Compound as cbl-b inhibitor

Abstract

The present invention relates to a compound of formula (A), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a polymorph or a prodrug thereof as a Cbl-b inhibitor. The present invention further relates to a composition comprising the compound, a preparation method therefor and a use thereof.

Description

Compounds used as Cbl-b inhibitors Field of the Invention

[0001] The present invention provides compounds and compositions for inhibiting Cbl-b enzymes and methods of using the same in vivo, in vitro or ex vivo to modulate the immune system, treat diseases and treat cells.

[0002] Background of the Invention

[0003] The ubiquitin-proteasome pathway is a complex system involved in the regulation of protein function and catabolism. Ubiquitin is activated by ubiquitin-activating enzymes, or E1 enzymes, which then transfer ubiquitin to ubiquitin-conjugating enzymes, or E2 enzymes. Finally, ubiquitin ligases, or E3 enzymes, facilitate the transfer of ubiquitin from the E2 enzymes to target proteins. Casitas B lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T cell activation. Approximately 35 E2 enzymes and over 500 E3 enzymes are encoded in the human genome.

[0004] The discovery of drugs that modulate E2 or E3 enzymes accordingly offers potential for therapies targeting disease processes involving specific E2 or E3 enzymes. The present invention is directed to providing compounds as drugs that inhibit one such E3 enzyme, Casitas B lineage lymphoma proto-oncogene-b (Cbl-b).

[0005] Summary of the Invention

[0006] The present invention generally provides a compound of formula (A), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof:

[0007] Wherein, each group is as defined below in the specification.

[0008] The present invention also discloses a method for regulating the activity of immune cells, which comprises contacting the immune cells with an effective amount of any compound disclosed above or disclosed herein, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs.

[0009] The present invention also discloses a method for treating a cancer responsive to inhibition of Cbl-b activity in an individual in need thereof, comprising administering to the individual an effective amount of any compound disclosed above or disclosed herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

[0010] The present invention also discloses a method for inhibiting Cbl-b activity in an individual in need thereof, comprising administering to the individual an effective amount of any compound disclosed above or disclosed herein, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0011] The present invention also discloses a method for treating or preventing a disease or condition associated with Cbl-b activity in a subject in need thereof, comprising administering to the subject any compound disclosed above or disclosed herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

[0012] The present invention also discloses a method for inhibiting abnormal cell proliferation, comprising administering to an individual in need thereof an effective amount of isolated modified immune cells, wherein the immune cells have been contacted with or are in contact with any compound disclosed above or disclosed herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

[0013] The present invention also discloses a method for inhibiting abnormal cell proliferation, comprising administering to an individual in need thereof a composition comprising a cell population containing isolated modified immune cells, wherein the immune cells have been contacted with or are in contact with any compound disclosed above or disclosed herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

[0014] The present invention also discloses a method for inhibiting abnormal cell proliferation, comprising administering an effective amount of any compound disclosed above or disclosed herein, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs.

[0015] The present invention also discloses a pharmaceutical composition comprising a Cbl-b inhibitor and one or both of an adjuvant and an antigen, wherein the Cbl-b inhibitor is any compound disclosed above or disclosed herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

[0016] The present invention also discloses the use of a Cbl-b inhibitor in the preparation of a medicament for treating or preventing a disease or condition associated with Cbl-b activity, wherein the Cbl-b inhibitor is any compound disclosed above or disclosed herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof.

[0017] In any embodiment disclosed herein, the Cbl-b protein can be mammalian Cbl-b or human Cbl-b.

[0018] Definition and Description

[0019] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0020] definition

[0021] Chemical definition

[0022] Definitions of specific functional groups and chemical terms are described in more detail below.

[0023] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-8 "Alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C 1-8 、C 1-7 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-8 、C 2-7 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-8 、C 3-7 、C 3-6 、C 3-5 、C 3-4 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-8 、C 5-7 、C 5-6 、C 6-8 、C 6-7 and C 7-8 .

[0024] “C 1-8 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms. In some embodiments, C 1-6 Alkyl, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), i-Bu(-CH2CH(CH3)2), and t-Bu(-C(CH3)3).

[0025] “C 2-8 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-6 Alkenyl and C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] “C 2-8 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-6 Alkynyl is preferred, more preferably C 2-4 Alkynyl. C2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] “C 1-8 "Alkylene" refers to the removal of C 1-8 In some embodiments, C 1-6 Alkylene, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0028] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0029] “C 1-8 "Haloalkyl" refers to the above-mentioned "C 1-8 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-6 Halogenated alkyl, C 1-4 Haloalkyl and C 1-2Haloalkyl is particularly preferred. Exemplary haloalkyl includes, but is not limited to: -CF , -CH F, -CHF , -CHFCH F, -CH CHF , -CF CF , -CCl , -CH Cl , -CHCl , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The haloalkyl group can be substituted at any available point of attachment, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "3 to 15 membered carbocyclyl or cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 15 ring carbon atoms and zero heteroatoms, including monocyclic carbocyclyl, bridged carbocyclyl, spirocarbocyclyl and fused carbocyclyl. More specifically, it includes any stable 3, 4, 5, 6 or 7 membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, 13, 14 or 15 membered bicyclic or tricyclic cycloalkyl. In some embodiments, C 3-7 Cycloalkyl monocyclic and C 3-6 Cycloalkyl monocyclic ring is particularly preferred, more preferably C 5-6Monocyclic cycloalkyl. In some embodiments, 6-10 membered bicyclic cycloalkyl is preferred, preferably 6-10 membered bicyclic spirocycloalkyl, more preferably 7-10 membered bicyclic spirocycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Examples of the carbocycle 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, spiro[3.3]heptane, fluorenyl, indanyl, adamantyl, and tetrahydronaphthyl. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] "3 to 15 membered heterocyclyl" refers to a group of a 3 to 15 membered non-aromatic ring system having ring carbon atoms and 1 to 5, 1 to 4 or 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. Optionally, the nitrogen atom is oxidized to form an N-oxide; the sulfur atom is oxidized to form a sulfone or sulfoxide. The 3 to 15 membered heterocyclyl includes a monocyclic heterocyclyl, a bridged heterocyclyl, a spiro heterocyclyl and a fused heterocyclyl. More specifically, it includes any stable 3, 4, 5, 6, 7 or 8 membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, 13, 14 or 15 membered bicyclic or tricyclic heterocyclyl. More preferably, it includes a 3 to 8 membered monocyclic heterocyclyl, a 6 to 10 membered bicyclic group, a 6 to 10 membered bridged bicyclic heterocyclyl, a 6 to 10 membered spiro bicyclic heterocyