 is selected from H and Me; in one more specific embodiment, R e11 , R e12 and R e13 is H.

[0216] In a more specific embodiment, R e9 and R e13 may be one, two, three or four R e 5- to 10-membered carbocyclyl, 5- to 10-membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R e9 and R e10 may be one, two, three or four R e 5- to 10-membered carbocyclyl, 5- to 10-membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R e9 and R e13 may be one, two, three or four R e In another more specific embodiment, R e9 and R e10 may be one, two, three or four R eIn another more specific embodiment, R e9 and R e13 may be one, two, three or four R e In another more specific embodiment, R e9 and R e13 together with the carbon atoms to which they are attached form a 5- to 7-membered heterocyclyl, alternatively a dihydrooxazinyl, which is a 5- to 7-membered heterocyclyl having 1, 2, 3, or 4 R e In another more specific embodiment, R e9 and R e10 together with the carbon atoms to which they are attached form a 5- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, alternatively a dihydrooxazinyl or a 5-membered azaaryl, which may be joined by 1, 2, 3, or 4 R e In another more specific embodiment, R e9 and R e13 along with the carbon atoms to which they are attached, [ka] In another more specific embodiment, R e9 and R e10 along with the carbon atoms to which they are attached, [ka] Alternatively, [ka] Form.

[0217] In one more specific embodiment, in another more specific embodiment, R e9 and R e10may be one, two, three or four R e and forming an optionally substituted 5- to 7-membered carbocyclyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl.

[0218] In a more specific embodiment, R e9 and R e10 along with the carbon atoms to which they are attached, [ka] Alternatively, [ka] Form.

[0219] In a more specific embodiment, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] is.

[0220] In one more specific embodiment, Y5 is selected from O, S and NR5, alternatively O or NR5, alternatively O; in another more specific embodiment, R5 is H, C 1-8 Alkyl and C 1-8 haloalkyl, alternatively H, C 1-6 Alkyl or C 1-6haloalkyl; in another more specific embodiment, R6 is selected from 3- to 10-membered carbocyclyl and 3- to 10-membered heterocyclyl, alternatively 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl, alternatively 3- to 7-membered heterocyclyl.

[0221] In a more specific embodiment, R E and its substituent R e Both [ka] In another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] and in another more specific embodiment, R E teeth [ka] is.

[0222] In a more specific embodiment, R E represents -L-3 to 10-membered carbocyclyl, -L-3 to 10-membered heterocyclyl, -LC 6-10 aryl and -L-5 to 10 membered heteroaryl, alternatively -LC 6-10 aryl or -L-5-10 membered heteroaryl, alternatively -L-5-10 membered heteroaryl, alternatively 5-10 membered heteroaryl, each of which is selected from 1, 2, 3, 4 or 5 R e may be substituted with.

[0223] In a more specific embodiment, R E and its substituent R e Both [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Form.

[0224] In a more specific embodiment, R E and its substituent R e Both [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Form.

[0225] R e

[0226] 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 is C 1-8 alkyl; in another embodiment, R e is C 1-8 haloalkyl; in another embodiment, R e is C 2-8 alkenyl, alternatively C 2-6 alkenyl, alternatively C 2-4 alkenyl; in one embodiment, R e is C 2-8 Alkynyl, alternatively C 2-6 Alkynyl, alternatively 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 —NO; in another embodiment, R e is -L'-SR'; in another embodiment, R e is -L'-C(O)OR'; in another embodiment, R eis -L'-C(O)NR'R''; in another embodiment, R e is -L'-S(O)R'; in another embodiment, R e is -L'-S(O)NR'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 Ha-L'-C 6-10 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 C 1-6 alkyl; in another embodiment, R e is C 1-6 haloalkyl; in another embodiment, R e is -L'-3 to 10-membered carbocyclyl, alternatively -L'-3 to 7-membered carbocyclyl, alternatively 3 to 7-membered carbocyclyl; in another embodiment, R e is -L'-3 to 10 membered heterocyclyl, alternatively -L'-3 to 7 membered heterocyclyl, alternatively 3 to 7 membered heterocyclyl; 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 —OCH; in another embodiment, R e is Me; in another embodiment, R e is one, two or three independent R esIn another embodiment, R e is unsubstituted; in another embodiment, R e is R e1 and in another embodiment, R e is R e2 is as defined above.

[0227] In one embodiment, two geminal R e together with the atom to which they are attached form a 3- to 7-membered carbocyclyl; in another embodiment, two geminal R e together with the atom to which they are attached form a 3- to 7-membered heterocyclyl; in another embodiment, the two geminal R e and the cyclic group formed by the atoms to which they are attached may be one, two or three independent R es In another embodiment, the two geminal R e and the cyclic group formed by the atoms to which they are attached is unsubstituted; in another embodiment, two geminal R e and the atoms to which they are attached together do not form a ring.

[0228] In a more specific embodiment, R e are independently H, D, halogen, -CN, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-NR'R'', -NO, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O)R', -L'-S(O)NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-3- to 10-membered carbocyclyl, and -L'-3- to 10-membered heterocyclyl; in another more specific embodiment, R e are independently H, D, halogen, -CN, -OR', -SR', -NR'R'', C 1-6 Alkyl and C 1-6haloalkyl; in another more specific embodiment, R e are independently H, D, halogen, -CN, -OR', C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R e is independently selected from H, D, Me, F, Cl, —CN, and —OCH3.

[0229] In a more specific embodiment, R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; in another more specific embodiment, R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, -OR' and -NR'R''; in another more specific embodiment, R e are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl, alternatively H or Me.

[0230] In a more specific embodiment, R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; in another more specific embodiment, R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, selected from -OR' and -NR'R''.

[0231] In a more specific embodiment, R e are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, —OR′ and —NR′R″; in another more specific embodiment, R e are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; in another more specific embodiment, R e is independently selected from Me and OMe.

[0232] In a more specific embodiment, two geminal R e together with the atom to which they are attached form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl.

[0233] R es

[0234] In one embodiment, R es is H; in another embodiment, R es is D; in another embodiment, R es is halogen; in another embodiment, Res is CN; in another embodiment, R es is C 1-6 alkyl; in another embodiment, R es is C 1-6 haloalkyl; in another embodiment, R es is -L'-OR'; in another embodiment, R es is -L'-NR'R''.

[0235] In a more specific embodiment, R es are independently 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 are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, —OR′ and —NR′R″; in another more specific embodiment, R es are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; in another more specific embodiment, R es is independently selected from H, D, F, Me, and OH; in another more specific embodiment, R es are independently H, D, halogen (F), C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R es is independently selected from H, D, F, and Me; in another more specific embodiment, R es is a halogen (F).

[0236] R d1

[0237] In one embodiment, R d1 is H; in another embodiment, R d1 is D; in another embodiment, R d1is halogen; in another embodiment, R d1 is —CN; in another embodiment, R d1 is C 1-8 alkyl; in another embodiment, R d1 is C 2-8 alkenyl; in another embodiment, R d1 is C 2-8 alkynyl; in another embodiment, R d1 is 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 Ha-LC 6-10 aryl; in another embodiment, R d1 is -L-3 to 14-membered carbocyclyl; in another embodiment, R d1 is -L-3 to 14 membered heterocyclyl; in another embodiment, R d1 is -L-5 to 14 membered heteroaryl; in another embodiment, R d1 is C 1-6 alkyl; in another embodiment, R d1 is C 1-6 haloalkyl; in another embodiment, R d1 is -L-3 to 10-membered carbocyclyl; in another embodiment, R d1 is -L-3 to 10-membered heterocyclyl.

[0238] In a more specific embodiment, R d1 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, and -L-3 to 10-membered heterocyclyl; in another more specific embodiment, R d1 H, D, halogen, C 1-6Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R d1 is H or D.

[0239] Ring A

[0240] In one embodiment, ring A is C 6-10In another embodiment, ring A is an aromatic ring; in another embodiment, ring A is a 3- to 14-membered carbocyclic 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 which 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 thiazole ring; 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 or a hexahydropyrazinoquinoline ring; alternatively, 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.

[0241] In a more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] 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.

[0242] In a more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] In another more specific embodiment, ring A is R d along with [ka] is.

[0243] In a more specific embodiment, ring A is R d along with [ka] , alternatively [ka] , alternatively [ka] where Z2 is the CR d2 and N, alternatively CR d2 , alternatively N; Z3 is CR d3 and N, alternatively CR d3 , alternatively N; Z4 is CR d4 and N, alternatively CR d4 , alternatively N; Z5 is a covalent bond, CR d5 and N, alternatively CR d5 or N, alternatively CR d5 , alternatively N.

[0244] In a more specific embodiment, R d3 and R d4 One of the groups is -NR' d6 C(O)R d6 , -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl, and the other, R d2 and R d5are independently 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, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R d2 , R d3 , R d4 and R d5 is 1, 2, 3 or 4 R dd In another more specific embodiment, R d3 and R d4 One of the groups is -NR' d6 C(O)R d6 or -L'-3 to 7-membered heterocyclyl, alternatively -L'-3 to 7-membered heterocyclyl, and the other, R d2 and R d5 are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R d2 , R d4 and R d5 are independently 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, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R d2 , R d4 and R d5 are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R d2 , R d4 and R d5 are independently H, D, halogen, C 1-3 Alkyl and C 1-3 haloalkyl; in another more specific embodiment, R d2 and R d5is independently selected from H, D, and halogen; in another more specific embodiment, R d5 is H or D; in another more specific embodiment, R d2 , R d4 and R d5 is independently selected from H, F, Me, and CHF; in another more specific embodiment, R d2 and R d5 is independently selected from H and F; in another more specific embodiment, R d5 is H.

[0245] In a more specific embodiment, R d3 and R d4 One of the groups is -NR' d6 C(O)R d6 , -C(O)NR d7 R' d7 , -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl, alternatively -NR' d6 C(O)R d6 , -C(O)NR d7 R' d7 or -L'-3 to 7-membered heterocyclyl, and R d2 and R d5 are independently 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 and -L'-3 to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 is selected from haloalkyl, OR' and NR'R''.

[0246] 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, for example F; in another embodiment, R d2 / R d4 / R d5 is CN; in another embodiment, R d2 / R d4 / R d5 is C 1-6 alkyl; in another embodiment, R d2 / R d4 / R d5 is C 1-6 haloalkyl, for example CHF; in another embodiment, R d2 / R d4 / R d5 is -L'-OR', alternatively OR', e.g., OCH3; in another embodiment, R d2 / R d4 / R d5 is -L'-SR', alternatively SR'; in another embodiment, R d2 / R d4 / R d5 is -L'-NR'R'', alternatively NR'R''; in another embodiment, R d2 / R d4 / R d5 is -L'-3 to 7-membered carbocyclyl, alternatively 3 to 7-membered carbocyclyl; in another embodiment, R d2 / R d4 / R d5 is -L'-3 to 7 membered heterocyclyl, alternatively 3 to 7 membered heterocyclyl.

[0247] In a more specific embodiment, R d2 , R d4 and R d5 are independently 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 are independently H, D, halogen, CN, C 1-4 Alkyl, C 1-4haloalkyl and -OR'; in another more specific embodiment, R d2 , R d4 and R d5 is 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 is H.

[0248] In a more specific embodiment, R d2 and R d5 are independently 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, and -L'-3- to 7-membered heterocyclyl; in another more specific embodiment, R d2 and R d5 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, OR' and NR'R''; in another more specific embodiment, R d2 and R d5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R d2 and R d5 is independently selected from H, D, and halogen; in another more specific embodiment, R d2 and R d5 is independently selected from H and F.

[0249] In one embodiment, R d3 / R d4 '-NR' d6 C(O)R d6 and in another embodiment, Rd3 / R d4 is -C(O)NR d7 R' d7 and 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 teeth [ka] and in another embodiment, R d3 / R d4 teeth [ka] and in another embodiment, R d3 / R d4 teeth [ka] is.

[0250] In one embodiment, R d7 and R' d7 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively independently selected from H or C 1-6 alkyl, alternatively Me.

[0251] In a more specific embodiment, R d3 teeth, [ka] , -NR' d6 C(O)R d6 and -C(O)NR d7 R' d7 In another more specific embodiment, R d3 teeth, [ka] and -NR' d6 C(O)R d6 and alternatively selected from [ka] , alternatively -NR' d6 C(O)R d6 and in another more specific embodiment, [ka] teeth [ka] and in another more specific embodiment, [ka] teeth [ka] is.

[0252] 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.

[0253] In one more specific embodiment, a and b are independently 0, 1, 2 or 3, alternatively independently 0, 1 or 2, alternatively a is 1 or 2 and b is 1, alternatively a and b are 1; in another more specific embodiment, a + b ≦ 5, alternatively a + b ≦ 3; in another more specific embodiment, n = 0, 1, 2, 3 or 4, alternatively n = 0, 1 or 2. In one more specific embodiment, a is 0 or 1; in another more specific embodiment, b is 0 or 1.

[0254] In a more specific embodiment, Y1 and Y2 are independently CRdd R dd , O, S and NR' dd or when Y1 is connected to L', Y1 is selected from CR dd or N; in another more specific embodiment, Y 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; and in another more specific embodiment, Y1 is NR' dd , alternatively 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, alternatively CH or N, alternatively N; in another more specific embodiment, Y2 is CR dd R dd , O or NR' dd , alternatively O.

[0255] In a more specific embodiment, Y2 is 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.

[0256] In a more specific embodiment, when Y 1 is connected to L′, Y 1 is selected from CH, C(OH) and N, alternatively CH and N, alternatively N.

[0257] In a more specific embodiment, ring A is R d Along with [ka] In another more specific embodiment, ring A is R d along with [ka] and alternatively [ka] In another more specific embodiment, ring A is not R d along with [ka] is.

[0258] In a more specific embodiment, ring A is R d along with [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] , alternatively [ka] is.

[0259] In one embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, Rd3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] and in another embodiment, R d3 teeth [ka] is.

[0260] R d

[0261] In one embodiment, R d is H; in another embodiment, R d is 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)NR'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, Rd is C 1-8 alkyl; in another embodiment, R d is C 2-8 alkenyl; in another embodiment, R d is C 2-8 alkynyl; in another embodiment, R d is C 1-8 haloalkyl; in another embodiment, R d Ha-L'-C 6-10 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 -L'-5 to 14 membered heteroaryl; in another embodiment, R d is C 1-6 alkyl; in another embodiment, R d is 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 atom to which they are attached form a 3- to 7-membered monocyclic heterocyclyl; in another embodiment, two adjacent R d together with the atoms to which they are attached form a 6- to 10-membered bridged bicyclic heterocyclyl; in another embodiment, two adjacent R d together with the atom to which they are attached form a 6- to 10-membered spiro bicyclic heterocyclyl; in another embodiment, two adjacent R d together with the atoms to which they are attached form a 6- to 10-membered fused bicyclic heterocyclyl; in another embodiment, R d is 1, 2, 3, 4, 5, 6, 7 or 8 R dd In another embodiment, R d is unsubstituted; in another embodiment, R d is R d2and in another embodiment, R d is R d3 and in another embodiment, R d is R d4 and in another embodiment, R d is R d5 is as defined above.

[0262] In a more specific embodiment, R d are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R d are independently 1, 2, 3, 4, 5, 6, 7, or 8 R dd C optionally substituted with 1-6 Alkyl, C 1-6 It is selected from haloalkyl, -L'-3 to 10-membered carbocyclyl and -L'-3 to 10-membered heterocyclyl.

[0263] In another more specific embodiment, R d are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl and -L'-3 to 7-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl may be substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R dd may be substituted with;

[0264] In another more specific embodiment, R d are independently H, D, C 1-6 Alkyl, C 1-6haloalkyl, -L'-NR'R'' and -L'-4- to 6-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl or 4- to 6-membered heterocyclyl is one or two R dd may be substituted with;

[0265] In another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d is F; in another more specific embodiment, R dis —OH; in another more specific embodiment, R d is —OCH3; in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] and in another more specific embodiment, R d teeth [ka] is.

[0266] R dd

[0267] In one embodiment, R dd is H; in another embodiment, R dd is D; in another embodiment, R dd is halogen, for example F; in another embodiment, R dd is —CN; in another embodiment, R dd is —NO; in another embodiment, R dd is oxo; in another embodiment, R dd is C 1-8 alkyl; in another embodiment, R dd is C 2-8 alkenyl; in another embodiment, R dd is C 2-8 alkynyl; in another embodiment, R dd is C 1-8 haloalkyl; in another embodiment, R dd is -L″-OR′, alternatively OR′, e.g., OH; in another embodiment, R dd is -L″-NR′R″, alternatively 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 Ha-L''-S(O) 0-2 R'; in another embodiment, R dd is -L"-S(O)NR'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 Ha-L''-C 6-10 aryl; in another embodiment, R dd is -L″-3 to 14-membered carbocyclyl; in another embodiment, Rdd is -L″-3 to 14 membered heterocyclyl; in another embodiment, R dd is -L″-5 to 14 membered heteroaryl; in another embodiment, R dd is C 1-6 alkyl; in another embodiment, R dd is C 1-6 haloalkyl; in another embodiment, R dd is -L"-3 to 10-membered carbocyclyl, alternatively -L"-3 to 7-membered carbocyclyl; in another embodiment, R dd is -L''-3 to 10-membered heterocyclyl, alternatively -L''-3 to 7-membered heterocyclyl, alternatively -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 is C(CH3)2OH.

[0268] In another embodiment, R dd is —CHOH; in another embodiment, R dd is —CHOMe; in another embodiment, R dd teeth [ka] and in another embodiment, R dd is -NHMe; in another embodiment, R dd is -CH2-cyclopropyl.

[0269] In a more specific embodiment, R dd are independently 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, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R ddare independently 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 are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R dd are independently H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R dd are independently H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR", -L"-NR'R", and -L"-3 to 7-membered carbocyclyl; in another more specific embodiment, R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR" and NR'R"; in another more specific embodiment, R dd are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl and -L"-OR"; in another more specific embodiment, R dd are independently H, F, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, [ka] and -NHMe; in another more specific embodiment, R ddare independently H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, [ka] and -NHMe; in another more specific embodiment, R dd are independently H, OH, Me, -C(CH3)2OH, -CH2OMe and [ka] In another more specific embodiment, R dd is independently selected from H, OH, Me, —CH2OMe, and —C(CH3)2OH.

[0270] In one embodiment, two R dd Both are C 1-8 form an alkylene; in another embodiment, two non-adjacent R dd Both are C 1-6 form an alkylene; in another embodiment, two non-adjacent R dd Both are C 1-4 form an alkylene; in another embodiment, two non-adjacent R dd Both are C 1-3 form an alkylene; in another embodiment, two non-adjacent R dd Both are C 1-2 form an alkylene; in another embodiment, two non-adjacent R dd together form -CHCH-; in another embodiment, two non-adjacent R dd together form -CHCH-; in another embodiment, two non-adjacent R dd Both are C 1-4 Form an alkylene, or R' dd and non-adjacent R dd Both are C 1-4 Form an alkylene, or two R' dd Both are C 1-4form an alkylene; in another embodiment, two R dd together form an alkylene which may be substituted with the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 and optionally substituted with one or more of aryl, -L''-3 to 10-membered carbocyclyl, and -L''-3 to 10-membered heterocyclyl, and may alternatively be substituted with H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; in another embodiment, two non-adjacent R dd together to form -CH2CH2- [ka] The following structure: [ka] In another embodiment, two non-adjacent R dd The cyclic group formed by is H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; in another embodiment, two non-adjacent R dd is unsubstituted; in another embodiment, two non-adjacent R dd does not form a ring.

[0271] In one embodiment, CR dd R dd forms a 3- to 7-membered carbocyclylene, such as cyclopropylene; in another embodiment, CR dd R dd is a 3- to 7-membered heterocyclylene, e.g. [ka] ,for example [ka] In another embodiment, CR dd R dd The cyclic group formed by is H, D, halogen, C 1-6 Alkyl, C 1-6 and optionally substituted with 1, 2, or 3 groups selected from haloalkyl, -OR', and -NR'R'', alternatively with one -OR', alternatively with one OH; in another embodiment, CR dd R dd is unsubstituted; in another embodiment, CR dd R dd does not form a ring.

[0272] In a more specific embodiment, CR dd R dd forms a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene; in another more specific embodiment, CR dd R dd is cyclopropylene, [ka] In another more specific embodiment, CR dd R dd is cyclopropylene or [ka] In another more specific embodiment, CR dd R dd forms cyclopropylene.

[0273] In one embodiment, two adjacent R dd together with the atom to which they are attached form a 3- to 7-membered carbocyclylene; in another embodiment, two adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene; in another embodiment, two adjacent Rdd together with the atom to which they are attached form a phenylene; in another embodiment, two adjacent R dd together with the atom to which they are attached form a 5- to 6-membered heteroarylene; in another embodiment, two adjacent R dd The rings that they form together with the atoms to which they are attached are H, D, halogens, CN, C 1-6 Alkyl, C 1-6 and optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, -OR', and -NR'R''; in another embodiment, two adjacent R dd The rings that they form together with the atoms to which they are attached are H, D, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in another embodiment, two adjacent R dd and the atoms to which they are attached together form a ring that is unsubstituted; in another embodiment, two adjacent R dd and the atoms to which they are attached do not form a ring.

[0274] In a more specific embodiment, two adjacent R dd together with the atom to which they are attached 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, two adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene; in another more specific embodiment, two adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene.

[0275] In one embodiment, R' dd is H; in another embodiment, R' dd is C 1-6 alkyl; in another embodiment, R' dd is C 1-6haloalkyl; 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 heterocyclyl.

[0276] In a more specific embodiment, R' dd are independently H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR", -L"-NR'R", -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R' dd are independently 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 are independently H, C 1-6 Alkyl, C 1-6 haloalkyl and -L''-3 to 7-membered carbocyclyl; in another more specific embodiment, R' dd is independently selected from H, Me, and —CH 2 -cyclopropyl.

[0277] In one embodiment, R' dd and adjacent R dd together with the atom to which they are attached, represent 3- to 7-membered heterocyclylene, e.g. [ka] In another embodiment, R' dd and adjacent R dd together with the atoms to which they are attached, form 5- to 6-membered heteroarylene, e.g. [ka] In another embodiment, R' dd , adjacent R dd and the rings they form together with the atoms to which they are attached are H, D, halogen, CN, C 1-6 Alkyl, C 1-6 and optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, -OR', and -NR'R''; in another embodiment, R' dd , adjacent R dd and the rings they form together with the atoms to which they are attached are H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another embodiment, R' dd , adjacent R dd and the ring formed by the atoms to which they are attached together is unsubstituted; dd , adjacent R dd and the atoms to which they are attached do not form a ring.

[0278] In a more specific embodiment, R' dd and adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene; in another more specific embodiment, R' dd and adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene; in another more specific embodiment, R' dd and adjacent R dd along with the atoms to which they are attached, [ka] In another more specific embodiment, R' dd and adjacent R dd along with the atoms to which they are attached, [ka] Form.

[0279] In a more specific embodiment, R dd are independently 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)NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-3- to 10-membered carbocyclyl and -L''-3- to 10-membered heterocyclyl; in another more specific embodiment, R dd are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR", -L"-SR" and -L"-NR'R"; in another more specific embodiment, R dd are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR" and -L"-NR'R"; in another more specific embodiment, R dd is independently selected from H, D, Me, N(CH3)2, and C(CH3)2OH.

[0280] In a more specific embodiment, R dd are independently 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, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR", -L"-NR'R", and -L"-3 to 7-membered carbocyclyl; in another more specific embodiment, R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR" and -L"-NR'R"; in another more specific embodiment, R dd are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl and -L"-OR"; in another more specific embodiment, R dd are independently H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, [ka] and —NHMe, alternatively H, oxo, OH, Me, —C(CH)OH, —CHOH, —CHOMe or —NHMe; in another more specific embodiment, R dd is independently selected from H, Me, and —C(CH 3 ) 2 OH.

[0281] In a more specific embodiment, R' dd are independently H, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR", -L"-SR", -L"-NR'R", -L"-3 to 7-membered carbocyclyl, and -L"-3 to 7-membered heterocyclyl; in another more specific embodiment, R' dd are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -OR', -C1-6 alkylene selected from -NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl; in another more specific embodiment, R' dd are independently 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 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene -OR', -C 1-4 alkylene-NR'R'' and -L''-3 to 7-membered carbocyclyl; in another more specific embodiment, R' dd are independently H, C 1-6 Alkyl, C 1-6 haloalkyl and -L''-3 to 7-membered carbocyclyl; in another more specific embodiment, R' dd is independently selected from H, Me, -CH2-cyclopropyl.

[0282] In a more specific embodiment, two non-adjacent R dd Both are C 1-4 Form an alkylene, or R' dd and non-adjacent R dd Both are C 1-4 Form an alkylene, or two R' dd Both are C 1-4 Form an alkylene, wherein the C 1-4 Alkylene is H, D, halogen, CN, C 1-6 Alkyl and C 1-6 It may be optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl.

[0283] L and L'

[0284] 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 one 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; and in another embodiment, L is a C(R')-, C(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-. 1-8 Alkylene, alternatively C 1-6 Alkylene, and alternatively C 1-4 It is alkylene.

[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'-; 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 one 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; and in another embodiment, L' is a C(R')-, C(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-. 1-8 Alkylene, alternatively C 1-6 alkylene, and alternatively C 1-4 It is alkylene.

[0286] In another embodiment, L' is a C(R')-, ... 1-8 Alkylene, alternatively C 1-6 alkylene, and alternatively C 1-4 It is alkylene.

[0287] In a more specific embodiment, L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)-, and -C(O)-; or L or L' are independently selected from -C(R')-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)- in which one or more methylene units may be independently replaced with -C(R')-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)-. 1-6 alkylene; and in another more specific embodiment, L or L' is independently a covalent bond, O, and C. 1-6 alkylene; in another more specific embodiment, L or L' is independently selected from a covalent bond, O and C 1-4 In a more specific embodiment, L or L' is independently selected from a covalent bond and C 1-6 alkylene; in another more specific embodiment, L or L′ is independently selected from a covalent bond and C 1-4 alkylene; in another more specific embodiment, L is independently selected from a covalent bond, —O—, —S—, —NR′—, and C 1-6 alkylene; in another more specific embodiment, L is independently selected from a covalent bond, —NR′—, and C 1-4 In another more specific embodiment, L is independently selected from a covalent bond and -NR'-; in another more specific embodiment, L is independently selected from a covalent bond, -NH-, and -CH(CH3)-; in another more specific embodiment, L is independently selected from a covalent bond and -NH-; in another more specific embodiment, L' is independently selected from a covalent bond and -C 1-2 alkylene; in another more specific embodiment, L' is independently selected from a covalent bond and methylene; in another more specific embodiment, each of L and L' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d-3- to 7-membered heterocyclyl, or alternatively C 1-6 Alkyl and C 1-6 It may be substituted with 1, 2, 3 or 4 groups selected from haloalkyl.

[0288] R' and R''

[0289] In one embodiment, R' is H; in another embodiment, R' is C 1-8 alkyl; in another embodiment, R' is C 1-8 In another embodiment, R' is C 1-8 haloalkyl; in another embodiment, R' is -L"-C 6-10 aryl; 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 In another embodiment, R' is 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.

[0290] In one embodiment, R" is H; in another embodiment, R" is C 1-8 alkyl; in another embodiment, R″ is C 1-8 In another embodiment, R″ is C 1-8 haloalkyl; in another embodiment, R″ is -L″-C 6-10aryl; 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, alternatively C 1-4 alkyl; in another embodiment, R″ is C 1-6 Haloalkyl, alternatively C 1-4 In another embodiment, R'' is 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 a more specific embodiment, each of R′ and R″ is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d In another more specific embodiment, each of R′ and R″ is independently selected from H, C 1-6 Alkyl, C 1-6 In another more specific embodiment, each of R′ and R″ is independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, each of R′ and R″ is independently selected from C 1-6 Alkyl and C 1-6 haloalkyl; in another more particular embodiment, R'' is H or Me, alternatively Me.

[0292] In a more specific embodiment, R″ is H, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R″ is C 1-4haloalkyl; in another more specific embodiment, R'' is selected from H, methyl, and CHF2; in another more specific embodiment, R'' is CHF2.

[0293] L''

[0294] 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 a C(O)-, C(O)-, C(O)O-, -S-, -S(O)-, or -S(O)-. 1-8 Alkylene, alternatively C 1-6 Alkylene, alternatively C 1-4 alkylene; in another embodiment, L'' is optionally substituted with one or more R, alternatively 1, 2, 3, or 4 R; in another embodiment, L'' is -C(R)2-, alternatively [ka] and in another embodiment, L'' is unsubstituted.

[0295] In a more specific embodiment, L″ is independently a covalent bond and C, each optionally substituted with 1, 2, 3, or 4 R. 1-6 In another more specific embodiment, L″ is independently selected from a covalent bond and C, each optionally substituted with 1, 2, 3, or 4 R. 1-6 alkylene; in another more specific embodiment, L″ is independently selected from a covalent bond, C 1-4 In another more specific embodiment, L″ is independently selected from a covalent bond and —C(R)2—. 1-4 alkylene.

[0296] In a more specific embodiment, L″ is independently a covalent bond and C, each optionally substituted with 1, 2, 3, or 4 R. 1-4 alkylene; R is independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene, alternatively a 3- to 5-membered carbocyclylene, alternatively [ka] Form.

[0297] R

[0298] In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is C 1-8 Alkyl, alternatively C 1-6 alkyl; in another embodiment, R is C 1-8 Haloalkyl, alternatively C 1-6 haloalkyl; in another embodiment, R is -L d -3 to 10-membered carbocyclyl, alternatively -L d -3- to 7-membered carbocyclyl; in another embodiment, R is -L d -3 to 10-membered heterocyclyl, alternatively -L d -3 to 7-membered heterocyclyl;

[0299] In one embodiment, two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene, alternatively a 3- to 10-membered heterocyclylene, alternatively a 3- to 7-membered carbocyclylene, alternatively a 3- to 7-membered heterocyclylene, alternatively a 3- to 5-membered carbocyclylene, alternatively a 3- to 5-membered heterocyclylene, alternatively [ka] Form.

[0300] In a more specific embodiment, R is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d In another more specific embodiment, R is independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl.

[0301] In a more specific embodiment, 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, alternatively a 3- to 7-membered carbocyclylene, alternatively a 3- to 5-membered carbocyclylene, alternatively [ka] Form.

[0302] L d

[0303] In one embodiment, L d is a covalent bond; in another embodiment, L d is C 1-8 alkylene; in another embodiment, L d is C 1-6 alkylene; in another embodiment, L d is C 1-4 It is alkylene.

[0304] In a more specific embodiment, L d are independently a covalent bond and C 1-6 alkylene; in another more specific embodiment, L d are independently a covalent bond and C 1-4 alkylene.

[0305] Any technical solution or any combination thereof in any one 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 in ring A can be combined with any of 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 disclosure is intended to encompass all such combinations of technical solutions, but to save space, they are not exhaustively listed here.

[0306] In a more specific embodiment, the disclosure provides a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka]

[0307] V is a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0308] W is NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0309] Q and Y are independently a covalent bond, -O-, -S-, or -NR A -, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NRA -, -OC(O)-, -OC(O)NR A -, -N(R A )C(O)O-, -N(R A )C(O)- and -N(R A )S(O)2-; Q and Y cannot simultaneously be a covalent bond;

[0310] Alternatively, Q and Y may independently be each independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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 C optionally replaced by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- 1-8 is alkylene;

[0311] R A is H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0312] R B is H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0313] R C , R' C , R 1a and R1b are independently H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0314] One of Z1 and Z6 is CR E and the other is CR d1 or N;

[0315] R E -LC 6-10 aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl, wherein 6-10 Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e optionally substituted with a group;

[0316] R e are independently H, D, halogen, -CN, oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, 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 selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl;

[0317] R d1 H, D, halogen, -CN, C1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0318] Ring A is C 6-10 selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring;

[0319] R d are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R d are 1, 2, 3, 4, 5, 6, 7 or 8 R dd C optionally substituted with 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0320] Or, two adjacent R d together with the atoms to which they are attached, 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd may be substituted with;

[0321] R dd are independently 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 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0322] Or two R's dd are both substituted with the following substituents: H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 C optionally substituted with one or more of aryl, -L''-3 to 10-membered carbocyclyl, -L''-3 to 10-membered heterocyclyl, and -L''-5 to 10-membered heteroaryl 1-8 Forming alkylene;

[0323] 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)-, and -N(R')S(O)2-; or L or 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)-, and -N(R')S(O)2-; or or multiple methylene units may be 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- 1-8 is alkylene;

[0324] R' and R'' are independently 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, and -L''-5- to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl;

[0325] L″ is selected from a covalent bond, —O—, and —S—; or L″ is C optionally substituted with one or more R. 1-8 alkylene, and 1-8 One or more methylene units in the alkylene may be independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0326] R is independently H, D, C 1-8 Alkyl, C 1-8 Haloalkyl, -L d -3 to 10-membered carbocyclyl and -L d - selected from 3- to 10-membered heterocyclyl;

[0327] or two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene;

[0328] L d are independently a covalent bond and C 1-8 alkylene;

[0329] f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0330] wherein each of the above groups may be deuterated up to fully deuterated.

[0331] In a more specific embodiment, the disclosure provides a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka]

[0332] V is a covalent bond, O, S, NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0333] W is NR', S(O), S(O)2, C(O), CR C and CR C R C 'Selected from;

[0334] Q and Y are independently a covalent bond, -O-, -S-, or -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)- and -N(R A )S(O)2-; Q and Y cannot simultaneously be a covalent bond;

[0335] Alternatively, Q and Y may independently be each independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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 C optionally replaced by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- 1-8is alkylene;

[0336] R A is H, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, -L''-C 6-10 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0337] R B is H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0338] R C , R' C , R 1a and R 1b are independently H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0339] One of Z1 and Z6 is CR E and the other is CR d1 or N;

[0340] R E -LC 6-10aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl, wherein 6-10 Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R e optionally substituted with a group;

[0341] R e are independently 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 selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl;

[0342] R d1 H, D, halogen, -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC 6-10 selected from aryl, -L-3 to 14-membered carbocyclyl, -L-3 to 14-membered heterocyclyl, and -L-5 to 14-membered heteroaryl;

[0343] Ring A is C 6-10 selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring;

[0344] R d are independently H, D, halogen, -CN, -L'-S(O) 0-2R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R d are 1, 2, 3, 4, 5, 6, 7 or 8 R dd C optionally substituted with 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0345] Or, two adjacent R d together with the atoms to which they are attached, 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd may be substituted with;

[0346] R dd are independently 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 selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl;

[0347] 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)-, and -N(R')S(O)2-; or L or 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)-, and -N(R')S(O)2-; or or multiple methylene units may be 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- 1-8 is alkylene;

[0348] R' and R'' are independently 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, and -L''-5- to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl;

[0349] L" is selected from a covalent bond, -O-, and -S-; or L" is a C group in which one or more methylene units may be independently replaced with -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. 1-8 is alkylene;

[0350] f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0351] wherein each of the above groups may be deuterated up to fully deuterated.

[0352] The structure of ring A in formula (I) should be understood such that two adjacent atoms on ring A are connected to Q and Y, respectively. The two adjacent atoms can be carbon atoms or heteroatoms, such as N.

[0353] In a more specific embodiment, the present disclosure provides a method for treating a hydroxyl group comprising administering to a subject a subject, the subject being a subject, ... C and CR C R C or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0354] In a more specific embodiment, the present disclosure provides a method for determining whether W is CR C or CR C R C '; Alternatively, CR C R C ', or alternatively CH2, CD, CHD or CD2, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0355] In a more specific embodiment, the present disclosure 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) above is represented by one of the following formulas: [ka]

[0356] In a more specific embodiment, the present disclosure provides a method for isolating a compound of formula (I) wherein Q and Y are independently a covalent bond, O, S, NR A , S(O), S(O)2, C(O) and CR 1a R 1band Q and Y are not simultaneously a covalent bond, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0357] Alternatively, Q is O, S, and NR A and alternatively S or NR A , alternatively NR A , and alternatively NH.

[0358] Alternatively, Y is a covalent bond, O, S, and CR. 1a R 1b and alternatively a covalent bond, O and CR 1a R 1b Alternatively, it is selected from a covalent bond, O, CH2, CF2 and C(CH3)2, and further alternatively it is C(CH3)2.

[0359] In a more specific embodiment, the present disclosure provides R A But H, C 1-6 Alkyl, C 1-6 haloalkyl, -L''-3 to 10-membered carbocyclyl, and -L''-3 to 10-membered heterocyclyl; alternatively H, C 1-6 Alkyl and C 1-6 haloalkyl; alternatively H; or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0360] In a more specific embodiment, the present disclosure provides R B But H, C 1-6 Alkyl, C 1-6 haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -L-3 to 10-membered carbocyclyl and -L-3 to 10-membered heterocyclyl; alternatively H, C 1-6 Alkyl and C 1-6haloalkyl; alternatively H; or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0361] In a more specific embodiment, the present disclosure provides R C and R' C are independently 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, and -L-3 to 10-membered heterocyclyl; alternatively, independently, H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and alternatively, independently, H or D.

[0362] In a more specific embodiment, the present disclosure provides R 1a and R 1b are independently 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, and -L-3 to 10-membered heterocyclyl; alternatively, independently, H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; alternatively, independently, H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; alternatively, independently, H, D, halogen, C 1-3 Alkyl and C 1-3haloalkyl; alternatively, independently selected from H, D, F and Me; and further alternatively, Me, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0363] In a more specific embodiment, the present disclosure provides R E , respectively, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R e Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrrolopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, pyrazolopyridyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyridyl, dihydropyridoxazinyl, indolyl, triazolopyridyl, tetrahydroimidazopyrazinyl, dihydropyrrolopyridyl, thienopyridyl, benzimido a compound of formula (I') or formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, selected from thienopyridyl, dihydroimidazooxazinyl, tetrahydropyrazolopyridyl, tetrahydropyrrolopyridyl, dihydropyrazolooxazinyl, dihydropyrroloiimidazolyl, oxazolopyridyl, pyrazoloazepanyl, pyrazolopiperidyl, imidazoazepanyl, imidazopiperidyl, pyrazolodiazepanyl, pyrazolodiazacyclohexyl and thienopyridyl;

[0364] Optionally, R E and its substituent R e Both [ka] The group selected from

[0365] In some embodiments of the present disclosure, R Eand its substituent R e Both [ka] forming a group selected from

[0366] where g=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0367] Alternatively, g=0, 1, 2, 3, 4, 5 or 6; alternatively, g=0, 1, 2, 3 or 4; alternatively, g=0, 1 or 2.

[0368] In a more specific embodiment, the present disclosure provides R e are independently 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, and -L'-3- to 10-membered heterocyclyl; alternatively, independently selected from H, D, halogen, -CN, -OR', -SR', -NR'R'', C 1-6 Alkyl and C 1-6 haloalkyl; alternatively, independently selected from H, D, halogen, —CN, —OR′, C 1-6 Alkyl and C 1-6 haloalkyl; alternatively, independently selected from H, D, Me, F, Cl, —CN and —OCH3, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0369] Optionally, R E and its substituent R e Both [ka] a group selected from: [ka] a group selected from: [ka] The group selected from

[0370] In a more specific embodiment, the present disclosure provides a method for manufacturing a semiconductor device, comprising: E and Z1 is CR d1 or N, or Z1 is CR E and Z6 is N; alternatively, Z6 is CR E and Z1 is CR d1 or N; alternatively, Z6 is CR E and Z1 is CR d1 and alternatively, the Z6 is CR E and Z1 is CH or CD, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0371] In a more specific embodiment, the present disclosure provides R d1 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 and -L-3 to 10-membered heterocyclyl; alternatively H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and alternatively H or D.

[0372] In a more specific embodiment, the present disclosure provides a compound according to the present invention, wherein ring A is 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 pyrazine ring, a pyrazolidine ring, a pyrazoline ring, a pyrazole ring, a pyridazine ring, a pyridine ring, a pyrrolidine ring, a pyrroline ring, a 2H-pyrrole ring, a pyrrole ring, Provided is a compound of formula (I') or (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein the ring is selected from a tetrahydrofuran ring, a tetrahydropyran ring, a thiazole ring, a thiophene ring, a triazine ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a xanthene ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and a hexahydropyrazinoquinoline ring; alternatively, selected from a benzene ring, a pyridine ring, a pyrazole ring, and an imidazole ring; and further alternatively, a benzene ring.

[0373] Optionally, ring A and its substituents R d Both [ka] Alternatively, a group selected from [ka] where f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0374] Optionally, f=0, 1, 2, 3, 4, 5 or 6; alternatively, f=0, 1, 2, 3 or 4; alternatively, f=0, 1 or 2.

[0375] In a more specific embodiment, the present disclosure 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 R d are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R d independently, 1, 2, 3, 4, 5, 6, 7, or 8 R dd C optionally substituted with 1-6 Alkyl, C 1-6 selected from haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl;

[0376] Or, two adjacent R d together with the atoms to which they are attached 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd and optionally substituted with:

[0377] Optionally, R d are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl and -L'-3 to 7-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl may be substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R dd may be substituted with.

[0378] Optionally, R d are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R'' and -L'-4- to 6-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl or 4- to 6-membered heterocyclyl is one or two R dd may be substituted with.

[0379] In some specific embodiments of the present disclosure, R d are independently H, D, [ka] Alternatively, independently selected from H, D, [ka] Selected from;

[0380] In some specific embodiments of the present disclosure, ring A and its substituents R d Both [ka] Alternatively, the group is [ka] , alternatively [ka] , or alternatively [ka] is.

[0381] In a more specific embodiment, the present disclosure provides R d are independently H, F, -OH, -OCH3, [ka] 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, selected from:

[0382] In a more specific embodiment, the present disclosure provides R dd are independently 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' is selected from -L''-S(O)NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-3- to 10-membered carbocyclyl and -L''-3- to 10-membered heterocyclyl; alternatively, independently, H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR', -L"-SR', and -L"-NR'R"; alternatively, independently selected from H, D, C 1-6 Alkyl, C 1-6 is selected from haloalkyl, -L"-OR" and -L"-NR'R", and alternatively, independently, selected from H, D, Me, N(CH3)2 and C(CH3)2OH, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0383] In one more specific embodiment, the present disclosure provides a ring A and its substituents R d together form a group selected from the following: [ka] [ka]

[0384] In a more specific embodiment, the present disclosure provides a compound wherein L and L' are independently selected from a chemical bond, -O-, -S-, -NR'-, -S(O)-, and -C(O)-; or L or L' is a compound wherein one or more methylene units may be independently replaced with -C(R')-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)-. 1-6 Provided is 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 is alkylene.

[0385] Alternatively, L or L' are independently a covalent bond, O and C. 1-6 alkylene, alternatively independently selected from a covalent bond, O and C 1-4 alkylene.

[0386] In a more specific embodiment, the present disclosure provides a compound wherein L″ is selected from a covalent bond, —O—, and —S—; or L″ is a C(O)—, in which one or more methylene units may be independently replaced with —O—, —C(O)—, —S—, —S(O)—, or —S(O)—. 1-6 alkylene; alternatively, L″ is a covalent bond and C 1-6 alkylene; and alternatively a covalent bond or C 1-4 Provided is 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 is alkylene.

[0387] In a more specific embodiment, the present disclosure 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, having the following structural formula: [ka]

[0388] During the ceremony,

[0389] [ka] indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic and R' e1 , R' e2 , R' e3 and R' e4 means that the double bond is not present; if a double bond is not present, it means that the ring in which it is located is not aromatic;

[0390] X1 is a CR e6 , N, O, S or NR' e6 and;

[0391] X2 is C or N;

[0392] X3 is C or N;

[0393] X4 is CR e4 , C.R. e4 R' e4 or N;

[0394] X5 is CR e5 , N, O, S or NR' e5 and;

[0395] X6 is C or N;

[0396] X7 is CR e1 or N;

[0397] X8 is CR e2 or N;

[0398] X9 is CR e3 or N;

[0399] X 10 is CR e7 , O, S, N and NR' e7 Selected from;

[0400] X 11 is CR e8 , O, S, N and NR' e8 Selected from;

[0401] R e1 , R e2 , R e3 , R e4 , R e5 and R e6 are independently 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 selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl;

[0402] R' e1 , R' e2 , R' e3 and R' e4 are independently absent, H, D, halogen, -CN, C 1-8 Alkyl and C 1-8 haloalkyl; or CR e1 R' e1 forms -C(O)- or CR e2 R' e2 forms -C(O)- or CR e3 R' e3forms -C(O)- or CR e4 R' e4 forms -C(O)-;

[0403] R' e5 and R' e6 are independently H, C 1-8 Alkyl and C 1-8 haloalkyl;

[0404] R e7 and R e8 are independently H, D, halogen, CN, C 1-8 Alkyl, C 1-8 selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl;

[0405] R' e7 and R' e8 are independently H, D, C 1-8 Alkyl, C 1-8 selected from haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl;

[0406] Or X 10 and X 11 Both of the substituents may contain one double bond. 3-5 Forms alkylene; 3-5 Alkylene can be one, two, three or four R e and the above C 3-5 One or more methylene units in the alkylene may be 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-;

[0407] E is CR e12 and N;

[0408] J is for CR e13 and N;

[0409] R e9 , R e10 , R e11 , R e12 and R e13 H, D, halogen, CN, C 1-8 Alkyl, C 1-8 Haloalkyl, 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 and -Y5-C 0-8 alkylene-R6;

[0410] Y5 is selected from O, S and NR5;

[0411] R5 is H, C 1-8 Alkyl and C 1-8 haloalkyl;

[0412] R6 is selected from 3- to 10-membered carbocyclyl and 3- to 10-membered heterocyclyl;

[0413] Alternatively, R e9 and R e13 may be one, two, three or four R e 5- to 10-membered carbocyclyl, 5- to 10-membered heterocyclyl, C 6-10 forms an aryl or a 5- to 10-membered heteroaryl;

[0414] Alternatively, R e9 and R e10 may be one, two, three or four R e 5- to 10-membered carbocyclyl, 5- to 10-membered heterocyclyl, C 6-10 Forms an aryl or 5- to 10-membered heteroaryl;

[0415] Z2 is R d2 is a C atom or a N atom optionally substituted with;

[0416] Z3 is R d3 is a C atom or a N atom optionally substituted with;

[0417] Z4 is R d4 is a C atom or a N atom optionally substituted with;

[0418] Z5 is covalent bond, CR d5 and N;

[0419] R d2 , R d3 , R d4 and R d5 are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R'', or R d2 , R d3 , R d4 and R d5 are independently 1, 2, 3, 4, 5, 6, 7, or 8 R dd C optionally substituted with 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, -L'-C 6-10 selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl;

[0420] Alternatively, R d2 and R d3 together with the atom 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 d5together with the atoms to which they are attached, 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, and 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 may be substituted with 1, 2, 3, 4, or 5 R dd may be substituted with;

[0421] n=0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0422] other groups are as defined herein;

[0423] Each of the above groups may be deuterated up to fully deuterated.

[0424] In a more specific embodiment, the present disclosure provides a compound of formula (II-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0425] V is a covalent bond, CR C and CR C R C 'Selected from;

[0426] Q and Y are independently a covalent bond, O, S, NR A , S(O), S(O)2, C(O) and CR 1a R 1b Q and Y are not simultaneously a covalent bond;

[0427] R A is H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-3 to 10-membered carbocyclyl, and -L''-3 to 10-membered heterocyclyl;

[0428] R Bis H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -L-3 to 10-membered carbocyclyl, and -L-3 to 10-membered heterocyclyl;

[0429] R C , R' C , R 1a and R 1b are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -L-3 to 10-membered carbocyclyl, and -L-3 to 10-membered heterocyclyl;

[0430] [ka] indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic and R' e1 , R' e2 , R' e3 and R' e4 means that the double bond is not present; if a double bond is not present, it means that the ring in which it is located is not aromatic;

[0431] X2 is C or N;

[0432] X3 is C or N;

[0433] X4 is CR e4 , C.R. e4 R' e4 or N;

[0434] R e1 , R e2 , R e3 , R e4 and R e5 are independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6selected from 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, and -L'-3- to 10-membered heterocyclyl;

[0435] R' e1 , R' e2 , R' e3 and R' e4 are independently H, D, halogen, -CN, C 1-6 Alkyl and C 1-6 haloalkyl; or CR e1 R' e1 forms -C(O)- or CR e2 R' e2 forms -C(O)- or CR e3 R' e3 forms -C(O)- or CR e4 R' e4 forms -C(O)-;

[0436] Z1 is CR d1 or N;

[0437] Z2 is R d2 is a C atom or a N atom optionally substituted with;

[0438] Z3 is R d3 is a C atom or a N atom optionally substituted with;

[0439] Z4 is R d4 is a C atom or a N atom optionally substituted with;

[0440] Z5 is covalent bond, CR d5 and N;

[0441] R d1 H, D, halogen, -CN, C 1-6 Alkyl, C1-6 selected from haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -L-3 to 10-membered carbocyclyl, and -L-3 to 10-membered heterocyclyl;

[0442] R d2 , R d3 , R d4 and R d5 are independently H, D, halogen, -CN, -L'-S(O) 0-2 R', -L'-S(O)NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R'', or R d2 , R d3 , R d4 and R d5 are independently 1, 2, 3, 4, 5, 6, 7, or 8 R dd C optionally substituted with 1-6 Alkyl, C 1-6 selected from haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl;

[0443] Alternatively, 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, 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, and 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 may be selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 R dd may be substituted with;

[0444] R ddare independently 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' is selected from -L''-S(O)NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-3- to 10-membered carbocyclyl and -L''-3- to 10-membered heterocyclyl;

[0445] L and L' are independently selected from a covalent bond, -O-, -S-, -NR'-, -S(O)2-, and -C(O)-; or L or L' are independently selected from -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-, in which one or more methylene units may be independently replaced with -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O)2-. 1-6 is alkylene;

[0446] R' and R'' are independently H, C 1-6 Alkyl, C 1-6 haloalkyl, -L''-3 to 10-membered carbocyclyl, and -L''-3 to 10-membered heterocyclyl; or R' and R'' together with the N atom to which they are attached form a 3 to 10-membered heterocyclyl;

[0447] L" is selected from a covalent bond, -O-, and -S-; or L" is a C(O)-, in which one or more methylene units may be independently replaced with -O-, -C(O)-, -S-, -S(O)-, or -S(O)-. 1-6 is alkylene;

[0448] wherein each of the above groups may be deuterated up to fully deuterated.

[0449] In a more specific embodiment, the present disclosure provides a compound of formula (II-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0450] V is a covalent bond, CR C and CR C R' C Selected from;

[0451] Q is O, S and NR A Selected from;

[0452] Y is a covalent bond, O, S and CR 1a R 1b Selected from;

[0453] R A and R B are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0454] R C and R' C are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0455] R 1a and R 1b are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl;

[0456] [ka] indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic and R' e1 , R' e2 , R' e3 and R' e4means that the double bond is not present; if a double bond is not present, it means that the ring in which it is located is not aromatic;

[0457] X2 is C or N;

[0458] X3 is C or N;

[0459] X4 is CR e4 , C.R. e4 R' e4 or N;

[0460] R e1 H, D, halogen, -CN, -OR', -SR', -NR'R'', C 1-6 Alkyl and C 1-6 haloalkyl;

[0461] R e2 , R e3 , R e4 and R e5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0462] R' e1 , R' e2 , R' e3 and R' e4 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0463] Z1 is CR d1 or N;

[0464] Z2 is R d2 is a C atom or a N atom optionally substituted with;

[0465] Z3 is R d3 is a C atom or a N atom optionally substituted with;

[0466] Z4 is R d4is a C atom or a N atom optionally substituted with;

[0467] Z5 is covalent bond, CR d5 and N;

[0468] R d1 and R d5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0469] R d2 , R d3 and R d4 are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl and -L'-3 to 7-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl may be substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R dd may be substituted with;

[0470] R dd are independently H, D, halogen, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-SR' and -L''-NR'R'';

[0471] R' and R'' are independently H, C 1-6 Alkyl, C 1-6 haloalkyl, -L''-3- to 7-membered carbocyclyl, and -L''-3- to 7-membered heterocyclyl; or R' and R'' together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl;

[0472] L' is a covalent bond, O and C 1-6 alkylene;

[0473] L'' is a covalent bond and C 1-6 alkylene;

[0474] Each of the above groups may be deuterated up to fully deuterated.

[0475] In a more specific embodiment, the present disclosure provides a compound of formula (II-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0476] V is selected from a covalent bond, CH, CH2, CD, CHD and CD2, alternatively a covalent bond;

[0477] Q is S and NR A and alternatively selected from NR A and;

[0478] Y is a covalent bond, O and CR 1a R 1b alternatively selected from a covalent bond, O, CH2, CF2 and C(CH3)2, further alternatively C(CH3)2;

[0479] R A and R B is H;

[0480] R 1a and R 1b are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively independently selected from H, D, F and Me;

[0481] [ka] indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic and R' e1 , R'e2 , R' e3 and R' e4 means that the double bond is not present; if a double bond is not present, it means that the ring in which it is located is not aromatic;

[0482] X2 is C or N;

[0483] X3 is C or N; alternatively, one of X2 and X3 is C and the other is N;

[0484] X4 is CR e4 , C.R. e4 R' e4 and N;

[0485] R e1 is selected from H, D, halogen, —CN and —OR′, alternatively H, D, F, Cl, —CN or —OCH3;

[0486] R e2 H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H, D or Me;

[0487] R e3 , R e4 and R e5 is independently selected from H and D;

[0488] R' e1 , R' e2 , R' e3 and R' e4 is independently selected from H and D;

[0489] Z1 is CR d1 or N;

[0490] Z2 is R d2 is a C atom or a N atom optionally substituted with;

[0491] Z3 is R d3is a C atom or a N atom optionally substituted with;

[0492] Z4 is R d4 is a C atom or a N atom optionally substituted with;

[0493] Z5 is covalent bond, CR d5 and N; alternatively, the ring on which Z2, Z3, Z4 and Z5 are located is selected from a benzene ring, a pyridine ring, a pyrazole ring and an imidazole ring;

[0494] R d1 and R d5 are independently H or D;

[0495] R d2 , R d3 and R d4 are independently H, D, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-NR'R'' and -L'-4- to 6-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl or 4- to 6-membered heterocyclyl is one or two R dd Alternatively, R d2 , R d3 and R d4 are independently H, D, [ka] and further alternatively, R d2 H, D, [ka] Selected from R d3 H, D, [ka] Selected from R d4 H, D and [ka] Selected from;

[0496] R dd are independently H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L"-OR" and -L"-NR'R", alternatively independently selected from H, D, Me, N(CH3)2 and C(CH3)2OH;

[0497] L' is a covalent bond, O and C 1-6 alkylene, and alternatively a covalent bond, O, or C 1-4 is alkylene;

[0498] L'' is a covalent bond and C 1-6 alkylene, and alternatively a covalent bond or C 1-4 is alkylene;

[0499] R' and R'' are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0500] Each of the above groups may be deuterated up to fully deuterated.

[0501] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0502] [ka] teeth, [ka] and alternatively selected from [ka] Selected from;

[0503] The rings on which Z2, Z3, Z4 and Z5 are located and the substituents thereon may both be selected from the following groups: [ka] , alternatively [ka] , alternatively [ka] , or alternatively [ka] Form.

[0504] In a more specific embodiment, the present disclosure provides a compound of formula (III), formula (IV) or formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

[0505] X2 is C or N;

[0506] X3 is C or N;

[0507] X4 is CR e4 or N;

[0508] R e1 H, D, halogen, -CN, -OR', -SR', -NR'R'', C 1-6 Alkyl and C 1-6 haloalkyl;

[0509] R e2 , R e3 , R e4 and R e5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0510] R 1a and R 1b are independently H, D, halogen, CN, C 1-6 Alkyl or C 1-6 is haloalkyl;

[0511] Z1 is CR d1 or N, alternatively CR d1 and;

[0512] Z2 is CR d2 or N, alternatively CR d2 and;

[0513] Z4 is CR d4 or N, alternatively CR d4 and;

[0514] Z5 is CR d5 or N, alternatively CR d5 and;

[0515] R d2 H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl and -L'-3 to 7-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl may be substituted with 1, 2, 3, 4, 5, 6, or 7 R dd may be substituted with;

[0516] R d1 , R d4 or R d5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0517] R dd H, D, halogen, C 1-6 Alkyl, C 1-6selected from haloalkyl, -L''-OR', -L''-SR' and -L''-NR'R'';

[0518] L' is a covalent bond, -O- and C 1-6 alkylene;

[0519] L'' is a covalent bond and C 1-6 alkylene;

[0520] n=0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0521] R' and R'' are independently H, C 1-6 Alkyl, C 1-6 haloalkyl, -L''-3- to 7-membered carbocyclyl, and -L''-3- to 7-membered heterocyclyl; or R' and R'' together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl;

[0522] wherein each of the above groups may be deuterated up to fully deuterated.

[0523] In a more specific embodiment, the present disclosure provides a compound of formula (III), formula (IV) or formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

[0524] X2 is C or N;

[0525] X3 is C or N;

[0526] X4 is CR e4 or N;

[0527] R e1 H, D, halogen, -CN, -OR', C 1-6 Alkyl and C 1-6 haloalkyl;

[0528] R e2 , R e3 , R e4 and R e5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0529] R 1a and R 1b independently, C 1-6 Alkyl or C 1-6 is haloalkyl;

[0530] Z1 is CR d1 or N, alternatively CR d1 and;

[0531] Z2 is CR d2 or N, alternatively CR d2 and;

[0532] Z4 is CR d4 or N, alternatively CR d4 and;

[0533] Z5 is CR d5 or N, alternatively CR d5 alternatively, the ring on which Z2, Z4 and Z5 are located is selected from a benzene ring and a pyridine ring, alternatively a benzene ring;

[0534] R d1 , R d2 , R d4 or R d5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0535] R dd H, D, halogen, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR'' and -L''-NR'R'';

[0536] L'' is a covalent bond and C 1-6 alkylene;

[0537] n=0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0538] R' and R'' are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0539] Each of the above groups may be deuterated up to fully deuterated.

[0540] In a more specific embodiment, the present disclosure provides a compound of formula (III) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0541] X2 is C or N;

[0542] X3 is C or N;

[0543] X4 is CR e4 or N;

[0544] R e1 is selected from H, D, halogen and -OR', alternatively H, D or halogen;

[0545] R e2 H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H or D;

[0546] R e3 , R e4 and R e5 are independently H or D;

[0547] R 1a and R 1b independently, C 1-3Alkyl or C 1-3 haloalkyl, alternatively Me;

[0548] Z1, Z2, Z4 and Z5 are CH or CD;

[0549] R dd H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -L''-OR'';

[0550] L'' is a covalent bond and C 1-6 alkylene;

[0551] n=0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0552] R' is H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0553] Each of the above groups may be deuterated up to fully deuterated.

[0554] In a more specific embodiment, the present disclosure provides a compound of formula (III) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0555] X2 is C or N;

[0556] X3 is C or N; alternatively, one of X2 and X3 is C and the other is N;

[0557] X4 is CR e4 or N;

[0558] R e1 is selected from H, F, Cl and OCH3, alternatively H, F or Cl;

[0559] Re2 is selected from H and Me, alternatively H;

[0560] R e3 , R e4 and R e5 is H; alternatively, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] Selected from;

[0561] R 1a and R 1b is Me;

[0562] Z1, Z2, Z4 and Z5 are CH;

[0563] R dd is H or -L''-OH, alternatively H or C(CH3)2OH;

[0564] L'' is a covalent bond and C 1-4 alkylene;

[0565] n=0 or 1; alternatively, [ka] teeth [ka] is.

[0566] In a more specific embodiment, the present disclosure provides a compound of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0567] X2 is C or N;

[0568] X3 is C or N;

[0569] X4 is CR e4 or N;

[0570] R e1 is selected from H, D, halogen, CN and OR', alternatively selected from H, D, F, CN and OR';

[0571] R e2 H, D, C 1-6 Alkyl and C 1-6 haloalkyl;

[0572] R e3 , R e4 and R e5 are independently H or D;

[0573] R 1a and R 1b independently, C 1-3 Alkyl or C 1-3 haloalkyl, alternatively Me;

[0574] Z1 is selected from CH, CD and N, alternatively CH or CD;

[0575] Z2, Z4 and Z5 are independently selected from CH, CD and N;

[0576] R dd H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -L''-OR'';

[0577] L'' is a covalent bond and C 1-6 alkylene;

[0578] n=0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0579] R' is H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0580] Each of the above groups may be deuterated up to fully deuterated.

[0581] In a more specific embodiment, the present disclosure provides a compound of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0582] X2 is C or N;

[0583] X3 is C or N; alternatively, one of X2 and X3 is C and the other is N;

[0584] X4 is CR e4 or N;

[0585] R e1 is selected from H, F, Cl, CN and OCH3, alternatively selected from H, F, CN and OCH3;

[0586] R e2 is selected from H and Me;

[0587] R e3 , R e4 and R e5 is H; alternatively, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] and further alternatively selected from [ka] Selected from;

[0588] R 1a and R 1b is Me;

[0589] Z1 is CH;

[0590] Z2, Z4 and Z5 are independently CH or N; alternatively Z2 and Z4 are independently CH or N and Z5 is CH; alternatively Z2 is CH or N and Z4 and Z5 are CH;

[0591] R dd is H or -L''-OH, alternatively H or C(CH3)2OH;

[0592] L'' is a covalent bond and C 1-4 alkylene;

[0593] n=0 or 1; alternatively, [ka] teeth [ka] is.

[0594] In a more specific embodiment, the present disclosure provides a compound of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0595] X2 is C or N;

[0596] X3 is C or N;

[0597] X4 is CR e4 or N, alternatively CR e4 and;

[0598] R e1 is selected from H, D, halogen and OR', alternatively OR';

[0599] R e2 H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H or D;

[0600] R e3 , R e4 and R e5 are independently H or D;

[0601] R 1a and R 1b independently, C 1-3 Alkyl or C 1-3 haloalkyl, alternatively Me;

[0602] Z1 is N, CH or CD, alternatively CH or CD;

[0603] Z2, Z4 and Z5 are independently CH or CD;

[0604] R dd H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -L''-OR', alternatively H or D;

[0605] L'' is a covalent bond and C 1-6 alkylene;

[0606] n=0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0607] R' is H, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively C 1-6 Alkyl or C 1-6 is haloalkyl;

[0608] Each of the above groups may be deuterated up to fully deuterated.

[0609] In a more specific embodiment, the present disclosure provides a compound of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0610] X2 is C or N;

[0611] X3 is C or N; alternatively, one of X2 and X3 is C and the other is N;

[0612] X4 is CR e4 or N, alternatively CR e4 and;

[0613] R e1 is selected from H, F, Cl and OCH3, alternatively OCH3;

[0614] R e2 is H;

[0615] R e3 , R e4 and R e5 is H; alternatively, [ka] teeth, [ka] and alternatively selected from [ka] and;

[0616] R 1a and R 1b is Me;

[0617] Z1 is CH or N;

[0618] Z2, Z4 and Z5 are CH;

[0619] R dd is H;

[0620] n=0.

[0621] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein [ka]

[0622] During the ceremony,

[0623] R E represents -L-3 to 10-membered carbocyclyl, -L-3 to 10-membered heterocyclyl, -LC 6-10 aryl and -L-5 to 10 membered heteroaryl, alternatively -LC 6-10 aryl or -L-5-10 membered heteroaryl, each of which is selected from 1, 2, 3, 4, or 5 R e may be substituted with;

[0624] R eare independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl;

[0625] Y is O, S and CR 1a R 1b Selected from;

[0626] R 1a and R 1b are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0627] Q, V, R B and Z1 are each as defined herein;

[0628] Z2 is CR d2 and N;

[0629] The Z3 is a CR d3 and N;

[0630] The Z4 is a CR d4 and N;

[0631] Z5 is covalent bond, CR d5 and N, alternatively CR d5 or N;

[0632] R d3 and R d4 One of the groups is -NR' d6 C(O)R d6 , -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl, and the other, R d2 and R d5 are independently H, D, halogen, CN, C 1-6Alkyl, C 1-6 selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl;

[0633] R d2 , R d3 , R d4 and R d5 is 1, 2, 3 or 4 R dd may be substituted with;

[0634] R dd are independently H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl;

[0635] Alternatively, two non-adjacent R dd Both are C 1-6 Forming an alkylene, alternatively C 1-4 Forms alkylene, which is H, D, halogen, CN, C 1-6 Alkyl and C 1-6 optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl;

[0636] R d6 is 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 and -L''-Y3-C 1-6 alkylene-R4;

[0637] Y3 is selected from O, S and NR3;

[0638] R' d6 and R3 are independently H, C 1-6 Alkyl and C 1-6haloalkyl;

[0639] R4 is selected from -OR', -SR' and -NR'R'';

[0640] L independently represents a covalent bond, -O-, -S-, -NR'-, or C 1-6 alkylene;

[0641] L' is independently a covalent bond and C 1-6 alkylene;

[0642] Each of L and L' is C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d - optionally substituted with 1, 2, 3, or 4 groups selected from 3- to 7-membered heterocyclyl;

[0643] L″ independently represents a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R. 1-6 alkylene; R is independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -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;

[0644] L d are independently a covalent bond and C 1-6 alkylene, and alternatively a covalent bond and C 1-4 alkylene;

[0645] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -Ld - selected from 3- to 7-membered heterocyclyl;

[0646] wherein each of the above groups may be deuterated up to fully deuterated.

[0647] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0648] R E is -L-5 to 10 membered heteroaryl, alternatively 5 to 10 membered heteroaryl; alternatively, R E wherein the heteroaryl is selected from the group consisting of 1, 2, 3, 4, and 5 R e selected from pyridyl, pyridonyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, imidazopyridyl, imidazopyridazinyl, imidazopyrazinyl, imidazopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, triazolopyridyl, imidazopyrrolidinyl, imidazocyclohexyl, imidazopiperidyl, imidazoazepanyl, dihydroimidazooxazinyl, imidazopyrazinonyl, imidazodiazacyclohexyl, imidazopiperazinonyl, pyrazolopiperidyl, pyrazolodiazacyclohexyl, dihydropyrazolooxazinyl, triazolopiperidyl, dihydropyridoxazinyl, pyrrolopyridyl and oxazolopyridyl, optionally substituted with;

[0649] R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6alkynyl, -OR' and -NR'R'';

[0650] Y is O or CR 1a R 1b , alternatively CR 1a R 1b and;

[0651] R 1a and R 1b independently, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively selected from Me and Et;

[0652] Q, V, R B and Z1 are each as defined herein;

[0653] Z2 is CR d2 and N;

[0654] The Z3 is a CR d3 and N;

[0655] The Z4 is a CR d4 and N;

[0656] The Z5 is a CR d5 and N;

[0657] R d3 and R d4 One of the groups is -NR' d6 C(O)R d6 or -L'-3 to 7-membered heterocyclyl, alternatively -L'-3 to 7-membered heterocyclyl, and the other, R d2 and R d5 are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl;

[0658] R d2 , R d3 , R d4 and Rd5 is 1, 2, 3 or 4 R dd may be substituted with;

[0659] R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl;

[0660] Alternatively, two non-adjacent R dd Both are H, D, halogen, CN, C 1-6 Alkyl and C 1-6 C optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl 1-3 Forming alkylene;

[0661] R d6 is C 1-6 Alkyl, C 1-6 Haloalkyl, -L''-3 to 7-membered carbocyclyl, -L''-3 to 7-membered heterocyclyl, and -L''-Y3-C 1-4 alkylene-R4;

[0662] Y3 is selected from O and NR3, alternatively O;

[0663] R' d6 and R3 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H, C 1-3 Alkyl or C 1-3 is haloalkyl;

[0664] R4 is selected from -OR' and -NR'R'', alternatively -OR';

[0665] L is independently a covalent bond, -NR'-, or C 1-4alkylene, alternatively a covalent bond or -NR'-; alternatively, L is a covalent bond, -NH-, or -CH(CH3)-, alternatively a covalent bond or -NH-;

[0666] L' is independently a covalent bond and C 1-4 alkylene;

[0667] Each of L and L' is C 1-6 Alkyl and C 1-6 optionally substituted with 1, 2, 3, or 4 groups selected from haloalkyl;

[0668] L″ independently represents a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R. 1-6 alkylene; R is independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene, alternatively a 3- to 5-membered carbocyclylene;

[0669] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d -3 to 7 membered heterocyclyl, alternatively H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0670] In a more specific embodiment, the present disclosure 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, [ka]

[0671] In the formula, R E is as defined herein;

[0672] R e are independently H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl and -L'-3 to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, -OR' and -NR'R'', each of which is selected from 1, 2 or 3 R es may be substituted with;

[0673] Or, two geminal R e together with the atom to which they are attached form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, alternatively a 3- to 7-membered heterocyclyl, which may be joined by one, two, or three R es may be substituted with;

[0674] R es are independently H, D, halogen, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -OR' and -NR'R'';

[0675] Q, V, R B , Z1 and Z7 are as defined herein;

[0676] Z2 is CR d2 and N;

[0677] The Z3 is a CR d3 and N;

[0678] The Z4 is a CR d4 and N;

[0679] Z5 is covalent bond, CR d5 and N, alternatively CR d5 or N;

[0680] R d3 and R d4 One of the groups is -NR' d6 C(O)R d6 , -C(O)NR d7 R' d7 , -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl, alternatively -NR' d6 C(O)R d6 , -C(O)NR d7 R' d7 or -L'-3 to 7-membered heterocyclyl, and R d2 and R d5 are independently 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 and -L'-3 to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, OR' and NR'R'';

[0681] R d2 , R d3 , R d4 and R d5 is 1, 2, 3 or 4 R dd may be substituted with;

[0682] R dd are independently H, D, oxo, halogen, CN, C 1-6 Alkyl, C1-6 haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl, and alternatively H, D, oxo, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl;

[0683] Or, CR dd R dd forms a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, which is substituted with H, D, halogen, C 1-6 Alkyl, C 1-6 optionally substituted with 1, 2 or 3 groups selected from haloalkyl, -OR' and -NR'R''; alternatively, optionally substituted with 1 -OR';

[0684] Alternatively, two non-adjacent R dd Both are C 1-6 Forming an alkylene, alternatively C 1-4 Forming an alkylene, alternatively C 1-3 Forms alkylene, which is H, D, halogen, CN, C 1-6 Alkyl and C 1-6 optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl;

[0685] Or, two adjacent R dd together with the atoms to which they are attached form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene, which is selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, -OR', and -NR'R'';

[0686] R d7 and R' d7 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0687] The remaining variables are as defined herein;

[0688] wherein each of the above groups may be deuterated up to fully deuterated.

[0689] In a more specific embodiment, the present disclosure 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, [ka]

[0690] During the ceremony,

[0691] R E is as defined herein;

[0692] X1 is a CR e6 , N, O, S or NR' e6 and;

[0693] X2 is C or N;

[0694] X3 is C or N;

[0695] X4 is CR e4 or N;

[0696] X5 is CR e5 , N, O, S or NR' e5 and;

[0697] X6 is C or N;

[0698] X7 is CR e1 or N;

[0699] X8 is CR e2 or N;

[0700] X9 is CR e3 or N;

[0701] R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl;

[0702] R e3 , R e4 , R e5 and R e6 are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl;

[0703] R' e5 and R' e6 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0704] R 1a and R 1b are independently H, D, halogen, C 1-6 Alkyl or C 1-6 is haloalkyl;

[0705] Z1 is CR d1 and N;

[0706] Z2 is CR d2 and N;

[0707] The Z4 is a CR d4 and N;

[0708] The Z5 is a CR d5 and N;

[0709] R d1 H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl;

[0710] R d2 , R d4 and R d5 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl;

[0711] R d3 teeth, [ka] and -NR' d6 C(O)R d6 Selected from;

[0712] a and b are independently 0, 1, 2, or 3, alternatively a+b≦5;

[0713] L' is independently C 1-6 Alkyl and C 1-6 a covalent bond and C optionally substituted with 1, 2, 3 or 4 groups selected from haloalkyl 1-6 alkylene;

[0714] Y1 and Y2 are independently CR dd R dd , O, S and NR' dd or when Y1 is connected to L', Y1 is selected from CR dd or N;

[0715] Rdd are independently H, D, oxo, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl;

[0716] Alternatively, two non-adjacent R dd Both are C 1-4 Form an alkylene, or R' dd and non-adjacent R dd Both are C 1-4 Form an alkylene, or two R' dd Both are C 1-4 Form an alkylene, wherein the C 1-4 Alkylene is H, D, halogen, CN, C 1-6 Alkyl and C 1-6 optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl;

[0717] R' dd are independently H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl;

[0718] n=0, 1, 2, 3, or 4;

[0719] R d6 is 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 and -L''-Y3-C 1-6 alkylene-R4;

[0720] L″ independently represents a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R.1-6 alkylene; R is independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -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;

[0721] L d are independently a covalent bond and C 1-6 alkylene, and alternatively a covalent bond and C 1-4 alkylene;

[0722] Y3 is selected from O, S and NR3;

[0723] R' d6 and R3 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0724] R4 is selected from -OR', -SR' and -NR'R'';

[0725] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d - selected from 3- to 7-membered heterocyclyl;

[0726] wherein each of the above groups may be deuterated up to fully deuterated.

[0727] Y1 or Y2 is CR dd R dd and R dd When one of R is oxo, the other R dd It should be understood that there should be no

[0728] In a more specific embodiment, the present disclosure 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,

[0729] In the formula, R E is as defined herein;

[0730] X1 is a CR e6 , N or NR' e6 , alternatively N;

[0731] X2 is C or N;

[0732] X3 is C or N;

[0733] X4 is CR e4 or N;

[0734] X5 is CR e5 , N or NR' e5 , alternatively CR e5 or N;

[0735] X6 is C or N, alternatively C;

[0736] X7 is CR e1 or N;

[0737] X8 is CR e2 or N;

[0738] X9 is CR e3 or N;

[0739] R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C1-6 Alkyl, C 1-6 selected from haloalkyl, -OR' and -NR'R'';

[0740] R e3 , R e4 , R e5 and R e6 are independently H, D, halogen, C 1-6 Alkyl or C 1-6 is haloalkyl;

[0741] R' e5 and R' e6 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0742] R 1a and R 1b independently, C 1-6 Alkyl or C 1-6 is haloalkyl;

[0743] Z1 is CR d1 and N, alternatively CR d1 and;

[0744] Z2 is CR d2 and N;

[0745] The Z4 is a CR d4 and N;

[0746] The Z5 is a CR d5 and N, alternatively CR d5 and;

[0747] R d1 , R d2 , R d4 and R d5 are independently H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl;

[0748] Rd3 teeth, [ka] and -NR' d6 C(O)R d6 Selected from;

[0749] a and b are independently 0, 1, or 2; alternatively, a+b≦3;

[0750] L' is independently a covalent bond and C 1-4 alkylene;

[0751] Y1 is CR dd R dd or NR' dd or when Y1 is connected to L', Y1 is CH, CD or N;

[0752] Y2 is CR dd R dd , O or NR' dd Alternatively, at least one of Y1 and Y2 is a heteroatom group;

[0753] R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl;

[0754] Alternatively, two non-adjacent R dd Both are H, D, halogen, CN, C 1-6 Alkyl and C 1-6 C optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl 1-3 Forming alkylene;

[0755] R' dd are independently 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, and -L''-3 to 7-membered heterocyclyl; alternatively, H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl;

[0756] n=0, 1, 2, 3, or 4;

[0757] R d6 is C 1-6 Alkyl, C 1-6 Haloalkyl, -L''-3 to 7-membered carbocyclyl, -L''-3 to 7-membered heterocyclyl, and -L''-Y3-C 1-4 alkylene-R4, and alternatively -L''-Y3-C 1-4 alkylene-R4;

[0758] L″ independently represents a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R. 1-6 alkylene; R is independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene;

[0759] Y3 is selected from O and NR3;

[0760] R' d6 and R3 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0761] R4 is selected from -OR' and -NR'R'';

[0762] Each of R' and R'' is independently H, C 1-6 Alkyl, C1-6 It is selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl.

[0763] In some embodiments of the present disclosure, up to five of X1-X9 are heteroatoms, alternatively up to four are heteroatoms, and alternatively up to three are heteroatoms.

[0764] In some embodiments of the present disclosure, one of X2 and X3 is N and the other is C.

[0765] In some embodiments of the present disclosure, at most one of X4 and X7-X9 is N.

[0766] In some embodiments of the present disclosure, at most two of Z2, Z4 and Z5 are N, alternatively at most one is N.

[0767] In a more specific embodiment, the present disclosure 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, wherein R E is as defined herein;

[0768] X1 is N;

[0769] X2 is C or N;

[0770] X3 is C or N;

[0771] X4 is CR e4 or N, alternatively N;

[0772] X5 is CR e5 or N, alternatively CR e5 and;

[0773] X6 is C;

[0774] X7 is CR e1 or N, alternatively CR e1 and;

[0775] X8 is CR e2 or N, alternatively N;

[0776] X9 is CR e3 or N, alternatively CR e3 and;

[0777] R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR', -O-3 to 7-membered carbocyclyl and 3 to 7-membered heterocyclyl, alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -OR';

[0778] R e3 , R e4 and R e5 are independently H or D;

[0779] R' e5 is H, C 1-3 Alkyl and C 1-3 haloalkyl;

[0780] R 1a and R 1b independently, C 1-3 Alkyl or C 1-3 is haloalkyl;

[0781] Z1 is CR d1 and N, alternatively CR d1 and;

[0782] Z2 is CR d2 and N;

[0783] The Z4 is a CR d4and N;

[0784] The Z5 is a CR d5 and N, alternatively CR d5 and;

[0785] R d1 is H or D;

[0786] R d2 , R d4 and R d5 are independently H, D, halogen, C 1-3 Alkyl and C 1-3 haloalkyl; alternatively R d2 and R d5 are independently selected from H, D and halogen; alternatively, R d5 is H or D;

[0787] R d3 teeth, [ka] and -NR' d6 C(O)R d6 Alternatively, [ka] teeth [ka] , alternatively [ka] and;

[0788] a and b are independently 0, 1 or 2, alternatively a and b are 1;

[0789] L' is independently a covalent bond and C 1-2 alkylene, alternatively selected from a covalent bond and methylene;

[0790] Y1 is NR' dd , alternatively NH; or when Y1 is connected to L', Y1 is CH, CD or N;

[0791] Y2 is CR dd R dd , O or NR' dd and;

[0792] R dd are independently H, D, oxo, and C 1-6 Alkyl, C 1-6 haloalkyl, -L''-OR', -L''-NR'R'' and -L''-3 to 7 membered carbocyclyl, and alternatively H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR" and -L"-NR'R"; alternatively, H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -L''-OR'';

[0793] Alternatively, two non-adjacent R dd Both are C 1-2 Forming alkylene;

[0794] R' dd are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene -OR', -C 1-4 alkylene-NR'R'' and -L''-3 to 7 membered carbocyclyl, alternatively H, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -L''-3 to 7-membered carbocyclyl;

[0795] n=0, 1, 2, 3, or 4;

[0796] R d6 is C 1-6 Alkyl, C 1-6Haloalkyl, -L''-3 to 7-membered carbocyclyl and -L''-OC 1-4 alkylene -OR', and alternatively -L''-OC 1-4 alkylene-OR';

[0797] R' d6 is H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0798] L'' independently represents a covalent bond, C 1-4 alkylene and -C(R)-, alternatively a covalent bond and C 1-4 alkylene, where two R together with the C atom to which they are attached form a 3- to 5-membered carbocyclylene, or alternatively [ka] Forming;

[0799] Each of R' and R'' is independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0800] In some specific embodiments of the present disclosure, when Y is N and Y is O, L′ is a covalent bond and R dd is not oxo.

[0801] In some specific embodiments of the present disclosure, R e2 Ga-OC 1-6 If it is alkyl, R e2 is -OMe, alternatively, R e2 Ga-OC 1-6 When R is haloalkyl, e2 is -O-halomethyl.

[0802] In some specific embodiments of the present disclosure, R d2 and R d4At least one of is H or D, alternatively at least one is H.

[0803] In a more specific embodiment, the present disclosure 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, wherein R E is as defined herein;

[0804] X1 is N;

[0805] X2 is C or N;

[0806] X3 is C or N;

[0807] X4 is CR e4 or N, alternatively N;

[0808] X5 is CR e5 or N, alternatively CR e5 and;

[0809] X6 is C;

[0810] X7 is CR e1 or N, alternatively CR e1 and;

[0811] X8 is CR e2 or N, alternatively N;

[0812] X9 is CR e3 or N, alternatively CR e3 and;

[0813] R e1 and R e2 are independently H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and [ka] and optionally selected from H, F, Cl, CN, Me, CHF2, OCH3 and OEt; and optionally selected from R e2 is not OEt;

[0814] R e3 , R e4 and R e5 is H;

[0815] R' e5 is Me;

[0816] R 1a and R 1b are independently Me or Et;

[0817] Z1 is CR d1 and N, alternatively CR d1 and;

[0818] Z2 is CR d2 and N;

[0819] The Z4 is a CR d4 and N;

[0820] The Z5 is a CR d5 and N, alternatively CR d5 and;

[0821] R d1 is H;

[0822] R d2 , R d4 and R d5 are independently selected from H, F, Me and CHF2, alternatively R d2 and R d5 are independently selected from H and F, alternatively R d5 is H;

[0823] R d3 teeth, [ka] and -NR' d6 C(O)R d6 and alternatively selected from [ka] and;

[0824] a is 1 or 2 and b is 1;

[0825] L' is independently selected from a covalent bond and methylene, alternatively a covalent bond;

[0826] Y1 is NH, CH or N, alternatively CH or N, alternatively N;

[0827] Y2 is CR dd R dd , O or NR' dd , alternatively O;

[0828] R dd are independently H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, [ka] and -NHMe, alternatively H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe or -NHMe;

[0829] Alternatively, two non-adjacent R dd together form -CH2CH2-, alternatively [ka] has the following structure: [ka]

[0830] R' ddis independently selected from H, Me, and —CH2-cyclopropyl;

[0831] n=0, 1 or 2;

[0832] R d6 is selected from -CH2-cyclopropyl and -CH2-O-CH2CH2-OH, alternatively -CH2-cyclopropyl;

[0833] R' d6 is H.

[0834] In some specific embodiments of the present disclosure, R d3 teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] is.

[0835] In some specific embodiments of the present disclosure, R d3 teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] is selected from.

[0836] In some specific embodiments of the present disclosure, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] Instead, [ka] is selected from.

[0837] In a more specific embodiment, the present disclosure 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, [ka]

[0838] During the ceremony,

[0839] R E is as defined herein;

[0840] X5 is CR e5 , N, O, S or NR' e5 , alternatively CR e5, O, N or NR' e5 , alternatively CR e5 or N;

[0841] X7 is CR e1 or N;

[0842] X8 is CR e2 or N;

[0843] R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl and -L'-3 to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, each of which is selected from 1, 2, or 3 R es may be substituted with;

[0844] R es are independently H, D, halogen, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -OR' and -NR'R'';

[0845] R e5 H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0846] Z1 is CR d1 and N, alternatively CR d1and;

[0847] Z2 is CR d2 and N;

[0848] The Z4 is a CR d4 and N;

[0849] The Z5 is a CR d5 and N, alternatively CR d5 and;

[0850] R d1 H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl;

[0851] R d2 , R d4 and R d5 are independently 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 and -L'-3 to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R''; alternatively, R d2 and R d5 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[0852] R d3 teeth, [ka] , -NR' d6 C(O)R d6 and -C(O)NR d7 R' d7 Selected from;

[0853] a and b are independently 0, 1, 2 or 3, alternatively 0, 1 or 2; alternatively a+b≦5, alternatively a+b≦3;

[0854] L' is independently a covalent bond and C 1-6 alkylene, and alternatively a covalent bond and C 1-4 alkylene, each of which is selected from C 1-6 Alkyl and C 1-6 optionally substituted with 1, 2, 3, or 4 groups selected from haloalkyl;

[0855] Y1 is CR dd R dd or NR' dd or if Y1 is connected to L', Y1 is CR dd or N;

[0856] Y2 is CR dd R dd , O, S, S(O), NR' dd and S(O)2, alternatively selected from CR dd R dd , O, NR' dd and S(O)2; alternatively, at least one of Y1 and Y2 is a heteroatom group;

[0857] R dd are independently 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 and -L''-3 to 7-membered heterocyclyl, and alternatively H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl;

[0858] Or, CR dd Rdd H, D, halogen, C 1-6 Alkyl, C 1-6 forming a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene optionally substituted by 1, 2, or 3 groups selected from haloalkyl, —OR′, and —NR′R″;

[0859] Alternatively, two non-adjacent R dd Both are H, D, halogen, CN, C 1-6 Alkyl and C 1-6 C optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl 1-3 Forming alkylene;

[0860] R' dd are independently H, C 1-6 Alkyl, C 1-6 haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl and -L''-3 to 7-membered heterocyclyl; alternatively, H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl;

[0861] Alternatively, R' dd and adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene, which is selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, -OR', and -NR'R'';

[0862] R d7 and R' d7 is H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0863] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d -3 to 7 membered heterocyclyl, alternatively H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl;

[0864] L d are independently a covalent bond and C 1-6 alkylene, and alternatively a covalent bond and C 1-4 alkylene;

[0865] The remaining variables are as defined herein;

[0866] wherein each of the above groups may be deuterated up to fully deuterated.

[0867] In a more specific embodiment, the present disclosure 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, wherein R E is as defined herein;

[0868] X5 is CR e5 or N, alternatively CR e5 and;

[0869] X7 is CR e1 or N, alternatively CR e1 and;

[0870] X8 is CR e2 or N, alternatively N;

[0871] R e1 and R e2 are independently H, D, halogen, CN, C1-6 Alkyl, C 1-6 Haloalkyl, 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, alternatively not -NR'R'', alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, —OR′, —O-3 to 7-membered carbocyclyl, 3 to 7-membered carbocyclyl, and 3 to 7-membered heterocyclyl, each of which is selected from 1, 2, or 3 R es Alternatively, R e1 is not heterocyclyl;

[0872] R es are independently H, D, halogen, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -OR', alternatively selected from H, D, F, Me and OH;

[0873] R e5 H, D, halogen, C 1-4 Alkyl and C 1-4 haloalkyl, alternatively H or D;

[0874] Z1 is CR d1 and N, alternatively CR d1 and;

[0875] Z2 is CR d2 and N;

[0876] The Z4 is a CR d4 and N;

[0877] The Z5 is a CR d5 and N, alternatively CR d5 and;

[0878] Rd1 is H or D;

[0879] R d2 , R d4 and R d5 are independently H, D, halogen, CN, C 1-4 Alkyl, C 1-4 haloalkyl and -OR'; alternatively, R d2 and R d5 are independently selected from H, D and halogen; alternatively, R d2 , R d4 and R d5 is H or D;

[0880] R d3 teeth, [ka] and -NR' d6 C(O)R d6 Alternatively, [ka] teeth [ka] , alternatively [ka] and;

[0881] a and b are independently 0, 1 or 2, alternatively a and b are 1;

[0882] L' is independently a covalent bond and C 1-2 alkylene, alternatively selected from a covalent bond and methylene;

[0883] Y1 is NR' dd or if Y1 is connected to L', Y1 is CR dd or N;

[0884] Y2 is CR dd R dd , O, NR' dd and S(O)2;

[0885] R dd are independently H, D, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L''-OR', -L''-NR'R'' and -L''-3 to 7 membered carbocyclyl, and alternatively H, D, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -L"-OR" and NR"R", and alternatively H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -L''-OR'';

[0886] Or, CR dd R dd forms a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, which is optionally substituted by one -OR', or alternatively by one OH;

[0887] Alternatively, two non-adjacent R dd Both are C 1-2 Forming alkylene;

[0888] R' dd are independently H, C 1-6 Alkyl, C 1-6 haloalkyl and -L''-3 to 7-membered carbocyclyl;

[0889] Alternatively, R' dd and adjacent R dd together with the atom to which they are attached form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene, which is free of H, D, halogen, C 1-6 Alkyl and C 1-6optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl;

[0890] L″ independently represents a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R. 1-4 alkylene; R is independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene, alternatively a 3- to 5-membered carbocyclylene, alternatively [ka] Forming;

[0891] Each of R' and R'' is independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0892] The remaining variables are as defined herein;

[0893] Alternatively, when Y1 is N and Y2 is O, L' is a covalent bond and R dd is not oxo;

[0894] Alternatively, R e2 Ga-OC 1-6 If it is alkyl, R e2 is -OMe, alternatively, R e2 Ga-OC 1-6 When R is haloalkyl, e2 is -O-halomethyl;

[0895] Alternatively,

[0896] R e1 H, D, halogen, CN, C 1-6 Alkyl, C 1-6selected from 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, alternatively not -NR'R'' or 3- to 7-membered heterocyclyl, alternatively 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; R e1 is one, two or three R es may be substituted with;

[0897] R e2 H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, -OR', -O-3 to 7-membered heterocyclyl, 3 to 7-membered carbocyclyl and 3 to 7-membered heterocyclyl, and alternatively H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl, -OMe, -O-halomethyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; R e2 is one, two or three R es may be substituted with;

[0898] Alternatively, R e2 When is heterocyclyl, R es are independently H, D, halogen (F), C 1-6 Alkyl and C 1-6 haloalkyl, alternatively selected from H, D, F and Me, alternatively halogen (F).

[0899] In a more specific embodiment, the present disclosure 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, wherein R E is as defined herein;

[0900] X5 is CR e5 or N, alternatively CR e5 and;

[0901] X7 is CR e1 or N, alternatively CR e1 and;

[0902] X8 is CR e2 or N, alternatively N;

[0903] R e1 and R e2 are independently H, F, Cl, CN, Me, Et, n-Bu, CHF2, [ka] , OH, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, [ka] , cyclopropyl, [ka] Alternatively, H, F, Cl, CN, Me, Et, n-Bu, CHF2, [ka] , OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, [ka] , cyclopropyl, [ka] and alternatively selected from [ka] Instead, alternatively, H, F, Cl, CN, Me, Et, CHF2, [ka] , OCH3, OEt, OCHF2, -O-cyclopropyl, cyclopropyl, [ka] Alternatively, R e1 teeth [ka] Alternatively, R e2 is not OEt;

[0904] R e5 is selected from H, D, F, Br and Me, alternatively H;

[0905] Z1 is CR d1 and N, alternatively CR d1 and;

[0906] Z2 is CR d2 and N;

[0907] The Z4 is a CR d4 and N;

[0908] The Z5 is a CR d5 and N, alternatively CR d5 and;

[0909] R d1 is H;

[0910] R d2 , R d4 and R d5 are independently selected from H, F, CN, Me, CHF2 and OCH3; alternatively, R d2 and R d5 are independently selected from H and F; alternatively, R d2 , R d4 and R d5 is H;

[0911] R d3 teeth, [ka] and -NR' d6 C(O)R d6 and alternatively selected from [ka] and;

[0912] a is 0, 1 or 2, alternatively 0 or 1, and b is 0 or 1;

[0913] L' is independently selected from a covalent bond and methylene, alternatively a covalent bond;

[0914] Y1 is NH; or when Y1 is connected to L', Y1 is selected from CH, C(OH) and N, alternatively CH and N, alternatively N;

[0915] Y2 is CR dd R dd , O, NR' dd and S(O)2, alternatively selected from CR dd R dd , O and NR' dd is selected from, alternatively O;

[0916] R dd are independently H, F, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, [ka] and -NHMe, alternatively selected from H, oxo, OH, Me, -C(CH3)2OH, -CH2OH, -CH2OMe, [ka] and -NHMe, alternatively selected from H, OH, Me, -C(CH3)2OH, -CH2OMe and [ka] Select from;

[0917] Or, CR dd R dd is cyclopropylene, [ka] and alternatively cyclopropylene or [ka] or alternatively forms cyclopropylene;

[0918] Alternatively, two non-adjacent R dd together form -CH2CH2-;

[0919] R' dd is independently selected from H, Me, and -CH2-cyclopropyl;

[0920] Alternatively, R' dd and adjacent R dd along with the atoms to which they are attached, [ka] Alternatively, [ka] Forming;

[0921] The remaining variables are as defined herein;

[0922] Alternatively,

[0923] R e1are H, F, Cl, CN, Me, Et, n-Bu, CHF2, OCH3, OEt, OCHF2, -NHCH3, -O-cyclopropyl, [ka] , cyclopropyl, [ka] Alternatively, H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl, [ka] and cyclopropyl, alternatively selected from H, F, CN, Me, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and cyclopropyl;

[0924] R e2 are H, F, Cl, CN, Me, CHF2, [ka] , OCH3, OEt, OCHF2, [ka] , cyclopropyl, [ka] Alternatively, H, F, Cl, CN, Me, CHF2, [ka] , OCH3, OCHF2, cyclopropyl, [ka] is selected from.

[0925] Alternatively,

[0926] Rd3 teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] is.

[0927] Alternatively,

[0928] R d3 teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] is selected from.

[0929] Alternatively, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] is selected from.

[0930] In a more specific embodiment, the present disclosure provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein [ka]

[0931] During the ceremony,

[0932] X1 is a CR e6 , O, S, N and NR' e6 Selected from;

[0933] X5 is CR e5 , N, O, S or NR' e5 and;

[0934] X6 is C or N;

[0935] X 10 is CR e7 , O, S, N and NR' e7 Selected from;

[0936] X 11 is CR e8 , O, S, N and NR' e8 Selected from;

[0937] R e7 and R e8 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl;

[0938] R' e7 and R' e8 are independently H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl;

[0939] Or X 10 and X 11 Both of the substituents may contain one double bond. 3-5 Forming alkylene, C 3-5 Alkylene can be one, two, three or four R e and the above C 3-5 one, two, or three methylene units in the alkylene may be independently replaced by -NR''-, -N(R'')C(O)-, -C(O)N(R'')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, or -S(O)-;

[0940] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d - selected from 3- to 7-membered heterocyclyl;

[0941] L' is independently C 1-6 Alkyl and C 1-6 a covalent bond optionally substituted with 1, 2, 3 or 4 groups selected from haloalkyl and C 1-6 alkylene;

[0942] L d are independently a covalent bond and C 1-6 alkylene, and alternatively a covalent bond and C 1-4alkylene;

[0943] R e is as defined herein, alternatively R e is not alkenyl or alkynyl;

[0944] R e5 , R' e5 , R e6 and R' e6 each of which is as defined herein;

[0945] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein;

[0946] wherein each of the above groups may be deuterated up to fully deuterated.

[0947] In a more specific embodiment, the present disclosure provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0948] X1 is a CR e6 , N and NR' e6 is selected from, alternatively N;

[0949] X5 is CR e5 , N or NR' e5 and;

[0950] X6 is C or N, alternatively C;

[0951] X 10 is CR e7 , N and NR' e7 Selected from;

[0952] X 11 is CR e8, O, N and NR' e8 Selected from;

[0953] R e7 H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl;

[0954] R' e7 H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl;

[0955] R e8 H, D, C 1-6 Alkyl and C 1-6 haloalkyl;

[0956] R' e8 is H, C 1-6 Alkyl and C 1-6 selected from haloalkyl;

[0957] Or X 10 and X 11 The substituents of both are C 3-5 alkylene, alternatively -(CH2)4-, which may contain one double bond, 3-5 Alkylene or -(CH2)4- can be one, two, three or four R e and the above C 3-5 One, two or three methylene units in alkylene or -(CH2)4- may be independently replaced by -NR''-, -C(O)N(R'')-, -C(O)-, or -O-, and alternatively, the above C 3-5 One methylene unit in alkylene or -(CH2)4- may be independently replaced with -O-;

[0958] Each of R' and R'' is independently H, C 1-6 Alkyl, C1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl;

[0959] R e is as defined herein, alternatively R e is not alkenyl or alkynyl;

[0960] R e5 , R' e5 , R e6 and R' e6 each of which is as defined herein;

[0961] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein.

[0962] In some specific embodiments of the present disclosure, X1, X5, X6, X 10 and X 11 Up to three of the atoms may be heteroatoms.

[0963] In a more specific embodiment, the present disclosure provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0964] X1 is N;

[0965] X5 is CR e5 , N or NR' e5 , alternatively CR e5 or N, or alternatively CR e5 and;

[0966] X6 is C or N, alternatively C;

[0967] X 10 is CR e7 or NR' e7 and;

[0968] X 11 is CR e8 , O and NR' e8 and alternatively selected from CR e8 or NR' e8 and;

[0969] R e7 is C 1-6 Alkyl, C 1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, and -O-3- to 7-membered heterocyclyl;

[0970] R' e7 is C 1-6 Alkyl, C 1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, alternatively 3- to 7-membered carbocyclyl;

[0971] R e8 H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively C 1-6 Alkyl or C 1-6 is haloalkyl;

[0972] R' e8 is C 1-6 Alkyl and C 1-6 selected from haloalkyl;

[0973] Or X 10 and X 11 The substituents of [ka] Alternatively, [ka] Instead of forming [ka] and alternatively forming a structure selected from [ka] Forming;

[0974] Each of R' and R'' is independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[0975] R e1 , R e2 , R e5 and R' e5 are as defined herein; alternatively, R e1 and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, —OR′, and —O-3 to 7-membered carbocyclyl; alternatively, H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -OR';

[0976] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein.

[0977] In some specific embodiments of the present disclosure, R e7 or R' e7 When is heterocyclyl, R e7 or R' e7 is a 3- to 7-membered oxacyclyl, alternatively a 4- to 6-membered oxacyclyl, alternatively a 5-membered oxacyclyl.

[0978] In a more specific embodiment, the present disclosure provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[0979] X1 is N;

[0980] X5 is CR e5 , N or NR' e5 , alternatively CR e5 or N, or alternatively CR e5 and;

[0981] X6 is C or N, alternatively C;

[0982] X 10 is CR e7 and NR' e7 Selected from;

[0983] X 11 is CR e8 , O and NR' e8 and alternatively selected from CR e8 or NR' e8 and;

[0984] R e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and -O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Selected from;

[0985] R' e7 is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and morpholinyl, alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and tetrahydropyranyl, alternatively selected from Me, Et, cyclopropyl and tetrahydrofuranyl, alternatively selected from Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] and is selected from Me, Et, cyclopropyl, and [ka] is selected from, alternatively cyclopropyl;

[0986] R e8 is selected from H, Me and Et, alternatively H or Me, alternatively Me;

[0987] R' e8 is Me or Et, alternatively Me;

[0988] Or X 10 and X 11 The substituents of [ka] Alternatively, [ka] Instead of forming [ka] and alternatively forming a structure selected from [ka] Forming;

[0989] R e1 and R e2 are independently H, F, Cl, CN, Me, Et, CHF2, OCH3, OEt, OCHF2, -O-cyclopropyl and [ka] , alternatively selected from H, F, CN, Me, OMe, OEt, OCHF2 and -O-cyclopropyl, alternatively selected from H, F, CN, Me, OCH3, OEt, OCHF2 and -O-cyclopropyl, alternatively selected from H, Me, OCH3 and OEt;

[0990] R e5 is H;

[0991] R' e5 is Me;

[0992] R″ is H or methyl;

[0993] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein.

[0994] In some specific embodiments of the present disclosure, X 10 and X 11 The substituents of [ka] Alternatively, a structure selected from [ka] Alternatively, a structure selected from [ka] Alternatively, a structure selected from [ka] forming a structure selected from:

[0995] In some specific embodiments of the present disclosure, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] is selected from.

[0996] In some specific embodiments of the present disclosure, R dd are independently selected from H, Me, and —C(CH3)2OH, or two non-adjacent R dd together form -CH2CH2-, alternatively [ka] has the following structure: [ka]

[0997] Alternatively, R d3teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] is.

[0998] In a more specific embodiment, the present disclosure provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein [ka]

[0999] During the ceremony,

[1000] X 10 is CR e7 or NR' e7 and;

[1001] X 11 is CR e8 , O and NR' e8 and alternatively CR e8 or NR' e8 and;

[1002] R e7 is 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; alternatively, R e7 is C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 7-membered carbocyclyl, tetrahydrofuranyl, morpholinyl, and —O-3- to 7-membered heterocyclyl; alternatively, R e7is a 3- to 7-membered carbocyclyl;

[1003] R' e7 is C 1-6 Alkyl, C 1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, alternatively 3- to 7-membered carbocyclyl;

[1004] R e8 H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively C 1-6 Alkyl or C 1-6 is haloalkyl;

[1005] R' e8 is C 1-6 Alkyl and C 1-6 selected from haloalkyl;

[1006] Or X 10 and X 11 The substituents of [ka] Alternatively, [ka] Instead of forming [ka] forming a structure selected from: [ka] Forming;

[1007] R e1 and R e2 each is as defined herein, and R' e1 and R' e2 are as defined herein; alternatively, R e1and R e2 are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 is selected from haloalkyl, —OR′, —O-3 to 7-membered carbocyclyl, and —O-3 to 7-membered heterocyclyl, and is alternatively not halogen; alternatively is H, D, C 1-6 Alkyl, C 1-6 haloalkyl, —OR′, and —O-3 to 7-membered carbocyclyl; alternatively, R e2 H, D, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl and -OR'; alternatively, R e2 is H, D or C 1-6 is haloalkyl;

[1008] R' e1 and R' e2 are independently H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively selected from H, D, halogen and C 1-6 selected from alkyl;

[1009] Or, CR e1 R' e1 forms a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, alternatively a 3- to 7-membered heterocyclyl;

[1010] Each of R' and R'' is independently H, C 1-6 Alkyl and C 1-6 haloalkyl; alternatively, R″ is C 1-4 is haloalkyl;

[1011] The remaining variables are as defined herein;

[1012] wherein each of the above groups may be deuterated up to fully deuterated.

[1013] In a more specific embodiment, the present disclosure provides a compound of formula (VI-2) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[1014] X 10 is CR e7 and NR' e7 Selected from;

[1015] X 11 is CR e8 , O and NR' e8 and alternatively selected from CR e8 or NR' e8 and;

[1016] R e7 is Me, Et, cyclopropyl, [ka] Alternatively, Me, Et, cyclopropyl, [ka] is selected from, alternatively cyclopropyl;

[1017] R' e7 is selected from Me, Et and cyclopropyl, alternatively cyclopropyl;

[1018] R e8 is selected from H, Me and Et, alternatively H or Me, alternatively Me;

[1019] R' e8 is Me or Et, alternatively Me;

[1020] Or X 10 and X 11 The substituents of [ka] Alternatively, [ka] Instead of forming [ka] and alternatively forming a structure selected from [ka] Forming;

[1021] R e1 and R e2 are independently H, F, CN, Me, CHF2, OH, OMe, OEt, OCHF2, -O-cyclopropyl and [ka] and is selected from H, CN, Me, CHF2, OH, OCH3, OEt, -O-cyclopropyl, and [ka] and optionally selected from H, Me, CHF2, OCH3, OEt, and -O-cyclopropyl; alternatively, R e2 is selected from H, F, CN, Me, CHF2, OH and OMe; alternatively, R e2 is H or CHF2;

[1022] R' e1 and R' e2 is independently selected from H, F and Me;

[1023] Or, CR e1 R' e1 teeth [ka] Forming;

[1024] R″ is selected from H, methyl and CHF2, alternatively CHF2;

[1025] The remaining variables are as defined herein.

[1026] Alternatively,

[1027] X 10 and X 11 The substituents of [ka] Alternatively, a structure selected from [ka] Alternatively, a structure selected from [ka] forming a structure selected from:

[1028] Alternatively, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] Selected from;

[1029] Alternatively, Y1 is CH or N and Y2 is CR dd R dd and O;

[1030] R ddare independently selected from H, OH, Me, -CH2OMe, and -C(CH3)2OH, or two non-adjacent R dd together form -CH2CH2-;

[1031] Alternatively, R d3 teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] is.

[1032] In a more specific embodiment, the present disclosure provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein [ka]

[1033] During the ceremony,

[1034] E is CR e12 and N;

[1035] J is for CR e13 and N;

[1036] R e9 , R e10 , R e11 , R e12 and R e13 H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, -L'-3 to 7-membered heterocyclyl and -Y5-C 0-6 alkylene-R6;

[1037] Y5 is selected from O, S and NR5;

[1038] R5 is H, C 1-6 Alkyl and C 1-6 haloalkyl;

[1039] R6 is selected from 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl;

[1040] Alternatively, R e9 and R e13 may be one, two, three or four R e or form an optionally substituted 5- to 7-membered carbocyclyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl;

[1041] Alternatively, R e9 and R e10 may be one, two, three or four R e forming an optionally substituted 5- to 7-membered carbocyclyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl;

[1042] R e is as defined herein, alternatively R e is not alkenyl or alkynyl;

[1043] L' is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d - a covalent bond optionally substituted with 1, 2, 3 or 4 groups selected from 3- to 7-membered heterocyclyl and C 1-6alkylene;

[1044] L d are independently a covalent bond and C 1-6 alkylene, and alternatively a covalent bond and C 1-4 alkylene;

[1045] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -3- to 7-membered carbocyclyl and -L d - selected from 3- to 7-membered heterocyclyl;

[1046] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein;

[1047] wherein each of the above groups may be deuterated up to fully deuterated.

[1048] In a more specific embodiment, the present disclosure provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[1049] E is CR e12 and N;

[1050] J is for CR e13 and N;

[1051] R e9 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR', -NR'R'', 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl and -Y5-C 0-6alkylene-R6, alternatively H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -OR' and -NR'R'';

[1052] Y5 is selected from O and NR5;

[1053] R5 is H, C 1-6 Alkyl and C 1-6 haloalkyl;

[1054] R6 is selected from 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl;

[1055] R e10 H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl;

[1056] R e11 , R e12 and R e13 H, D, C 1-6 Alkyl or C 1-6 Is it a haloalkyl?

[1057] Alternatively, R e9 and R e13 may be one, two, three or four R e or form an optionally substituted 5- to 7-membered carbocyclyl or 5- to 7-membered heterocyclyl;

[1058] Alternatively, R e9 and R e10 may be one, two, three or four R e forming an optionally substituted 5- to 7-membered carbocyclyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl;

[1059] R eis as defined herein, alternatively R e is not alkenyl or alkynyl;

[1060] Each of R' and R'' is independently H, C 1-6 Alkyl, C 1-6 selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl;

[1061] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein.

[1062] In some specific embodiments of the present disclosure, at least one of E and J is N; alternatively, only one of E and J is N.

[1063] In a more specific embodiment, the present disclosure provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[1064] E is CR e12 and N;

[1065] J is for CR e13 and N;

[1066] R e9 H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 Alkynyl, -NR'R'', 3- to 7-membered heterocyclyl and -OC 0-4 alkylene-3 to 7 membered heterocyclyl, alternatively H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 selected from alkynyl and -NR'R'';

[1067] Re10 H, D, C 1-6 Alkyl and C 1-6 haloalkyl;

[1068] R e11 , R e12 and R e13 is H or D;

[1069] Alternatively, R e9 and R e13 together with the carbon atoms to which they are attached form a 5- to 7-membered heterocyclyl, alternatively a dihydrooxazinyl, which is a 5- to 7-membered heterocyclyl having 1, 2, 3, or 4 R e may be substituted with;

[1070] Alternatively, R e9 and R e10 together with the carbon atoms to which they are attached form a 5- to 7-membered carbocyclyl, a 5- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl, alternatively a 5- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, alternatively a dihydrooxazinyl or a 5-membered azaaryl, which may be substituted with 1, 2, 3, or 4 R e may be substituted with;

[1071] R e is as defined herein, alternatively R e is not alkenyl or alkynyl; alternatively, R e are independently H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, -OR' and -NR'R'', and alternatively H, D, C 1-6 Alkyl, C 1-6 selected from haloalkyl and -OR', alternatively selected from Me and OMe;

[1072] Each of R' and R'' is independently H, C 1-6 Alkyl and C 1-6 haloalkyl;

[1073] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein.

[1074] In some specific embodiments of the present disclosure, R e are independently H, D, C 1-6 Alkyl and C 1-6 haloalkyl, alternatively H or Me.

[1075] In a more specific embodiment, the present disclosure provides a compound of formula (VI-3) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein:

[1076] E is CR e12 and N;

[1077] J is for CR e13 and N;

[1078] R e9 -H, -NHMe, [ka] and is selected from H, -NHMe, and [ka] Selected from;

[1079] R e10 is selected from H and Me;

[1080] R e11 , R e12 and R e13 Is H;

[1081] Alternatively, R e9 and R e13 along with the carbon atoms to which they are attached, [ka] or form;

[1082] Alternatively, R e9 and R e10 along with the carbon atoms to which they are attached, [ka] Alternatively, [ka] Alternatively, [ka] Alternatively, [ka] Forming;

[1083] R 1a , R 1b , Z1, Z2, Z4, Z5 and R d3 each of which is as defined herein.

[1084] In some specific embodiments of the present disclosure, [ka] teeth, [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] and alternatively selected from [ka] is.

[1085] In a more specific embodiment, the present disclosure provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[1086] In a more specific embodiment, the present disclosure provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, selected from: [ka] [ka]

[1087] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[1088] In one embodiment, the present disclosure relates to the use of a compound of the present disclosure, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition comprising same, in the manufacture of a medicament for the prevention and / or treatment of an HPK1-mediated disorder, disease, or condition.

[1089] In one embodiment, the present disclosure relates to a compound of the present disclosure, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition comprising same, for use in the prevention and / or treatment of an HPK1-mediated disorder, disease, or condition.

[1090] In one embodiment, the present disclosure relates to a method of preventing and / or treating an HPK1-mediated disorder, disease, or condition, comprising administering to a subject a compound of the present disclosure, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition comprising same.

[1091] Further, the disorder, disease or condition is a proliferative disorder.

[1092] Further, the proliferative disorder is cancer.

[1093] Furthermore, the above-mentioned proliferative disorders are associated with one or more activating mutations in HPK1.

[1094] In one embodiment, the disorder, disease or condition is a chronic viral infection.

[1095] In one embodiment, the present disclosure relates to the use of a compound of the present disclosure, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition comprising same, in the manufacture of a medicament for increasing the efficacy of vaccination.

[1096] In one embodiment, the present disclosure relates to a compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition comprising same, for use in increasing the efficacy of vaccination.

[1097] In one embodiment, the present disclosure relates to a method of increasing the efficacy of vaccination comprising administering to a subject a compound of the present disclosure, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition comprising same.

[1098] Pharmaceutical Compositions and Kits

[1099] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as an "active ingredient") and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[1100] Pharmaceutically acceptable carrier, adjuvant or vehicle for use in the present disclosure refers to non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is formulated together.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present disclosure includes but is not limited to ion exchanger, alumina, aluminum stearate, lecithin, serum protein (for example, human serum albumin), buffer substance (for example, phosphate), glycine, sorbic acid, potassium sorbate, mixture of partial glycerides of saturated vegetable fatty acids, water, salt or electrolyte (for example, protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

[1101] Suitable formulations for administering the compounds of the present disclosure will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (particularly solutions for injection (subcutaneous, intravenous, or intramuscular) and infusion (injection)), elixirs, syrups, wafers, emulsions, inhalants, or dispersible powders. If necessary, the indicated dose may be administered several times per day.

[1102] The present disclosure also includes kits (e.g., pharmaceutical packs). The provided kits may include a compound disclosed herein, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound disclosed herein or another therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound disclosed herein and / or another therapeutic agent. In some embodiments, the compound disclosed herein provided in the first container and the other therapeutic agent provided in the second container are combined to form a unit dosage form.

[1103] use

[1104] The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more kinases. In some embodiments, the kinase inhibited by the compounds and methods of the present disclosure is HPK1.

[1105] The compounds disclosed herein can be used to inhibit the activity of HPK1. 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), causing activation of MAPK Jnk, thereby exerting the function of MAP4K.

[1106] 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 disclosure.

[1107] In some embodiments, the presently disclosed subject matter relates to a method of enhancing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure. In some aspects of this embodiment, the subject's T cells exhibit at least one of enhanced stimulation, enhanced activation, enhanced migration, enhanced proliferation, improved survival, and enhanced cytolytic activity compared to before administration of the compound or pharmaceutical composition. In some aspects of this embodiment, T cell activation is characterized by an increased incidence of γ-IFN+CD8 T cells or enhanced production of IL-2 or granzyme B by T cells compared to before administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the number of T cells is increased compared to before administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the T cells are antigen-specific CD8 T cells. In some aspects of this embodiment, the subject's antigen-presenting cells exhibit enhanced maturation and activation compared to before 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 the antigen-presenting cells is characterized by an increas...

Claims

1. A compound of formula (I') or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: 【Chemical 1】 During the ceremony, V is a covalent bond, O, S, NR', S(O), S(O) ２ , C(O), CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; W is NR', S(O), S(O) ２ , C(O), CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; Z ７ Is C; Alternatively, V is not connected to W, and Z ７ is C or N, and W is H, C １－６ Alkyl and C １－６ haloalkyl, alternatively H and C １－６ alkyl; V is absent, H, D, halogen, C １－８ Alkyl and C １－８ haloalkyl, alternatively selected from absent, H, D and halogen; Q and Y are independently a covalent bond, —O—, —S—, or —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)— and —N(R Ａ ) S (O) ２ -; Q and Y are not simultaneously a covalent bond; Alternatively, Q and Y are independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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) ２ N (R Ａ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; R Ａ is H, C １－８ Alkyl, C １－８ Alkoxy, C １－８ Haloalkyl, -L″-C ６－１０ selected from aryl, -L''-3- to 14-membered carbocyclyl, -L''-3- to 14-membered heterocyclyl, and -L''-5- to 14-membered heteroaryl; R Ｂ is H, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; R Ｃ , R' Ｃ , R １ａ and R １ｂ are independently H, D, halogen, —CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; Z １ and Z ６ One of them is CR Ｅ and the other is CR ｄ１ or N; R Ｅ Is -L-C ６－１０ aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl, wherein ６－１０ Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R ｅ optionally substituted with a group; R ｅ are independently one, two or three R ｅｓ H, D, halogen, —CN, oxo, C １－８ Alkyl, C １－８ Haloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -L'-OR', -L'-NR'R'', -NO ２ , -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O) ２ R', -L'-S(O) ２ NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-C ６－１０ selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl; Or, two geminal R ｅ may be one, two or three R's together with the atoms to which they are attached. ｅｓ forming an optionally substituted 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl; R ｅｓ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L'-OR' and -L'-NR'R''; R ｄ１ is H, D, halogen, -CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; Ring A is C ６－１０ selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring; R ｄ are independently H, D, halogen, —CN, —L′-S(O) ０－２ R', -L'-S(O) ２ is selected from -NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R ｄ are 1, 2, 3, 4, 5, 6, 7 or 8 R ｄｄ C optionally substituted with １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ haloalkyl, -L'-C ６－１０ selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl; Alternatively, two adjacent R ｄ together with the atoms to which they are attached 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 selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, halogen, —CN, or —NO ２ , 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) ２ NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-C ６－１０ selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl; Or, CR ｄｄ R ｄｄ H, D, halogen, C １－６ Alkyl, C １－６ forming a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene optionally substituted by 1, 2, or 3 groups selected from haloalkyl, —OR′, and —NR′R″; Alternatively, two non-adjacent R ｄｄ are both selected from the following substituents: H, D, halogen, CN, C １－８ Alkyl, C １－８ Alkoxy, C １－８ Haloalkyl, -L″-C ６－１０ C optionally substituted with one or more of aryl, -L''-3 to 10-membered carbocyclyl, -L''-3 to 10-membered heterocyclyl, and -L''-5 to 10-membered heteroaryl １－８ Forming an alkylene; Alternatively, two adjacent R ｄｄ along with the atoms to which they are attached, H, D, halogens, CN, C １－６ Alkyl, C １－６ forming a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene, or a 5- to 6-membered heteroarylene optionally substituted by 1, 2, 3, or 4 substituents selected from haloalkyl, —OR′, and —NR′R″; L and L' are independently a covalent bond, -O-, -S-, -NR'-, or -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)- and -N(R')S(O) ２ -; or L or L' is selected from one or more methylene units independently selected from -C(R') ２ -, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O) ２ -, -S(O) ２ N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; R' and R'' are independently 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, and -L''-5 to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3 to 14-membered heterocyclyl; L″ is selected from a covalent bond, —O—, and —S—; or L″ is a C optionally substituted with one or more R. １－８ alkylene, １－８ One or more methylene units in the alkylene are independently —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) ２ may be replaced by -; R is independently H, D, C １－８ Alkyl, C １－８ Haloalkyl, -L ｄ -3 to 10-membered carbocyclyl and -L ｄ - selected from 3- to 10-membered heterocyclyl; or two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene; L ｄ are independently a covalent bond and C １－８ alkylene; f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein each of the above groups may be 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: 【Chemistry 2】 During the ceremony, V is a covalent bond, O, S, NR', S(O), S(O) ２ , C(O), CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; W is NR', S(O), S(O) ２ , C(O), CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; Q and Y are independently a covalent bond, —O—, —S—, or —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)— and —N(R Ａ ) S (O) ２ -; Q and Y are not simultaneously a covalent bond; Alternatively, Q and Y are independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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) ２ N (R Ａ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; R Ａ is H, C １－８ Alkyl, C １－８ Alkoxy, C １－８ Haloalkyl, -L″-C ６－１０ selected from aryl, -L''-3- to 14-membered carbocyclyl, -L''-3- to 14-membered heterocyclyl, and -L''-5- to 14-membered heteroaryl; R Ｂ is H, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; R Ｃ , R' Ｃ , R １ａ and R １ｂ are independently H, D, halogen, —CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; Z １ and Z ６ One of them is CR Ｅ and the other is CR ｄ１ or N; R Ｅ Is -L-C ６－１０ aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl, wherein ６－１０ Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R ｅ optionally substituted with a group; R ｅ are independently H, D, halogen, —CN, oxo, C １－８ Alkyl, C １－８ Haloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -L'-OR', -L'-NR'R'', -NO ２ , -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O) ２ R', -L'-S(O) ２ NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-C ６－１０ selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl; R ｄ１ is H, D, halogen, -CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; Ring A is C ６－１０ selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring; R ｄ are independently H, D, halogen, —CN, —L′-S(O) ０－２ R', -L'-S(O) ２ is selected from -NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R ｄ are 1, 2, 3, 4, 5, 6, 7 or 8 R ｄｄ C optionally substituted with １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ haloalkyl, -L'-C ６－１０ selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl; Alternatively, two adjacent R ｄ together with the atoms to which they are attached 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 selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, halogen, —CN, or —NO ２ , 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) ２ NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-C ６－１０ selected from aryl, -L''-3 to 14-membered carbocyclyl, -L''-3 to 14-membered heterocyclyl, and -L''-5 to 14-membered heteroaryl; Or, two R ｄｄ are both selected from the following substituents: H, D, halogen, CN, C １－８ Alkyl, C １－８ Alkoxy, C １－８ Haloalkyl, -L″-C ６－１０ C optionally substituted with one or more of aryl, -L''-3 to 10-membered carbocyclyl, -L''-3 to 10-membered heterocyclyl, and -L''-5 to 10-membered heteroaryl １－８ Forming an alkylene; L and L' are independently a covalent bond, -O-, -S-, -NR'-, or -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)- and -N(R')S(O) ２ -; or L or L' is selected from one or more methylene units independently selected from -C(R') ２ -, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O) ２ -, -S(O) ２ N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; R' and R'' are independently 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, and -L''-5 to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3 to 14-membered heterocyclyl; L″ is selected from a covalent bond, —O—, and —S—; or L″ is a C optionally substituted with one or more R. １－８ alkylene, １－８ One or more methylene units in the alkylene are independently —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) ２ may be replaced by -; R is independently H, D, C １－８ Alkyl, C １－８ Haloalkyl, -L ｄ -3 to 10-membered carbocyclyl and -L ｄ - selected from 3- to 10-membered heterocyclyl; or two R together with the C atom to which they are attached form a 3- to 10-membered carbocyclylene or a 3- to 10-membered heterocyclylene; L ｄ are independently a covalent bond and C １－８ alkylene; f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein each of the above groups may be 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: 【Chemistry 3】 During the ceremony, V is a covalent bond, O, S, NR', S(O), S(O) ２ , C(O), CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; W is NR', S(O), S(O) ２ , C(O), CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; Q and Y are independently a covalent bond, —O—, —S—, or —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)— and —N(R Ａ ) S (O) ２ -; Q and Y are not simultaneously a covalent bond; Alternatively, Q and Y are independently selected from the group consisting of one or more methylene units independently selected from the group consisting of -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) ２ N (R Ａ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; R Ａ is H, C １－８ Alkyl, C １－８ Alkoxy, C １－８ Haloalkyl, -L″-C ６－１０ selected from aryl, -L''-3- to 14-membered carbocyclyl, -L''-3- to 14-membered heterocyclyl, and -L''-5- to 14-membered heteroaryl; R Ｂ is H, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; R Ｃ , R' Ｃ , R １ａ and R １ｂ are independently H, D, halogen, —CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; Z １ and Z ６ One of them is CR Ｅ and the other is CR ｄ１ or N; R Ｅ Is -L-C ６－１０ aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl, wherein ６－１０ Each of aryl, 3- to 14-membered carbocyclyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R ｅ optionally substituted with a group; R ｅ are independently H, D, halogen, —CN, oxo, C １－８ Alkyl, C １－８ Haloalkyl, -L'-OR', -L'-NR'R'', -NO ２ , -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O) ２ R', -L'-S(O) ２ NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-C ６－１０ selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl; R ｄ１ is H, D, halogen, -CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, -L-OR', -L-NR'R'', -LC(O)NR'R'', -LC ６－１０ selected from aryl, -L-3- to 14-membered carbocyclyl, -L-3- to 14-membered heterocyclyl, and -L-5- to 14-membered heteroaryl; Ring A is C ６－１０ selected from an aromatic ring, a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, and a 5- to 14-membered heteroaromatic ring; R ｄ are independently H, D, halogen, —CN, —L′-S(O) ０－２ R', -L'-S(O) ２ is selected from -NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R ｄ are 1, 2, 3, 4, 5, 6, 7 or 8 R ｄｄ C optionally substituted with １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ haloalkyl, -L'-C ６－１０ selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl; Alternatively, two adjacent R ｄ together with the atoms to which they are attached 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 selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, halogen, —CN, or —NO ２ , 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) ２ NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-C ６－１０ selected from aryl, -L''-3- to 14-membered carbocyclyl, -L''-3- to 14-membered heterocyclyl, and -L''-5- to 14-membered heteroaryl; L and L' are independently a covalent bond, -O-, -S-, -NR'-, or -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)- and -N(R')S(O) ２ -; or L or L' is selected from one or more methylene units independently selected from -C(R') ２ -, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O) ２ -, -S(O) ２ N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; R' and R'' are independently 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, and -L''-5 to 14-membered heteroaryl; or R' and R'' together with the N atom to which they are attached form a 3 to 14-membered heterocyclyl; L" is selected from a covalent bond, -O-, and -S-; or L" is selected from a group consisting of one or more methylene units independently selected from -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－８ alkylene; f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein each of the above groups may be deuterated up to fully deuterated.

4. V is a covalent bond, CR Ｃ and C.R. Ｃ R Ｃ '; alternatively a covalent bond, CH, CH ２ , CD, CHD and CD ２ and optionally a covalent bond, selected from the group consisting of:

5. W is CR Ｃ or CR Ｃ R Ｃ '; alternatively CR Ｃ R Ｃ ', and alternatively CH ２ , CD, CHD or CD ２ or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, of formula (I') or formula (I) according to any one of claims 1 to 4, wherein:

6. 6. The compound of formula (I') or formula (I) according to any one of claims 1 to 5, wherein said compound of formula (I) is one of the following formulae: 【Chemistry 4】

7. Q and Y are independently a covalent bond, O, S, NR Ａ , S(O), S(O) ２ , C(O) and CR １ａ R １ｂ Q and Y are not simultaneously a covalent bond; Alternatively, Q is O, S, and NR Ａ and alternatively S or NR Ａ , alternatively NR Ａ and alternatively NH; Alternatively, Y is a covalent bond, O, S, and CR １ａ R １ｂ and alternatively a covalent bond, O and CR １ａ R １ｂ Alternatively, a covalent bond, O, CH ２ , C.F. ２ and C(CH ３ ) ２ and alternatively selected from C(CH ３ ) ２ or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, of formula (I') or formula (I) according to any one of claims 1 to 6, wherein:

8. R Ａ But H, C １－６ Alkyl, C １－６ haloalkyl, -L''-3 to 10-membered carbocyclyl, and -L''-3 to 10-membered heterocyclyl; alternatively H, C １－６ Alkyl and C １－６ haloalkyl; alternatively is H; or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

9. R Ｂ But H, C １－６ Alkyl, C １－６ haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; alternatively H, C １－６ Alkyl and C １－６ haloalkyl; alternatively is H; or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

10. R Ｃ and R' Ｃ are independently H, D, halogen, —CN, C １－６ Alkyl, C １－８ haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; alternatively, independently selected from H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; and alternatively, independently, H or D. Alternatively, 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.

11. R １ａ and R １ｂ are independently H, D, halogen, —CN, C １－６ Alkyl, C １－６ haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; alternatively, independently selected from H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; alternatively, independently selected from H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; alternatively, independently selected from H, D, halogen, C １－３ Alkyl and C １－３ haloalkyl; alternatively, independently selected from H, D, F and Me; and further alternatively, Me, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

12. R Ｅ are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R ｅ phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrrolopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, pyrazolopyridyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyridyl, dihydropyridoxazinyl, indolyl, triazolopyridyl, selected from tetrahydroimidazopyrazinyl, dihydropyrrolopyridyl, thienopyridyl, benzimidazolyl, dihydroimidazooxazinyl, tetrahydropyrazolopyridyl, tetrahydropyrrolopyridyl, dihydropyrazolooxazinyl, dihydropyrrolylimidazolyl, oxazolopyridyl, pyrazoloazepanyl, pyrazolopiperidyl, imidazoazepanyl, imidazopiperidyl, pyrazolodiazepanyl, pyrazolodiazacyclohexyl and thienopyridyl; Alternatively, R Ｅ and its substituent R ｅ But both, 【Chemistry 5】 Alternatively, a group selected from 【Chemistry 6】 where g=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Alternatively, g=0, 1, 2, 3, 4, 5 or 6; alternatively, g=0, 1, 2, 3 or 4; alternatively, g=0, 1 or 2; or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

13. R ｅ are independently H, D, halogen, —CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, -L'-OR', -L'-NR'R'', -NO ２ , -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O) ２ R', -L'-S(O) ２ and -NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-3- to 10-membered carbocyclyl, and -L'-3- to 10-membered heterocyclyl; alternatively, independently selected from H, D, halogen, -CN, -OR', -SR', -NR'R'', C １－６ Alkyl and C １－６ haloalkyl; alternatively, independently selected from H, D, halogen, —CN, —OR′, C １－６ Alkyl and C １－６ haloalkyl; alternatively, independently, H, D, Me, F, Cl, —CN, and —OCH ３ Selected from: Alternatively, R Ｅ and its substituent R ｅ But both, 【Chemistry 7】 Alternatively, a group selected from 【Chemistry 8】 a group selected from: 【Chemistry 9】 A 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, which forms a group selected from:

14. Z ６ is CR Ｅ and Z １ is CR ｄ１ or N, or Z １ is CR Ｅ and Z ６ is N; alternatively, Z ６ is CR Ｅ and Z １ is CR ｄ１ or N; alternatively, Z ６ is CR Ｅ and Z １ is CR ｄ１ and further alternatively, Z ６ is CR Ｅ and Z １ is CH or CD, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

15. R ｄ１ H, D, halogen, -CN, C １－６ Alkyl, C １－６ haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; alternatively H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; and alternatively H or D.

16. Ring A is 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 pyrazine ring, a pyrazolidine ring, a pyrazoline ring, a pyrazole ring, a pyridazine ring, or a pyridine ring. a pyrrolidine ring, a pyrroline ring, a 2H-pyrrole ring, a pyrrole ring, a tetrahydrofuran ring, a tetrahydropyran ring, a thiazole ring, a thiophene ring, a triazine ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a xanthene ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and a hexahydropyrazinoquinoline ring; alternatively, a benzene ring, a pyridine ring, a pyrazole ring, and an imidazole ring; and further alternatively, a benzene ring; Alternatively, ring A and its substituents R ｄ But both, 【Chemistry 10】 Alternatively, a group selected from 【Chemistry 11】 where f=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Alternatively, f=0, 1, 2, 3, 4, 5 or 6; alternatively, f=0, 1, 2, 3 or 4; alternatively, f=0, 1 or 2; or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

17. R ｄ are independently H, D, halogen, —CN, —L′-S(O) ０－２ R', -L'-S(O) ２ is selected from -NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R''; or R ｄ are independently 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ C optionally substituted with １－６ Alkyl, C １－６ selected from haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl; Alternatively, two adjacent R ｄ together with the atoms to which they are attached 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, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl, or 6- to 10-membered fused bicyclic heterocyclyl is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; Alternatively, R ｄ are independently H, D, halogen, C １－６ Alkyl, C １－６ haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl and -L'-3- to 7-membered heterocyclyl; １－６ Alkyl, C １－６ Haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; Alternatively, R ｄ But independently, H, D, C １－６ Alkyl, C １－６ haloalkyl, -L'-NR'R'' and -L'-4- to 6-membered heterocyclyl; １－６ Alkyl, C １－６ Haloalkyl or 4- to 6-membered heterocyclyl is one or two R ｄｄ optionally substituted with; Alternatively, R ｄ But independently, H, D, 【Chemistry 12】 Alternatively, independently selected from H, D, 【Chemistry 13】 Selected from: Alternatively, ring A and its substituents R ｄ But both, 【Chemistry 14】 Alternatively, the group is 【Chemistry 15】 , alternatively 【Chemistry 16】 , or alternatively 【Chemistry 17】 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:

18. R ｄ are independently H, F, —OH, —OCH ３ , 【Chemistry 18】 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, selected from:

19. R ｄｄ are independently H, D, halogen, —CN, —NO ２ , 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) ２ and -NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-3- to 10-membered carbocyclyl and -L''-3- to 10-membered heterocyclyl; alternatively, independently, H, D, halogen, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR', -L"-SR', and -L"-NR'R"; alternatively, independently selected from H, D, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR' and -L"-NR'R", alternatively independently selected from H, D, Me, N(CH ３ ) ２ and C(CH ３ ) ２ 18. A compound of formula (F') or formula (F) according to any one of claims 1 to 17, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, selected from: OH.

20. Ring A and its substituent R ｄ But both, 【Chemistry 19-1】 【Chemistry 19-2】 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, which forms a group selected from:

21. L and L' are independently a chemical bond, -O-, -S-, -NR'-, -S(O) ２ - and -C(O)-; or L or L' is selected from one or more methylene units independently selected from -C(R') ２ -, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－６ alkylene; Alternatively, L or L' are independently a covalent bond, O and C. １－６ alkylene, alternatively independently selected from a covalent bond, O and C １－４ 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, selected from alkylene.

22. L" is selected from a covalent bond, -O-, and -S-; or L" is selected from a group consisting of one or more methylene units independently selected from -O-, -C(O)-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－６ alkylene; alternatively, L″ is a covalent bond and C １－６ alkylene; and alternatively, a covalent bond or C １－４ 22. A 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, which is alkylene.

23. 23. A compound of formula (I') or formula (I) according to any one of claims 1 to 22, having the following structural formula: or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: 【Chemistry 20】 During the ceremony, 【Chemical 21】 indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic, and R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ means that the double bond is absent, and if the double bond is absent, it means that the ring in which it is located is not aromatic; X １ is CR ｅ６ , N, O, S or NR' ｅ６ and X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ , C.R. ｅ４ R' ｅ４ or N; X ５ is CR ｅ５ , N, O, S or NR' ｅ５ and X ６ is C or N; X ７ is CR ｅ１ or N; X ８ is CR ｅ２ or N; X ９ is CR ｅ３ or N; X １０ is CR ｅ７ , O, S, N and NR' ｅ７ Selected from: X １１ is CR ｅ８ , O, S, N and NR' ｅ８ Selected from: R ｅ１ , R ｅ２ , R ｅ３ , R ｅ４ , R ｅ５ and R ｅ６ are independently H, D, halogen, —CN, C １－８ Alkyl, C １－８ Haloalkyl, -L'-OR', -L'-NR'R'', -NO ２ , -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O) ２ R', -L'-S(O) ２ NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-C ６－１０ selected from aryl, -L'-3- to 14-membered carbocyclyl, -L'-3- to 14-membered heterocyclyl, and -L'-5- to 14-membered heteroaryl; R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ are independently absent, H, D, halogen, —CN, C １－８ Alkyl and C １－８ haloalkyl; or CR ｅ１ R' ｅ１ forms —C(O)—, or CR ｅ２ R' ｅ２ forms —C(O)—, or CR ｅ３ R' ｅ３ forms —C(O)—, or CR ｅ４ R' ｅ４ forms —C(O)—; R' ｅ５ and R' ｅ６ are independently H, C １－８ Alkyl and C １－８ haloalkyl; R ｅ７ and R ｅ８ are independently H, D, halogen, CN, C １－８ Alkyl, C １－８ selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl; R' ｅ７ and R' ｅ８ are independently H, D, C １－８ Alkyl, C １－８ selected from haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl; Or, X １０ and X １１ Both of the substituents C may contain one double bond. ３－５ Forms an alkylene, ３－５ Alkylene is one, two, three or four R ｅ and the C ３－５ One or more methylene units in the alkylene are independently -NR''-, -N(R'')C(O)-, -C(O)N(R'')-, -N(R'')S(O) ２ -, -S(O) ２ N(R″)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) ２ may be replaced by -; E is CR ｅ１２ and N; J is for CR ｅ１３ and N; R ｅ９ , R ｅ１０ , R ｅ１１ , R ｅ１２ and R ｅ１３ H, D, halogen, CN, C １－８ Alkyl, C １－８ Haloalkyl, 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 and -Y ５ -C ０－８ Alkylene-R ６ Selected from: Y ５ is O, S and NR ５ Selected from: R ５ is H, C １－８ Alkyl and C １－８ haloalkyl; R ６ is selected from 3- to 10-membered carbocyclyl and 3- to 10-membered heterocyclyl; Or, R ｅ９ and R ｅ１３ together with the carbon atoms to which they are attached, may be one, two, three or four R ｅ 5- to 10-membered carbocyclyl, 5- to 10-membered heterocyclyl, C ６－１０ forming an aryl or 5-10 membered heteroaryl; Or, R ｅ９ and R ｅ１０ together with the carbon atoms to which they are attached, may be one, two, three or four R ｅ 5- to 10-membered carbocyclyl, 5- to 10-membered heterocyclyl, C ６－１０ forming an aryl or 5-10 membered heteroaryl; Z ２ is R ｄ２ is a C atom or N atom optionally substituted with Z ３ is R ｄ３ is a C atom or N atom optionally substituted with Z ４ is R ｄ４ is a C atom or N atom optionally substituted with Z ５ is a covalent bond, CR ｄ５ and N; R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ are independently H, D, halogen, —CN, —L′-S(O) ０－２ R', -L'-S(O) ２ selected from -NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R'', or R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ are independently 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ C optionally substituted with １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ haloalkyl, -L'-C ６－１０ selected from aryl, -L'-3 to 14-membered carbocyclyl, -L'-3 to 14-membered heterocyclyl, and -L'-5 to 14-membered heteroaryl; 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 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, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl, or 6- to 10-membered fused bicyclic heterocyclyl is selected from the group consisting of 1, 2, 3, 4, or 5 R ｄｄ optionally substituted with; n=0, 1, 2, 3, 4, 5, 6, 7 or 8; Other radicals are as defined in claims 1 to 20; Each of the above groups may be deuterated up to fully deuterated.

24. V is a covalent bond, CR Ｃ and C.R. Ｃ R Ｃ ' is selected from; Q and Y are independently a covalent bond, O, S, NR Ａ , S(O), S(O) ２ , C(O) and CR １ａ R １ｂ Q and Y are not simultaneously a covalent bond; R Ａ But H, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-3 to 10-membered carbocyclyl, and -L''-3 to 10-membered heterocyclyl; R Ｂ But H, C １－６ Alkyl, C １－６ selected from haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; R Ｃ , R' Ｃ , R １ａ and R １ｂ are independently H, D, halogen, —CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; 【Chemical Formula 22】 indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic, and R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ means that the double bond is absent, and if the double bond is absent, it means that the ring in which it is located is not aromatic; X ２ is C or N; X ３ is C or N; X ４ But, CR ｅ４ , C.R. ｅ４ R' ｅ４ or N; R ｅ１ , R ｅ２ , R ｅ３ , R ｅ４ and R ｅ５ are independently H, D, halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, -L'-OR', -L'-NR'R'', -NO ２ , -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R'', -L'-S(O) ２ R', -L'-S(O) ２ selected from -NR'R'', -L'-OC(O)R', -L'-OC(O)NR'R'', -L'-3- to 10-membered carbocyclyl, and -L'-3- to 10-membered heterocyclyl; R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ are independently H, D, halogen, —CN, C １－６ Alkyl and C １－６ haloalkyl; or CR ｅ１ R' ｅ１ forms —C(O)—, or CR ｅ２ R' ｅ２ forms —C(O)—, or CR ｅ３ R' ｅ３ forms —C(O)—, or CR ｅ４ R' ｅ４ forms —C(O)—; Z １ is CR ｄ１ or N; Z ２ But, R ｄ２ is a C atom or N atom optionally substituted with Z ３ But, R ｄ３ is a C atom or N atom optionally substituted with Z ４ But, R ｄ４ is a C atom or N atom optionally substituted with Z ５ is a covalent bond, CR ｄ５ and N; R ｄ１ H, D, halogen, -CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L-OR', -L-NR'R'', -L-C(O)NR'R'', -L-3- to 10-membered carbocyclyl, and -L-3- to 10-membered heterocyclyl; R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ are independently H, D, halogen, —CN, —L′-S(O) ０－２ R', -L'-S(O) ２ selected from -NR'R'', -L'-S(O)NR'R'', -L'-OR', -L'-NR'R'', -L'-C(O)OR' and -L'-C(O)NR'R'', or R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ are independently 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ C optionally substituted with １－６ Alkyl, C １－６ selected from haloalkyl, -L'-3 to 10-membered carbocyclyl, and -L'-3 to 10-membered heterocyclyl; 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 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, 6- to 10-membered bridged bicyclic heterocyclyl, 6- to 10-membered spiro bicyclic heterocyclyl, or 6- to 10-membered fused bicyclic heterocyclyl is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, halogen, —CN, —NO ２ , 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) ２ selected from -NR'R'', -L''-S(O)NR'R'', -L''-OC(O)R', -L''-OC(O)NR'R'', -L''-3- to 10-membered carbocyclyl, and -L''-3- to 10-membered heterocyclyl; L and L' are independently a covalent bond, -O-, -S-, -NR'-, -S(O) ２ - and -C(O)-; or L or L' is selected from one or more methylene units independently selected from -C(R') ２ -, -N(R')-, -O-, -C(O)-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－６ alkylene; R' and R'' are independently H, C １－６ Alkyl, C １－６ haloalkyl, -L''-3- to 10-membered carbocyclyl, and -L''-3- to 10-membered heterocyclyl; or R' and R'' together with the N atom to which they are attached form a 3- to 10-membered heterocyclyl; L" is selected from a covalent bond, -O-, and -S-; or L" is selected from a group consisting of one or more methylene units independently selected from -O-, -C(O)-, -S-, -S(O)-, or -S(O) ２ C which may be replaced by - １－６ alkylene; 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 each of the above groups may be deuterated up to fully deuterated.

25. V is a covalent bond, CR Ｃ and C.R. Ｃ R' Ｃ Selected from: Q is O, S and NR Ａ Selected from: Y is a covalent bond, O, S, or CR １ａ R １ｂ Selected from: R Ａ and R Ｂ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; R Ｃ and R' Ｃ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R １ａ and R １ｂ are independently H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; ​ indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic, and R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ means that the double bond is absent, and if the double bond is absent, it means that the ring in which it is located is not aromatic; X ２ is C or N; X ３ is C or N; X ４ But, CR ｅ４ , C.R. ｅ４ R' ｅ４ or N; R ｅ１ is H, D, halogen, -CN, -OR', -SR', -NR'R'', C １－６ Alkyl and C １－６ haloalkyl; R ｅ２ , R ｅ３ , R ｅ４ and R ｅ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; Z １ is CR ｄ１ or N; Z ２ But, R ｄ２ is a C atom or N atom optionally substituted with Z ３ But, R ｄ３ is a C atom or N atom optionally substituted with Z ４ But, R ｄ４ is a C atom or N atom optionally substituted with Z ５ is a covalent bond, CR ｄ５ and N; R ｄ１ and R ｄ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R ｄ２ , R ｄ３ and R ｄ４ are independently H, D, halogen, C １－６ Alkyl, C １－６ haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl and -L'-3- to 7-membered heterocyclyl; １－６ Alkyl, C １－６ Haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is 1, 2, 3, 4, 5, 6, 7, or 8 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, halogen, C １－６ Alkyl, C １－６ selected from haloalkyl, -L"-OR', -L"-SR' and -L"-NR'R"; R' and R'' are independently H, C １－６ Alkyl, C １－６ haloalkyl, -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl; or R' and R'' together with the N atom to which they are attached form a 3 to 7-membered heterocyclyl; L' is a covalent bond, O and C １－６ alkylene; L″ is a covalent bond and C １－６ alkylene; 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 each of the above groups is optionally deuterated up to fully deuterated.

26. V is a covalent bond, CH, CH ２ , CD, CHD and CD ２ and is selected from, alternatively a covalent bond; Q is S and NR Ａ and alternatively NR Ａ and Y is a covalent bond, O and CR １ａ R １ｂ Alternatively, a covalent bond, O, CH ２ , C.F. ２ and C(CH ３ ) ２ and alternatively selected from C(CH ３ ) ２ and R Ａ and R Ｂ is H; R １ａ and R １ｂ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl, alternatively independently selected from H, D, F and Me; 【Chemistry 24】 indicates that a double bond may or may not be present; if a double bond is present, the ring on which it is located is aromatic, and R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ means that the double bond is absent, and if the double bond is absent, it means that the ring in which it is located is not aromatic; X ２ is C or N; X ３ is C or N; alternatively, X ２ and X ３ one of which is C and the other is N; X ４ But, CR ｅ４ , C.R. ｅ４ R' ｅ４ and N; R ｅ１ is selected from H, D, halogen, —CN and —OR′, alternatively H, D, F, Cl, —CN or —OCH ３ and R ｅ２ But H, D, C １－６ Alkyl and C １－６ haloalkyl, alternatively H, D or Me; R ｅ３ , R ｅ４ and R ｅ５ is independently selected from H and D; R' ｅ１ , R' ｅ２ , R' ｅ３ and R' ｅ４ is independently selected from H and D; Z １ is CR ｄ１ or N; Z ２ But, R ｄ２ is a C atom or N atom optionally substituted with Z ３ But, R ｄ３ is a C atom or N atom optionally substituted with Z ４ But, R ｄ４ is a C atom or N atom optionally substituted with Z ５ is a covalent bond, CR ｄ５ and N; alternatively, Z ２ , Z ３ , Z ４ and Z ５ is located on a ring selected from a benzene ring, a pyridine ring, a pyrazole ring, and an imidazole ring; R ｄ１ and R ｄ５ is independently H or D; R ｄ２ , R ｄ３ and R ｄ４ But independently, H, D, C １－６ Alkyl, C １－６ haloalkyl, -L'-NR'R'' and -L'-4- to 6-membered heterocyclyl; １－６ Alkyl, C １－６ Haloalkyl or 4- to 6-membered heterocyclyl is one or two R ｄｄ Alternatively, R ｄ２ , R ｄ３ and R ｄ４ But independently, H, D, 【Chemistry 25】 and further alternatively, R ｄ２ But H, D, 【Chemical Formula 26】 and R ｄ３ But H, D, 【Chemical 27】 and R ｄ４ However, H, D and 【Chemical Formula 28】 Selected from: R ｄｄ But independently, H, D, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR' and -L"-NR'R", alternatively independently selected from H, D, Me, N(CH ３ ) ２ and C(CH ３ ) ２ OH; L' is a covalent bond, O and C １－６ alkylene, alternatively a covalent bond, O or C １－４ alkylene; L″ is a covalent bond and C １－６ alkylene, alternatively a covalent bond or C １－４ alkylene; R' and R'' are independently H, C １－６ Alkyl and C １－６ haloalkyl; 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 each of the above groups is optionally deuterated up to fully deuterated.

27.

29. but, 【Chemistry 30】 and alternatively selected from 【Chemical 31】 Selected from: Z ２ , Z ３ , Z ４ and Z ５ is located on a ring and its substituents, which are both the following groups: 【Chemical 32】 , alternatively 【Chemical 33】 , alternatively 【Chemical Formula 34】 , or alternatively 【Chemical 35】 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, which forms:

28. X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N; R ｅ１ is H, D, halogen, -CN, -OR', -SR', -NR'R'', C １－６ Alkyl and C １－６ haloalkyl; R ｅ２ , R ｅ３ , R ｅ４ and R ｅ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R １ａ and R １ｂ are independently H, D, halogen, CN, C １－６ Alkyl or C １－６ haloalkyl; Z １ is CR ｄ１ or N, alternatively CR ｄ１ and Z ２ is CR ｄ２ or N, alternatively CR ｄ２ and Z ４ is CR ｄ４ or N, alternatively CR ｄ４ and Z ５ is CR ｄ５ or N, alternatively CR ｄ５ and R ｄ２ But H, D, halogen, C １－６ Alkyl, C １－６ haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl and -L'-3- to 7-membered heterocyclyl; １－６ Alkyl, C １－６ haloalkyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is 1, 2, 3, 4, 5, 6, or 7 R ｄｄ optionally substituted with; R ｄ１ , R ｄ４ or R ｄ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R ｄｄ But H, D, halogen, C １－６ Alkyl, C １－６ selected from haloalkyl, -L"-OR', -L"-SR' and -L"-NR'R"; L' is a covalent bond, -O- and C １－６ alkylene; L″ is a covalent bond and C １－６ alkylene; n=0, 1, 2, 3, 4, 5, 6, 7 or 8; R' and R'' are independently H, C １－６ Alkyl, C １－６ haloalkyl, -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl; or R' and R'' together with the N atom to which they are attached form a 3 to 7-membered heterocyclyl; 24. The compound of formula (III), formula (IV) or formula (V) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein each of the above groups is optionally deuterated up to fully deuterated.

29. X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N; R ｅ１ H, D, halogen, -CN, -OR', C １－６ Alkyl and C １－６ haloalkyl; R ｅ２ , R ｅ３ , R ｅ４ and R ｅ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R １ａ and R １ｂ But independently, C １－６ Alkyl or C １－６ haloalkyl; Z １ is CR ｄ１ or N, alternatively CR ｄ１ and Z ２ is CR ｄ２ or N, alternatively CR ｄ２ and Z ４ is CR ｄ４ or N, alternatively CR ｄ４ and Z ５ is CR ｄ５ or N, alternatively CR ｄ５ Alternatively, Z ２ , Z ４ and Z ５ is located on a ring selected from a benzene ring and a pyridine ring, and is alternatively a benzene ring; R ｄ１ , R ｄ２ , R ｄ４ or R ｄ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R ｄｄ But H, D, halogen, C １－６ Alkyl, C １－６ selected from haloalkyl, -L"-OR' and -L"-NR'R"; L″ is a covalent bond and C １－６ alkylene; n=0, 1, 2, 3, 4, 5, 6, 7 or 8; R' and R'' are independently H, C １－６ Alkyl and C １－６ haloalkyl; 29. The compound of formula (III), formula (IV) or formula (V) according to claim 28, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein each of the above groups is optionally deuterated up to fully deuterated.

30. X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N; R ｅ１ is selected from H, D, halogen and —OR′, alternatively H, D or halogen; R ｅ２ But H, D, C １－６ Alkyl and C １－６ haloalkyl, alternatively H or D; R ｅ３ , R ｅ４ and R ｅ５ is independently H or D; R １ａ and R １ｂ But independently, C １－３ Alkyl or C １－３ haloalkyl, alternatively Me; Z １ , Z ２ , Z ４ and Z ５ is CH or CD; R ｄｄ But H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and -L"-OR'; L″ is a covalent bond and C １－６ alkylene; n=0, 1, 2, 3, 4, 5, 6, 7 or 8; R' is H, C １－６ Alkyl and C １－６ haloalkyl; 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 each of the above groups is optionally deuterated up to fully deuterated.

31. X ２ is C or N; X ３ is C or N; alternatively, X ２ and X ３ one of which is C and the other is N; X ４ is CR ｅ４ or N; R ｅ１ H, F, Cl and OCH ３ is selected from, alternatively H, F or Cl; R ｅ２ is selected from H and Me, alternatively H; R ｅ３ , R ｅ４ and R ｅ５ is H; alternatively, 【Chemical 36】 but, 【Chemical 37】 and alternatively selected from 【Chemical Formula 38】 and alternatively selected from 【Chemical Formula 39】 Selected from: R １ａ and R １ｂ is Me; Z １ , Z ２ , Z ４ and Z ５ is CH; R ｄｄ is H or -L″-OH, alternatively H or C(CH ３ ) ２ OH; L″ is a covalent bond and C １－４ alkylene; n=0 or 1; alternatively 【Chemistry 40】 but 【Chemistry 41】 31. The compound of formula (III) of claim 30, wherein:

32. X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N; R ｅ１ is selected from H, D, halogen, CN and —OR′, alternatively selected from H, D, F, CN and OR′; R ｅ２ But H, D, C １－６ Alkyl and C １－６ haloalkyl; R ｅ３ , R ｅ４ and R ｅ５ is independently H or D; R １ａ and R １ｂ But independently, C １－３ Alkyl or C １－３ haloalkyl, alternatively Me; Z １ is selected from CH, CD and N, alternatively CH or CD; Z ２ , Z ４ and Z ５ is independently selected from CH, CD, and N; R ｄｄ But H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and -L"-OR'; L″ is a covalent bond and C １－６ alkylene; n=0, 1, 2, 3, 4, 5, 6, 7 or 8; R' is H, C １－６ Alkyl and C １－６ haloalkyl; 30. The compound of formula (IV) of claim 29, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein each of the above groups is optionally deuterated up to fully deuterated.

33. X ２ is C or N; X ３ is C or N; alternatively, X ２ and X ３ one of which is C and the other is N; X ４ is CR ｅ４ or N; R ｅ１ H, F, Cl, CN and OCH ３ and alternatively selected from H, F, CN and OCH ３ Selected from: R ｅ２ is selected from H and Me; R ｅ３ , R ｅ４ and R ｅ５ is H; alternatively, 【Chemistry 42】 but, 【Chemistry 43】 and alternatively selected from 【Chemical Formula 44】 and alternatively selected from 【Chemistry 45】 and alternatively selected from 【Chemistry 46】 Selected from: R １ａ and R １ｂ is Me; Z １ is CH; Z ２ , Z ４ and Z ５ is independently CH or N; alternatively, Z ２ and Z ４ is independently CH or N, and Z ５ is CH; alternatively, Z ２ is CH or N, and Z ４ and Z ５ is CH; R ｄｄ is H or -L″-OH, alternatively H or C(CH ３ ) ２ OH; L″ is a covalent bond and C １－４ alkylene; n=0 or 1; alternatively 【Chemistry 47】 but 【Chemistry 48】 33. The compound of formula (IV) of claim 32, wherein:

34. X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N, alternatively CR ｅ４ and R ｅ１ is selected from H, D, halogen and —OR′, alternatively —OR′; R ｅ２ But H, D, C １－６ Alkyl and C １－６ haloalkyl, alternatively H or D; R ｅ３ , R ｅ４ and R ｅ５ is independently H or D; R １ａ and R １ｂ But independently, C １－３ Alkyl or C １－３ haloalkyl, alternatively Me; Z １ is N, CH or CD, alternatively CH or CD; Z ２ , Z ４ and Z ５ is independently CH or CD; R ｄｄ But H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and -L"-OR', alternatively H or D; L″ is a covalent bond and C １－６ alkylene; n=0, 1, 2, 3, 4, 5, 6, 7 or 8; R' is H, C １－６ Alkyl and C １－６ haloalkyl, alternatively selected from C １－６ Alkyl or C １－６ haloalkyl; 30. The compound of formula (V) of claim 29, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein each of the above groups is optionally deuterated up to fully deuterated.

35. X ２ is C or N; X ３ is C or N; alternatively, X ２ and X ３ one of which is C and the other is N; X ４ is CR ｅ４ or N, alternatively CR ｅ４ and R ｅ１ H, F, Cl and OCH ３ and alternatively OCH ３ and R ｅ２ is H; R ｅ３ , R ｅ４ and R ｅ５ is H; alternatively, 【Chemistry 49】 but, 【Chemistry 50】 and alternatively selected from 【Chemistry 51】 and R １ａ and R １ｂ is Me; Z １ is CH or N; Z ２ , Z ４ and Z ５ is CH; R ｄｄ is H; 35. The compound of formula (V) of claim 34, wherein n=0, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

36.

52. During the ceremony, R Ｅ is -L-3 to 10-membered carbocyclyl, -L-3 to 10-membered heterocyclyl, -L-C ６－１０ aryl and -L-5 to 10 membered heteroaryl, alternatively -LC ６－１０ aryl or -L-5 to 10 membered heteroaryl, each of which is selected from 1, 2, 3, 4, or 5 R ｅ optionally substituted with; R ｅ are independently H, D, halogen, CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3- to 7-membered carbocyclyl, and -L'-3- to 7-membered heterocyclyl; Y is O, S and CR １ａ R １ｂ Selected from: R １ａ and R １ｂ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; Q, V, R Ｂ and Z １ each of which is as defined in any one of claims 23 to 25; Z ２ But, CR ｄ２ and N; Z ３ But, CR ｄ３ and N; Z ４ But, CR ｄ４ and N; Z ５ is a covalent bond, CR ｄ５ and N, alternatively CR ｄ５ or N; R ｄ３ and R ｄ４ one of the groups is —NR′ ｄ６ C(O)R ｄ６ , -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl, and the other, R ｄ２ and R ｄ５ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl; R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ , 1, 2, 3 or 4 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, oxo, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7 membered carbocyclyl, and -L''-3 to 7 membered heterocyclyl; Alternatively, two non-adjacent R ｄｄ Both are C １－６ alkylene, alternatively C １－４ Forms alkylene, which is H, D, halogen, CN, C １－６ Alkyl and C １－６ optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl; R ｄ６ But 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 and -L''-Y ３ -C １－６ Alkylene-R ４ Selected from: Y ３ is O, S and NR ３ Selected from: R' ｄ６ and R ３ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; R ４ is selected from -OR', -SR', and -NR'R''; L is independently a covalent bond, —O—, —S—, —NR′—, or C １－６ alkylene; L' is independently a covalent bond and C １－６ alkylene; Each of L and L' is C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - optionally substituted with 1, 2, 3, or 4 groups selected from 3- to 7-membered heterocyclyl; L″ is independently a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R; １－６ alkylene; R is independently selected from H, D, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 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 are independently a covalent bond and C １－６ alkylene, alternatively a covalent bond and C １－４ alkylene; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 3- to 7-membered heterocyclyl; 24. The compound of formula (II) of claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein each of the groups is optionally deuterated up to fully deuterated.

37. R Ｅ is -L-5 to 10 membered heteroaryl, alternatively 5 to 10 membered heteroaryl; alternatively, R Ｅ wherein each of the heteroaryls in ｅ pyridyl, pyridonyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, imidazopyridyl, imidazopyridazinyl, imidazopyrazinyl, imidazopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, triazolopyridyl, imidazopyrrolidinyl, imidazocyclohexyl, imidazopiperidyl, imidazoazepanyl, dihydroimidazooxazinyl, imidazopyrazinonyl, imidazodiazacyclohexyl, imidazopiperazinonyl, pyrazolopiperidyl, pyrazolodiazacyclohexyl, dihydropyrazolooxazinyl, triazolopiperidyl, dihydropyridoxazinyl, pyrrolopyridyl and oxazolopyridyl, optionally substituted with; R ｅ are independently H, D, halogen, CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; alternatively, H, D, halogen, CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ selected from alkynyl, —OR′ and —NR′R″; Y is O or CR １ａ R １ｂ , alternatively CR １ａ R １ｂ and R １ａ and R １ｂ But independently, C １－６ Alkyl and C １－６ haloalkyl, alternatively selected from Me and Et; Q, V, R Ｂ and Z １ each of which is as defined in any one of claims 23 to 25; Z ２ But, CR ｄ２ and N; Z ３ But, CR ｄ３ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N; R ｄ３ and R ｄ４ one of the groups is —NR′ ｄ６ C(O)R ｄ６ or -L'-3 to 7 membered heterocyclyl, alternatively -L'-3 to 7 membered heterocyclyl, and the other, R ｄ２ and R ｄ５ are independently H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ , 1, 2, 3 or 4 R ｄｄ optionally substituted with; R ｄｄ are independently H, D, oxo, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7 membered carbocyclyl, and -L''-3 to 7 membered heterocyclyl; Alternatively, two non-adjacent R ｄｄ Both are H, D, halogen, CN, C １－６ Alkyl and C １－６ C optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl １－３ Forming an alkylene; R ｄ６ But C １－６ Alkyl, C １－６ Haloalkyl, -L''-3 to 7-membered carbocyclyl, -L''-3 to 7-membered heterocyclyl and -L''-Y ３ -C １－４ Alkylene-R ４ Selected from: Y ３ However, O and NR ３ is selected from, alternatively O; R' ｄ６ and R ３ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl, alternatively H, C １－３ Alkyl or C １－３ haloalkyl; R ４ is selected from -OR' and -NR'R'', alternatively -OR'; L is independently a covalent bond, —NR′—, and C １－４ alkylene, alternatively a covalent bond or —NR′—; alternatively, L is a covalent bond, —NH—, or —CH(CH ３ )-, alternatively a covalent bond or -NH-; L' is independently a covalent bond and C １－４ alkylene; Each of L and L' is C １－６ Alkyl and C １－６ optionally substituted with 1, 2, 3, or 4 groups selected from haloalkyl; L″ is independently a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R; １－６ alkylene; R is independently selected from H, D, C １－６ Alkyl and C １－６ haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene, alternatively a 3- to 5-membered carbocyclylene; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 3 to 7 membered heterocyclyl, alternatively H, C １－６ Alkyl and C １－６ 37. The compound of formula (II) of claim 36, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, selected from haloalkyl.

38. 【Catalog 53】 During the ceremony, R Ｅ is as defined in claim 36 or 37; R ｅ are independently H, D, halogen, CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7 membered carbocyclyl and -L'-3 to 7 membered heterocyclyl, and alternatively H, D, halogen, CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; alternatively, H, D, halogen, CN, oxo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkynyl, —OR′ and —NR′R″, each of which is selected from 1, 2 or 3 R ｅｓ may be substituted with; Or, two geminal R ｅ together with the atom to which they are attached form a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, alternatively a 3- to 7-membered heterocyclyl, which is ｅｓ optionally substituted with; R ｅｓ are independently H, D, halogen, C １－６ Alkyl, C １－６ selected from haloalkyl, —OR′ and —NR′R″; Q, V, R Ｂ , Z １ and Z ７ each of which is as defined in claim 1 and any one of claims 23 to 25; Z ２ But, CR ｄ２ and N; Z ３ But, CR ｄ３ and N; Z ４ But, CR ｄ４ and N; Z ５ is a covalent bond, CR ｄ５ and N, alternatively CR ｄ５ or N; R ｄ３ and R ｄ４ one of the groups is —NR′ ｄ６ C(O)R ｄ６ , —C(O)NR ｄ７ R' ｄ７ , -L'-3 to 7-membered carbocyclyl or -L'-3 to 7-membered heterocyclyl, alternatively -NR' ｄ６ C(O)R ｄ６ , —C(O)NR ｄ７ R' ｄ７ or -L'-3 to 7-membered heterocyclyl, and R ｄ２ and R ｄ５ are independently 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 and -L'-3 to 7 membered heterocyclyl, alternatively H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, OR′ and NR′R″; R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ , 1, 2, 3 or 4 R ｄｄ optionally substituted with; R ｄｄ are independently 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, and -L"-3 to 7-membered heterocyclyl; alternatively H, D, oxo, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7 membered carbocyclyl, and -L''-3 to 7 membered heterocyclyl; Or, CR ｄｄ R ｄｄ forms a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, which is selected from H, D, halogen, C １－６ Alkyl, C １－６ optionally substituted with 1, 2, or 3 groups selected from haloalkyl, -OR', and -NR'R'', or alternatively with 1 -OR'; Alternatively, two non-adjacent R ｄｄ Both are C １－６ alkylene, alternatively C １－４ alkylene, alternatively C １－３ Forms alkylene, which is H, D, halogen, CN, C １－６ Alkyl and C １－６ optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl; Alternatively, two adjacent R ｄｄ together with the atom to which they are attached form a 3- to 7-membered carbocyclylene, a 3- to 7-membered heterocyclylene, a phenylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene, which is selected from the group consisting of H, D, halogen, CN, C １－６ Alkyl, C １－６ optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, —OR′, and —NR′R″; R ｄ７ and R' ｄ７ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; The remaining variables are as defined in claim 36 or 37; 24. 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, wherein each of the above groups is optionally deuterated up to fully deuterated.

39.

54. During the ceremony, R Ｅ is as defined in any one of claims 36 to 38; X １ But, CR ｅ６ , N, O, S or NR' ｅ６ and X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N; X ５ But, CR ｅ５ , N, O, S or NR' ｅ５ and X ６ is C or N; X ７ is CR ｅ１ or N; X ８ is CR ｅ２ or N; X ９ is CR ｅ３ or N; R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl; R ｅ３ , R ｅ４ , R ｅ５ and R ｅ６ are independently H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; R' ｅ５ and R' ｅ６ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; R １ａ and R １ｂ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; Z １ But, CR ｄ１ and N; Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N; R ｄ１ H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; R ｄ２ , R ｄ４ and R ｄ５ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl; R ｄ３ but, 【Chemistry 55】 and -NR' ｄ６ C(O)R ｄ６ Selected from: a and b are independently 0, 1, 2, or 3, alternatively a+b≦5; L' are independently C １－６ Alkyl and C １－６ a covalent bond optionally substituted with 1, 2, 3 or 4 groups selected from haloalkyl and C １－６ alkylene; Y １ and Y ２ But independently, CR ｄｄ R ｄｄ , O, S and NR' ｄｄ or Y １ is connected to L', Y １ is CR ｄｄ or N; R ｄｄ are independently H, D, oxo, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7 membered carbocyclyl, and -L''-3 to 7 membered heterocyclyl; Alternatively, two non-adjacent R ｄｄ Both are C １－４ form an alkylene, or R' ｄｄ and non-adjacent R ｄｄ Both are C １－４ Form an alkylene, or two R' ｄｄ Both are C １－４ alkylene, wherein the C １－４ Alkylene is H, D, halogen, CN, C １－６ Alkyl and C １－６ optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl; R' ｄｄ However, independently, H, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-SR', -L''-NR'R'', -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl; n=0, 1, 2, 3 or 4; R ｄ６ But 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 and -L''-Y ３ -C １－６ Alkylene-R ４ Selected from: L″ is independently a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R; １－６ alkylene; R is independently selected from H, D, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 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 are independently a covalent bond and C １－６ alkylene, alternatively a covalent bond and C １－４ alkylene; Y ３ is O, S and NR ３ Selected from: R' ｄ６ and R ３ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; R ４ is selected from -OR', -SR', and -NR'R''; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 3- to 7-membered heterocyclyl; 24. The compound of formula (VI) or formula (VI-1) according to claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein each of the above groups may be deuterated up to fully deuterated.

40. R Ｅ is as defined in any one of claims 36 to 38; X １ But, CR ｅ６ , N or NR' ｅ６ , alternatively N; X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N; X ５ But, CR ｅ５ , N or NR' ｅ５ , alternatively CR ｅ５ or N; X ６ is C or N, alternatively C; X ７ is CR ｅ１ or N; X ８ is CR ｅ２ or N; X ９ is CR ｅ３ or N; R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ haloalkyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; alternatively, H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, —OR′ and —NR′R″; R ｅ３ , R ｅ４ , R ｅ５ and R ｅ６ are independently H, D, halogen, C １－６ Alkyl or C １－６ haloalkyl; R' ｅ５ and R' ｅ６ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; R １ａ and R １ｂ But independently, C １－６ Alkyl or C １－６ haloalkyl; Z １ But, CR ｄ１ and N, alternatively CR ｄ１ and Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N, alternatively CR ｄ５ and R ｄ１ , R ｄ２ , R ｄ４ and R ｄ５ are independently H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; R ｄ３ but, 【Chemical Formula 56】 and -NR' ｄ６ C(O)R ｄ６ Selected from: a and b are independently 0, 1, or 2; alternatively, a+b≦3; L' is independently a covalent bond and C １－４ alkylene; Y １ But, CR ｄｄ R ｄｄ or NR' ｄｄ or Y １ is connected to L', Y １ is CH, CD or N; Y ２ But, CR ｄｄ R ｄｄ , O or NR' ｄｄ Alternatively, Y １ and Y ２ at least one of the groups is a heteroatom group; R ｄｄ are independently H, D, oxo, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7 membered carbocyclyl, and -L''-3 to 7 membered heterocyclyl; Alternatively, two non-adjacent R ｄｄ Both are H, D, halogen, CN, C １－６ Alkyl and C １－６ C optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl １－３ Forming an alkylene; R' ｄｄ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, —C １－６ Alkylene -OR', -C １－６ alkylene selected from -NR'R'', -L''-3 to 7 membered carbocyclyl and -L''-3 to 7 membered heterocyclyl, alternatively H, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl; n=0, 1, 2, 3 or 4; R ｄ６ But C １－６ Alkyl, C １－６ Haloalkyl, -L''-3 to 7-membered carbocyclyl, -L''-3 to 7-membered heterocyclyl and -L''-Y ３ -C １－４ Alkylene-R ４ and alternatively -L″-Y ３ -C １－４ Alkylene-R ４ rather than; L″ is independently a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R; １－６ alkylene; R is independently selected from H, D, C １－６ Alkyl and C １－６ haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene; Y ３ However, O and NR ３ Selected from: R' ｄ６ and R ３ However, independently, H, C １－６ Alkyl and C １－６ haloalkyl; R ４ is selected from -OR' and -NR'R''; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; Alternatively, X １ ~X ９ of which up to 5 are heteroatoms, alternatively up to 4 are heteroatoms, alternatively up to 3 are heteroatoms; Alternatively, X ２ and X ３ one of which is N and the other is C; Alternatively, X ４ and X ７ ~X ９ at most one of is N; Alternatively, Z ２ , Z ４ and Z ５ or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein a maximum of two of are N, alternatively a maximum of one is N.

41. R Ｅ is as defined in any one of claims 36 to 38; X １ is N; X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N, alternatively N; X ５ is CR ｅ５ or N, alternatively CR ｅ５ and X ６ is C; X ７ is CR ｅ１ or N, alternatively CR ｅ１ and X ８ is CR ｅ２ or N, alternatively N; X ９ is CR ｅ３ or N, alternatively CR ｅ３ and R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ haloalkyl, —OR′, —O-3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, alternatively H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl and —OR′; R ｅ３ , R ｅ４ and R ｅ５ is independently H or D; R' ｅ５ But H, C １－３ Alkyl and C １－３ haloalkyl; R １ａ and R １ｂ But independently, C １－３ Alkyl or C １－３ haloalkyl; Z １ But, CR ｄ１ and N, alternatively CR ｄ１ and Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N, alternatively CR ｄ５ and R ｄ１ is H or D; R ｄ２ , R ｄ４ and R ｄ５ are independently H, D, halogen, C １－３ Alkyl and C １－３ haloalkyl; alternatively, R ｄ２ and R ｄ５ is independently selected from H, D and halogen; alternatively, R ｄ５ is H or D; R ｄ３ but, 【Chemical 57】 and -NR' ｄ６ C(O)R ｄ６ Alternatively, 【Chemistry 58】 but 【Chemical 59】 , alternatively 【Chemistry 60】 and a and b are independently 0, 1 or 2, alternatively a and b are 1; L' is independently a covalent bond and C １－２ alkylene, alternatively selected from a covalent bond and methylene; Y １ NR' ｄｄ , alternatively NH; or Y １ is connected to L', Y １ is CH, CD or N; Y ２ But, CR ｄｄ R ｄｄ , O or NR' ｄｄ and R ｄｄ are independently H, D, oxo, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR', -L"-NR'R" and -L"-3 to 7 membered carbocyclyl, alternatively H, D, oxo, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR" and -L"-NR'R"; alternatively H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and -L"-OR'; Alternatively, two non-adjacent R ｄｄ Both are C １－２ Forming an alkylene; R' ｄｄ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, —C １－４ Alkylene -OR', -C １－４ alkylene-NR'R'' and -L''-3 to 7 membered carbocyclyl, alternatively H, C １－６ Alkyl, C １－６ selected from haloalkyl and -L''-3- to 7-membered carbocyclyl; n=0, 1, 2, 3 or 4; R ｄ６ But C １－６ Alkyl, C １－６ Haloalkyl, -L''-3 to 7-membered carbocyclyl and -L''-O-C １－４ alkylene -OR', and alternatively -L''-O-C １－４ not alkylene-OR'; R' ｄ６ But H, C １－６ Alkyl and C １－６ haloalkyl; L″ is independently a covalent bond, C １－４ Alkylene and —C(R) ２ -, alternatively a covalent bond and C １－４ alkylene, wherein the —C(R) ２ Two R's in - together with the C atom to which they are attached form a 3- to 5-membered carbocyclylene, alternatively 【Hua 61】 Forming; Each of R′ and R″ is independently H, C １－６ Alkyl and C １－６ haloalkyl; Alternatively, Y １ is N and Y ２ is O, L′ is a covalent bond, and R ｄｄ is not oxo; Alternatively, R ｅ２ Ga-O-C １－６ When R is alkyl, ｅ２ is -OMe, alternatively, R ｅ２ Ga-O-C １－６ When R is haloalkyl, ｅ２ is —O-halomethyl; Alternatively, R ｄ２ and R ｄ４ or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, according to claim 39 or 40, wherein at least one of

42. R Ｅ is as defined in any one of claims 36 to 38; X １ is N; X ２ is C or N; X ３ is C or N; X ４ is CR ｅ４ or N, alternatively N; X ５ is CR ｅ５ or N, alternatively CR ｅ５ and X ６ is C; X ７ is CR ｅ１ or N, alternatively CR ｅ１ and X ８ is CR ｅ２ or N, alternatively N; X ９ is CR ｅ３ or N, alternatively CR ｅ３ and R ｅ１ and R ｅ２ are independently H, F, Cl, CN, Me, Et, CHF ２ , OCH ３ , OEt, OCHF ２ , —O-cyclopropyl and 【Hua 62】 Alternatively selected from H, F, Cl, CN, Me, CHF ２ , OCH ３ and OEt, alternatively, R ｅ２ but not OEt; R ｅ３ , R ｅ４ and R ｅ５ is H; R' ｅ５ is Me; R １ａ and R １ｂ is independently Me or Et; Z １ But, CR ｄ１ and N, alternatively CR ｄ１ and Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N, alternatively CR ｄ５ and R ｄ１ is H; R ｄ２ , R ｄ４ and R ｄ５ are independently H, F, Me, and CHF ２ Alternatively, R ｄ２ and R ｄ５ is independently selected from H and F, alternatively R ｄ５ is H; R ｄ３ but, 【Chemistry 63】 and -NR' ｄ６ C(O)R ｄ６ and alternatively selected from 【Hua 64】 and a is 1 or 2 and b is 1; L' is independently selected from a covalent bond and methylene, alternatively a covalent bond; Y １ is NH, CH or N, alternatively CH or N, alternatively N; Y ２ But, CR ｄｄ R ｄｄ , O or NR' ｄｄ , alternatively O; R ｄｄ are independently H, oxo, OH, Me, -C(CH ３ ) ２ OH, -CH ２ OH, -CH ２ OMe, 【Chemistry 65】 and —NHMe, alternatively selected from H, oxo, OH, Me, —C(CH ３ ) ２ OH, -CH ２ OH, -CH ２ -OMe or -NHMe; Alternatively, two non-adjacent R ｄｄ Both are -CH ２ CH ２ -, alternatively 【Hua 66】 has the following structure: 【Hua 67】 R' ｄｄ are independently H, Me and —CH ２ -cyclopropyl; n=0, 1 or 2; R ｄ６ But -CH ２ -cyclopropyl and -CH ２ -O-CH ２ CH ２ -OH, and alternatively -CH ２ -cyclopropyl; R' ｄ６ is H; Alternatively, R ｄ３ but, 【Chemistry 68】 and alternatively selected from 【Chemical Formula 69】 and alternatively selected from 【Chemistry 70】 and alternatively selected from 【Chemical Formula 71】 and alternatively selected from 【Chemical 72】 and Alternatively, R ｄ３ but, 【Chemical 73】 and alternatively selected from 【Chemical 74】 and alternatively selected from 【Chemistry 75】 and alternatively selected from 【Chemical Formula 76】 Selected from: Alternatively, 【Chemical 77】 but, 【Chemical 78】 and alternatively selected from 【Chemical 79】 and alternatively selected from 【Chemistry 80】 Instead, 【Chemistry 81】 42. The 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, selected from:

43. 【Catalog 82】 During the ceremony, R Ｅ is as defined in any one of claims 36 to 38; X ５ But, CR ｅ５ , N, O, S or NR' ｅ５ , alternatively CR ｅ５ , O, N or NR' ｅ５ , alternatively CR ｅ５ or N; X ７ is CR ｅ１ or N; X ８ is CR ｅ２ or N; R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ alkynyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7 membered carbocyclyl and -L'-3 to 7 membered heterocyclyl, and alternatively H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, each of which is selected from 1, 2, or 3 R ｅｓ optionally substituted with; R ｅｓ are independently H, D, halogen, C １－６ Alkyl, C １－６ selected from haloalkyl, —OR′ and —NR′R″; R ｅ５ H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl, alternatively H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; Z １ But, CR ｄ１ and N, alternatively CR ｄ１ and Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N, alternatively CR ｄ５ and R ｄ１ H, D, halogen, CN, C １－６ Alkyl and C １－６ haloalkyl; R ｄ２ , R ｄ４ and R ｄ５ are independently 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 and -L'-3 to 7 membered heterocyclyl, alternatively H, D, halogen, CN, C １－６ Alkyl, C １－６ haloalkyl, —OR′ and —NR′R″; alternatively, R ｄ２ and R ｄ５ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R ｄ３ but, 【Chemistry 83】 , -NR' ｄ６ C(O)R ｄ６ and —C(O)NR ｄ７ R' ｄ７ Selected from: a and b are independently 0, 1, 2 or 3, alternatively 0, 1 or 2; alternatively a+b≦5, alternatively a+b≦3; L' is independently a covalent bond and C １－６ alkylene, alternatively a covalent bond and C １－４ alkylene, each of which is selected from C １－６ Alkyl and C １－６ optionally substituted with 1, 2, 3, or 4 groups selected from haloalkyl; Y １ is CR ｄｄ R ｄｄ or NR' ｄｄ or Y １ is connected to L', Y １ is CR ｄｄ or N; Y ２ But, CR ｄｄ R ｄｄ ,O,S,S(O),NR' ｄｄ and S(O) ２ and alternatively CR ｄｄ R ｄｄ , O, NR' ｄｄ and S(O) ２ Alternatively, Y １ and Y ２ at least one of the groups is a heteroatom group; R ｄｄ are independently 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 and -L"-3 to 7 membered heterocyclyl, and alternatively H, D, halogen, oxo, C １－６ Alkyl, C １－６ selected from haloalkyl, -L''-OR', -L''-NR'R'', -L''-3 to 7 membered carbocyclyl, and -L''-3 to 7 membered heterocyclyl; Or, CR ｄｄ R ｄｄ But H, D, halogen, C １－６ Alkyl, C １－６ forming a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene optionally substituted by 1, 2, or 3 groups selected from haloalkyl, —OR′, and —NR′R″; Alternatively, two non-adjacent R ｄｄ Both are H, D, halogen, CN, C １－６ Alkyl and C １－６ C optionally substituted with 1, 2, 3 or 4 substituents selected from haloalkyl １－３ Forming an alkylene; R' ｄｄ However, independently, H, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR', -L"-NR'R", -L"-3 to 7 membered carbocyclyl and -L"-3 to 7 membered heterocyclyl; alternatively H, C １－６ Alkyl, C １－６ haloalkyl, -L''-3 to 7-membered carbocyclyl, and -L''-3 to 7-membered heterocyclyl; Alternatively, R' ｄｄ and adjacent R ｄｄ together with the atom to which they are attached form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene, which is selected from the group consisting of H, D, halogen, CN, C １－６ Alkyl, C １－６ optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, —OR′, and —NR′R″; R ｄ７ and R' ｄ７ But H, C １－６ Alkyl and C １－６ haloalkyl; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 3 to 7 membered heterocyclyl, alternatively H, C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; L ｄ are independently a covalent bond and C １－６ alkylene, alternatively a covalent bond and C １－４ alkylene; The remaining variables are as defined in claims 39 to 42; 24. The compound of formula (VI) or formula (VI-1) according to claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein each of the above groups may be deuterated up to fully deuterated.

44. R Ｅ is as defined in any one of claims 36 to 38; X ５ is CR ｅ５ or N, alternatively CR ｅ５ and X ７ is CR ｅ１ or N, alternatively CR ｅ１ and X ８ is CR ｅ２ or N, alternatively N; R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ selected from 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, alternatively not —NR′R″, alternatively H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkynyl, —OR′, —O-3 to 7-membered carbocyclyl, 3 to 7-membered carbocyclyl, and 3 to 7-membered heterocyclyl, each of which is selected from 1, 2, or 3 R ｅｓ Alternatively, R ｅ１ is not heterocyclyl; R ｅｓ are independently H, D, halogen, C １－６ Alkyl, C １－６ selected from haloalkyl and —OR′, alternatively selected from H, D, F, Me, and OH; R ｅ５ But H, D, halogen, C １－４ Alkyl and C １－４ haloalkyl, alternatively H or D; Z １ But, CR ｄ１ and N, alternatively CR ｄ１ and Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N, alternatively CR ｄ５ and R ｄ１ is H or D; R ｄ２ , R ｄ４ and R ｄ５ are independently H, D, halogen, CN, C １－４ Alkyl, C １－４ haloalkyl and —OR′, alternatively R ｄ２ and R ｄ５ is independently selected from H, D, and halogen; alternatively, R ｄ２ , R ｄ４ and R ｄ５ is H or D; R ｄ３ but, 【Chemistry 84】 and -NR' ｄ６ C(O)R ｄ６ Alternatively, 【Chemistry 85】 but 【Chemistry 86】 , alternatively 【Hua 87】 and a and b are independently 0, 1 or 2, alternatively a and b are 1; L' is independently a covalent bond and C １－２ alkylene, alternatively selected from a covalent bond and methylene; Y １ NR' ｄｄ or Y １ is connected to L', Y １ is CR ｄｄ or N; Y ２ But, CR ｄｄ R ｄｄ , O, NR' ｄｄ and S(O) ２ Selected from: R ｄｄ are independently H, D, halogen, oxo, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR', -L"-NR'R" and -L"-3 to 7 membered carbocyclyl, alternatively H, D, oxo, C １－６ Alkyl, C １－６ haloalkyl, -L"-OR" and NR'R"; alternatively H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and -L"-OR'; Or, CR ｄｄ R ｄｄ forms a 3- to 7-membered carbocyclylene or a 3- to 7-membered heterocyclylene, which is optionally substituted by one —OR′ and alternatively by one OH; Alternatively, two non-adjacent R ｄｄ Both are C １－２ Forming an alkylene; R' ｄｄ However, independently, H, C １－６ Alkyl, C １－６ haloalkyl and -L''-3 to 7 membered carbocyclyl; Alternatively, R' ｄｄ and adjacent R ｄｄ together with the atom to which they are attached form a 3- to 7-membered heterocyclylene or a 5- to 6-membered heteroarylene, alternatively a 3- to 7-membered heterocyclylene, which is selected from the group consisting of H, D, halogen, C １－６ Alkyl and C １－６ optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl; L″ is independently a covalent bond and C, each of which may be substituted with 1, 2, 3, or 4 R; １－４ alkylene; R is independently selected from H, D, C １－６ Alkyl and C １－６ haloalkyl, or two R together with the C atom to which they are attached form a 3- to 7-membered carbocyclylene, alternatively a 3- to 5-membered carbocyclylene, alternatively 【Hua 88】 Forming; Each of R′ and R″ is independently H, C １－６ Alkyl and C １－６ haloalkyl; The remaining variables are as defined in claims 39 to 42; Alternatively, Y １ is N and Y ２ is O, L' is a covalent bond, and R ｄｄ but not oxo; Alternatively, R ｅ２ Ga-O-C １－６ When R is alkyl, ｅ２ is —OMe, alternatively, R ｅ２ Ga-O-C １－６ When R is haloalkyl, ｅ２ is —O-halomethyl; Alternatively, R ｅ１ H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from 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, alternatively not —NR′R″ or 3- to 7-membered heterocyclyl, alternatively 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, each of which is selected from 1, 2, or 3 R ｅｓ optionally substituted with; R ｅ２ H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkynyl, —OR′, —O-3 to 7 membered heterocyclyl, 3 to 7 membered carbocyclyl and 3 to 7 membered heterocyclyl, and alternatively H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkynyl, —OMe, —O-halomethyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, each of which is selected from 1, 2, or 3 R ｅｓ optionally substituted with; Alternatively, R ｅ２ When is heterocyclyl, R ｅｓ are independently H, D, halogen (F), C １－６ Alkyl and C １－６ 44. The compound of formula (VI) or formula (VI-1) according to claim 43, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

45. R Ｅ is as defined in any one of claims 36 to 38; X ５ is CR ｅ５ or N, alternatively CR ｅ５ and X ７ is CR ｅ１ or N, alternatively CR ｅ１ and X ８ is CR ｅ２ or N, alternatively N; R ｅ１ and R ｅ２ are independently H, F, Cl, CN, Me, Et, n-Bu, CHF ２ , 【Chemistry 89】 , OH, OCH ３ , OEt, OCHF ２ , -NHCH ３ , —O-cyclopropyl, 【Chemistry 90】 , cyclopropyl, 【Chemistry 91】 Alternatively selected from H, F, Cl, CN, Me, Et, n-Bu, CHF ２ , 【Chemistry 92】 , OCH ３ , OEt, OCHF ２ , -NHCH ３ , —O-cyclopropyl, 【Chemistry 93】 , cyclopropyl, 【Chemistry 94】 and alternatively selected from 【Chemistry 95】 Instead of H, F, Cl, CN, Me, Et, CHF ２ , 【Chemistry 96】 , OCH ３ , OEt, OCHF ２ , —O-cyclopropyl, cyclopropyl, 【Chemistry 97】 Alternatively, R ｅ１ but 【Chemistry 98】 Alternatively, instead of R ｅ２ but not OEt; R ｅ５ is selected from H, D, F, Br and Me, alternatively H; Z １ But, CR ｄ１ and N, alternatively CR ｄ１ and Z ２ But, CR ｄ２ and N; Z ４ But, CR ｄ４ and N; Z ５ But, CR ｄ５ and N, alternatively CR ｄ５ and R ｄ１ is H; R ｄ２ , R ｄ４ and R ｄ５ are independently H, F, CN, Me, CHF ２ and OCH ３ Alternatively, R ｄ２ and R ｄ５ is independently selected from H and F; alternatively, R ｄ２ , R ｄ４ and R ｄ５ is H; R ｄ３ but, 【Hua99】 and -NR' ｄ６ C(O)R ｄ６ and alternatively selected from 【Chemistry 100】 and a is 0, 1 or 2, alternatively 0 or 1, and b is 0 or 1; L' is independently selected from a covalent bond and methylene, alternatively a covalent bond; Y １ is NH; or Y １ is connected to L', Y １ is selected from CH, C(OH) and N, alternatively selected from CH and N, alternatively N; Y ２ But, CR ｄｄ R ｄｄ , O, NR' ｄｄ and S(O) ２ and alternatively CR ｄｄ R ｄｄ , O and NR' ｄｄ is selected from, alternatively O; R ｄｄ are independently H, F, oxo, OH, Me, -C(CH ３ ) ２ OH, -CH ２ OH, -CH ２ OMe, 【Chemistry 101】 and —NHMe, alternatively selected from H, oxo, OH, Me, —C(CH ３ ) ２ OH, -CH ２ OH, -CH ２ OMe, 【Chemistry 102】 and —NHMe, alternatively selected from H, OH, Me, —C(CH ３ ) ２ OH, -CH ２ OMe and 【Chemistry 103】 Selected from; Or, CR ｄｄ R ｄｄ But cyclopropylene, 【Chemistry 104】 and alternatively cyclopropylene or 【Chemistry 105】 or alternatively forming cyclopropylene; Alternatively, two non-adjacent R ｄｄ Both are -CH ２ CH ２ -forming; R' ｄｄ are independently H, Me and —CH ２ -cyclopropyl; Alternatively, R' ｄｄ and adjacent R ｄｄ along with the atoms to which they are bonded, 【Chemistry 106】 Alternatively, 【Chemistry 107】 Forming; The remaining variables are as defined in claims 39 to 42; Alternatively, R ｅ１ is H, F, Cl, CN, Me, Et, n-Bu, CHF ２ , OCH ３ , OEt, OCHF ２ , -NHCH ３ , —O-cyclopropyl, 【Chemistry 108】 , cyclopropyl, 【Chemistry 109】 Alternatively selected from H, F, Cl, CN, Me, Et, CHF ２ , OCH ３ , OEt, OCHF ２ , —O-cyclopropyl, 【Chemistry 110】 and cyclopropyl, alternatively H, F, CN, Me, CHF ２ , OCH ３ , OEt, OCHF ２ , —O-cyclopropyl, and cyclopropyl; R ｅ２ But H, F, Cl, CN, Me, CHF ２ , 【Chemistry 111】 ,OCH ３ ,OOEt,OCHF ２ 、 【Chemistry 112】 , cyclopropyl, 【Chemistry 113】 Alternatively selected from H, F, Cl, CN, Me, CHF ２ , 【Chemistry 114】 , OCH ３ , OCHF ２ , cyclopropyl, 【Chemistry 115】 Selected from: Alternatively, R ｄ３ but, 【Chemistry 116】 and alternatively selected from 【Chemistry 117】 and alternatively selected from 【Chemistry 118】 and alternatively selected from 【Chemistry 119】 and alternatively selected from 【Chemistry 120】 and Alternatively, R ｄ３が 、 【Chemistry 121】 and alternatively selected from 【Chemical 122】 and alternatively selected from 【Chemical 123】 and alternatively selected from 【Chemical 124】 Selected from: Alternatively, 【Chemistry 125】 but, 【126】 and alternatively selected from 【Chemistry 127】 and alternatively selected from 【128】 45. The compound of formula (VI) or formula (VI-1) according to claim 43 or 44, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, selected from:

46.

129. During the ceremony, X １ But, CR ｅ６ , O, S, N and NR' ｅ６ Selected from: X ５ But, CR ｅ５ , N, O, S or NR' ｅ５ and X ６ is C or N; X １０ But, CR ｅ７ , O, S, N and NR' ｅ７ Selected from: X １１ But, CR ｅ８ , O, S, N and NR' ｅ８ Selected from: R ｅ７ and R ｅ８ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ selected from haloalkyl, -L'-OR', -L'-SR', -L'-NR'R'', -L'-3 to 7-membered carbocyclyl, and -L'-3 to 7-membered heterocyclyl; R' ｅ７ and R' ｅ８ But independently, H, D, C １－６ Alkyl, C １－６ selected from haloalkyl, -L'-3 to 7 membered carbocyclyl, and -L'-3 to 7 membered heterocyclyl; Or, X １０ and X １１ Both of the substituents C may contain one double bond. ３－５ Forms an alkylene, ３－５ The alkylene may be one, two, three or four R ｅ and the C ３－５ 1, 2, or 3 methylene units in the alkylene may be independently replaced by —NR″—, —N(R″)C(O)—, —C(O)N(R″)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, or —S(O)—; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 3- to 7-membered heterocyclyl; L' are independently C １－６ Alkyl and C １－６ a covalent bond optionally substituted with 1, 2, 3 or 4 groups selected from haloalkyl and C １－６ alkylene; L ｄ are independently a covalent bond and C １－６ alkylene, alternatively a covalent bond and C １－４ alkylene; R ｅ is as defined in any one of claims 36 to 38, alternatively R ｅ is not alkenyl or alkynyl; R ｅ５ , R' ｅ５ , R ｅ６ and R' ｅ６ each of which is as defined in any one of claims 39 to 45; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; wherein each of the groups may be deuterated up to fully deuterated.

24. The compound of formula (VI-2) according to claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

47. X １ But, CR ｅ６ , N and NR' ｅ６ is selected from, alternatively N; X ５ But, CR ｅ５ , N or NR' ｅ５ and X ６ is C or N, alternatively C; X １０ But, CR ｅ７ , N and NR' ｅ７ Selected from: X １１ But, CR ｅ８ , O, N and NR' ｅ８ Selected from: R ｅ７ But H, D, C １－６ Alkyl, C １－６ selected from haloalkyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; R' ｅ７ But H, D, C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; R ｅ８ But H, D, C １－６ Alkyl and C １－６ haloalkyl; R' ｅ８ But H, C １－６ Alkyl and C １－６ haloalkyl; Or, X １０ and X １１ The substituents are both C ３－５ Forms an alkylene, alternatively -(CH ２ ) ４ -, which may contain one double bond, ３－５ Alkylene or -(CH ２ ) ４ - is 1, 2, 3 or 4 R ｅ and the C ３－５ Alkylene or -(CH ２ ) ４ In the formula (I), one, two or three methylene units may be independently replaced by -NR"-, -C(O)N(R")-, -C(O)-, or -O-. Alternatively, the formula (I) may be replaced by any of the formulas (I) and (II). ３－５ Alkylene or -(CH ２ ) ４ one methylene unit in - may be independently replaced by -O-; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; R ｅ is as defined in any one of claims 36 to 38, alternatively R ｅ is not alkenyl or alkynyl; R ｅ５ , R' ｅ５ , R ｅ６ and R' ｅ６ each of which is as defined in any one of claims 39 to 45; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; Alternatively, X １ , X ５ , X ６ , X １０ and X １１ or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, according to claim 46, wherein up to three of

48. X １ is N; X ５ But, CR ｅ５ , N or NR' ｅ５ , alternatively CR ｅ５ or N, and alternatively CR ｅ５ and X ６ is C or N, alternatively C; X １０ is CR ｅ７ or NR' ｅ７ and X １１ But, CR ｅ８ , O and NR' ｅ８ and alternatively CR ｅ８ or NR' ｅ８ and R ｅ７ But C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, and —O-3- to 7-membered heterocyclyl; R' ｅ７ But C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, alternatively 3- to 7-membered carbocyclyl; Alternatively, R ｅ７ or R' ｅ７ When is heterocyclyl, R ｅ７ or R' ｅ７ is a 3- to 7-membered oxacyclyl, alternatively a 4- to 6-membered oxacyclyl, alternatively a 5-membered oxacyclyl; R ｅ８ But H, D, C １－６ Alkyl and C １－６ haloalkyl, alternatively selected from C １－６ Alkyl or C １－６ haloalkyl; R' ｅ８ But C １－６ Alkyl and C １－６ haloalkyl; Or, X １０ and X １１ The substituents of 【Chemistry 130】 Alternatively, 【Chemistry 131】 Instead of forming 【Chemistry 132】 and alternatively forming a structure selected from 【Chemistry 133】 Forming; Each of R′ and R″ is independently H, C １－６ Alkyl and C １－６ haloalkyl; R ｅ１ , R ｅ２ , R ｅ５ and R' ｅ５ are as defined in any one of claims 39 to 45; alternatively, R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ haloalkyl, —OR′, and —O-3 to 7 membered carbocyclyl; alternatively, H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and —OR′; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, according to claim 46 or 47, wherein each of

49. X １ is N; X ５ But, CR ｅ５ , N or NR' ｅ５ , alternatively CR ｅ５ or N, and alternatively CR ｅ５ and X ６ is C or N, alternatively C; X １０ But, CR ｅ７ and NR' ｅ７ Selected from: X １１ But, CR ｅ８ , O and NR' ｅ８ and alternatively CR ｅ８ or NR' ｅ８ and R ｅ７ is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl and —O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl and —O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and —O-tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and —O-tetrahydrofuranyl; alternatively Me, Et, cyclopropyl, 【Chemistry 134】 Alternatively selected from Me, Et, cyclopropyl, 【Chemistry 135】 Alternatively selected from Me, Et, cyclopropyl, 【Chemistry 136】 Alternatively selected from Me, Et, cyclopropyl, 【Chemistry 137】 Selected from: R' ｅ７ is selected from Me, Et, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and morpholinyl; alternatively selected from Me, Et, cyclopropyl, tetrahydrofuranyl and tetrahydropyranyl; alternatively selected from Me, Et, cyclopropyl and tetrahydrofuranyl; alternatively selected from Me, Et, cyclopropyl, 【Chemistry 138】 Alternatively selected from Me, Et, cyclopropyl, 【Chemistry 139】 Alternatively selected from Me, Et, cyclopropyl, 【Chemistry 140】 and alternatively selected from Me, Et, cyclopropyl, and 【Chemistry 141】 is selected from, alternatively cyclopropyl; R ｅ８ is selected from H, Me and Et, alternatively H or Me, alternatively Me; R' ｅ８ is Me or Et, alternatively Me; Or, X １０ and X １１ The substituents of 【142】 Alternatively, 【143】 Instead of forming 【Chemical 144】 and alternatively forming a structure selected from 【Chemistry 145】 Forming; R ｅ１ and R ｅ２ are independently H, F, Cl, CN, Me, Et, CHF ２ , OCH ３ , OEt, OCHF ２ , —O-cyclopropyl and 【Chemistry 146】 Alternatively selected from H, F, CN, Me, OMe, OEt, OCHF ２ and —O-cyclopropyl, alternatively selected from H, F, CN, Me, OCH ３ , OEt, OCHF ２ and —O-cyclopropyl, alternatively selected from H, Me, OCH ３ and OEt; R ｅ５ is H; R' ｅ５ is Me; R″ is H or methyl; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; Alternatively, X １０ and X １１ The substituents of 【147】 Alternatively, a structure selected from 【148】 Alternatively, a structure selected from 【149】 Alternatively, a structure selected from 【Chemistry 150】 forming a structure selected from: Alternatively, 【Chemistry 151】 but, 【Chemistry 152】 and alternatively selected from 【Chemistry 153】 and alternatively selected from 【Chemistry 154】 Selected from: Alternatively, R ｄｄ are independently H, Me and —C(CH ３ ) ２ OH, or two non-adjacent R ｄｄ Both are -CH ２ CH ２ -, alternatively 【Chemistry 155】 has the following structure: 【Chemistry 156】 Alternatively, R ｄ３ but, 【Chemistry 157】 and alternatively selected from 【158】 and alternatively selected from 【Chemistry 159】 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

50. 【Catalog 160】 During the ceremony, X １０ is CR ｅ７ or NR' ｅ７ and X １１ But, CR ｅ８ , O and NR' ｅ８ and alternatively CR ｅ８ or NR' ｅ８ and R ｅ７ But 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; alternatively, C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, tetrahydrofuranyl, morpholinyl, and —O-3- to 7-membered heterocyclyl; alternatively 3- to 7-membered carbocyclyl; R' ｅ７ But C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl, alternatively 3- to 7-membered carbocyclyl; R ｅ８ But H, D, C １－６ Alkyl and C １－６ haloalkyl, alternatively selected from C １－６ Alkyl or C １－６ haloalkyl; R' ｅ８ But C １－６ Alkyl and C １－６ haloalkyl; Or, X １０ and X １１ The substituents of 【Chemistry 161】 Alternatively, 【Chemistry 162】 Instead of forming 【Chemistry 163】 and alternatively forming a structure selected from 【Chemical 164】 Forming; R ｅ１ and R ｅ２ each of which is as defined in any one of claims 39 to 45, and R' ｅ１ and R' ｅ２ are as defined in any one of claims 23 to 26; alternatively, R ｅ１ and R ｅ２ are independently H, D, halogen, CN, C １－６ Alkyl, C １－６ is selected from haloalkyl, —OR′, —O-3 to 7 membered carbocyclyl, and —O-3 to 7 membered heterocyclyl, and is alternatively not halogen; alternatively is H, D, C １－６ Alkyl, C １－６ haloalkyl, —OR′, and —O-3- to 7-membered carbocyclyl; alternatively, R ｅ２ H, D, halogen, CN, C １－６ Alkyl, C １－６ haloalkyl and —OR′, alternatively R ｅ２ But H, D or C １－６ haloalkyl; R' ｅ１ and R' ｅ２ are independently H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl, alternatively selected from H, D, halogen and C １－６ selected from alkyl; Or, CR ｅ１ R' ｅ１ forms a 3- to 7-membered carbocyclyl or a 3- to 7-membered heterocyclyl, alternatively forms a 3- to 7-membered heterocyclyl; Each of R′ and R″ is independently H, C １－６ Alkyl and C １－６ haloalkyl; alternatively, R″ is selected from C １－４ haloalkyl; The remaining variables are as defined in any one of claims 46 to 49; wherein each of the groups may be deuterated up to fully deuterated, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, according to claim 23 or 46.

51. X １０ But, CR ｅ７ and NR' ｅ７ Selected from: X １１ But, CR ｅ８ , O and NR' ｅ８ and alternatively CR ｅ８ or NR' ｅ８ and R ｅ７ is Me, Et, cyclopropyl, 【Chemistry 165】 Alternatively selected from Me, Et, cyclopropyl, 【Chemistry 166】 is selected from, alternatively cyclopropyl; R' ｅ７ is selected from Me, Et and cyclopropyl, alternatively cyclopropyl; R ｅ８ is selected from H, Me and Et, alternatively H or Me, alternatively Me; R' ｅ８ is Me or Et, alternatively Me; Or, X １０ and X １１ The substituents of 【167】 Alternatively, 【168】 Instead of forming 【169】 and alternatively forming a structure selected from 【Chemistry 170】 Forming; R ｅ１ and R ｅ２ are independently H, F, CN, Me, CHF ２ ,OH,OMe,OEt,OCHF ２ , —O-cyclopropyl and 【171】 Alternatively, H, CN, Me, CHF ２ , OH, OCH ３ , OEt, —O-cyclopropyl and 【172】 Alternatively, H, Me, CHF ２ , OCH ３ , OEt and —O-cyclopropyl; alternatively, R ｅ２ H, F, CN, Me, CHF ２ , OH and OMe, alternatively R ｅ２ is H or CHF ２ and R' ｅ１ and R' ｅ２ is independently selected from H, F and Me; Or, CR ｅ１ R' ｅ１ but 【Chemistry 173】 Forming; R″ is H, methyl and CHF ２ and alternatively CHF ２ and The remaining variables are as defined in any one of claims 46 to 49; Alternatively, X １０ and X １１ The substituents of 【Chemical 174】 Alternatively, a structure selected from 【Chemistry 175】 Alternatively, a structure selected from 【176】 forming a structure selected from: Alternatively, 【Chemical 177】 but, 【Chemical 178】 and alternatively selected from 【179】 and alternatively selected from 【Chemistry 180】 Selected from: Alternatively, Y １ is CH or N, and Y ２ But, CR ｄｄ R ｄｄ and O; R ｄｄ are independently H, OH, Me, -CH ２ OMe and -C(CH ３ ) ２ OH, or two non-adjacent R ｄｄ Both are -CH ２ CH ２ -forming; Alternatively, R ｄ３ but, 【Chemistry 181】 and alternatively selected from 【Chemistry 182】 and alternatively selected from 【Chemistry 183】 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

52. 【Catalog 184】 During the ceremony, E is CR ｅ１２ and N; J is CR ｅ１３ and N; R ｅ９ , R ｅ１０ , R ｅ１１ , R ｅ１２ and R ｅ１３ H, D, halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, 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 and -Y ５ -C ０－６ Alkylene-R ６ Selected from: Y ５ is O, S and NR ５ Selected from: R ５ But H, C １－６ Alkyl and C １－６ haloalkyl; R ６ is selected from 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl; Or, R ｅ９ and R ｅ１３ together with the carbon atoms to which they are attached, 1, 2, 3 or 4 R ｅ forming a 5- to 7-membered carbocyclyl, a 5- to 7-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl optionally substituted with Or, R ｅ９ and R ｅ１０ together with the carbon atoms to which they are attached, 1, 2, 3 or 4 R ｅ forming an optionally substituted 5- to 7-membered carbocyclyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R ｅ is as defined in any one of claims 36 to 38, alternatively R ｅ is not alkenyl or alkynyl; L' are independently C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - a covalent bond optionally substituted with 1, 2, 3 or 4 groups selected from 3- to 7-membered heterocyclyl and C １－６ alkylene; L ｄ are independently a covalent bond and C １－６ alkylene, alternatively a covalent bond and C １－４ alkylene; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -3 to 7-membered carbocyclyl and -L ｄ - selected from 3- to 7-membered heterocyclyl; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; wherein each of the groups may be deuterated up to fully deuterated.

24. The compound of formula (VI-3) according to claim 23, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

53. E is CR ｅ１２ and N; J is CR ｅ１３ and N; R ｅ９ But H, D, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —OR′, —NR′R″, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, and —Y ５ -C ０－６ Alkylene-R ６ Alternatively, H, D, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, —OR′ and —NR′R″; Y ５ However, O and NR ５ Selected from: R ５ But H, C １－６ Alkyl and C １－６ haloalkyl; R ６ is selected from 3- to 7-membered carbocyclyl and 3- to 7-membered heterocyclyl; R ｅ１０ But H, D, halogen, C １－６ Alkyl and C １－６ haloalkyl; R ｅ１１ , R ｅ１２ and R ｅ１３ But H, D, C １－６ Alkyl or C １－６ Is it haloalkyl? Or, R ｅ９ and R ｅ１３ together with the carbon atoms to which they are attached, 1, 2, 3 or 4 R ｅ forming an optionally substituted 5- to 7-membered carbocyclyl or 5- to 7-membered heterocyclyl; Or, R ｅ９ and R ｅ１０ together with the carbon atoms to which they are attached, 1, 2, 3 or 4 R ｅ forming an optionally substituted 5- to 7-membered carbocyclyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R ｅ is as defined in any one of claims 36 to 38, alternatively R ｅ is not alkenyl or alkynyl; Each of R′ and R″ is independently H, C １－６ Alkyl, C １－６ selected from haloalkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; Alternatively, at least one of E and J is N; alternatively, only one of E and J is N. The compound of formula (VI-3) according to claim 52, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

54. E is CR ｅ１２ and N; J is CR ｅ１３ and N; R ｅ９ But H, D, C １－６ Alkyl, C １－６ Haloalkyl, C ２－４ Alkynyl, —NR′R″, 3- to 7-membered heterocyclyl, and —O—C ０－４ alkylene-3 to 7 membered heterocyclyl, alternatively H, D, C １－６ Alkyl, C １－６ Haloalkyl, C ２－４ selected from alkynyl and —NR′R″; R ｅ１０ But H, D, C １－６ Alkyl and C １－６ haloalkyl; R ｅ１１ , R ｅ１２ and R ｅ１３ is H or D; Or, R ｅ９ and R ｅ１３ together with the carbon atoms to which they are attached form a 5- to 7-membered heterocyclyl, alternatively a dihydrooxazinyl, which is a 5- to 7-membered heterocyclyl having 1, 2, 3, or 4 R ｅ may be substituted with; Or, R ｅ９ and R ｅ１０ together with the carbon atoms to which they are attached form a 5- to 7-membered carbocyclyl, a 5- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, alternatively a 5- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, alternatively a dihydrooxazinyl or a 5-membered azaaryl, which is selected from the group consisting of 1, 2, 3 or 4 R ｅ optionally substituted with; R ｅ is as defined in any one of claims 36 to 38, alternatively R ｅ is not alkenyl or alkynyl; alternatively, R ｅ are independently H, D, halogen, C １－６ Alkyl, C １－６ haloalkyl, —OR′ and —NR′R″; alternatively, H, D, C １－６ Alkyl, C １－６ selected from haloalkyl and —OR′, alternatively selected from Me and OMe; Each of R′ and R″ is independently H, C １－６ Alkyl and C １－６ haloalkyl; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; Alternatively, R ｅ But independently, H, D, C １－６ Alkyl and C １－６ 54. The compound of formula (VI-3) according to claim 52 or 53, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein haloalkyl is selected from, alternatively, H or Me.

55. E is CR ｅ１２ and N; J is CR ｅ１３ and N; R ｅ９ H, -NHMe, 【Chemistry 185】 and alternatively selected from H, —NHMe, and 【Chemistry 186】 Selected from: R ｅ１０ is selected from H and Me; R ｅ１１ , R ｅ１２ and R ｅ１３ is H; Or, R ｅ９ and R ｅ１３ together with the carbon atoms to which they are attached. 【187】 Forming or; Or, R ｅ９ and R ｅ１０ together with the carbon atoms to which they are attached. 【Chemistry 188】 Alternatively, 【Chemistry 189】 Alternatively, 【190】 Alternatively, 【Chemistry 191】 Forming; R １ａ , R １ｂ , Z １ , Z ２ , Z ４ , Z ５ and R ｄ３ each of which is as defined in any one of claims 39 to 45; Alternatively, 【Chemistry 192】 but, 【Chemistry 193】 and alternatively selected from 【Chemistry 194】 and alternatively selected from 【Chemistry 195】 and alternatively selected from 【Chemistry 196】 and alternatively selected from 【Chemistry 197】 and alternatively selected from 【Chemistry 198】 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

56. 【Chemical 199-1】 【Hua 199-2】 【Hua 199-3】 【Chemistry 199-4】 【Hua 199-5】 【Hua 199-6】 【Hua 199-7】 【Hua 199-8】 【Hua 199-9】 【Chemistry 199-10】 【Hua 199-11】 【Chemistry 199-12】 【Chemistry 199-13】 【Chemistry 199-14】 【Chemistry 199-15】 【Chemistry 199-16】 【Hua 199-17】 【Chemistry 199-18】 2. The 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. 57. A pharmaceutical composition comprising 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, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

58. 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 manufacture of a medicament for the prevention and / or treatment of an HPK1 mediated disorder, disease or condition.

59. 58. 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 the prevention and / or treatment of 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 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.

61. 61. The use of claim 58, the compound of claim 59, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or pharmaceutical composition thereof, or the method of claim 60, wherein the disorder, disease or condition is a proliferative disorder.

62. 62. The use, compound, pharmaceutical composition or method of claim 61, wherein the proliferative disorder is cancer.

63. 62. The use, compound, pharmaceutical composition, or method of claim 61, wherein said proliferative disorder is associated with one or more activating mutations in HPK1.

64. 61. The use of claim 58, the compound of claim 59, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or composition thereof, or the method of claim 60, wherein the disorder, disease or condition is a chronic viral infection.

65. 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 manufacture of a medicament for increasing the efficacy of vaccination.

66. 58. 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. 57. A method of increasing the efficacy of vaccination, 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.

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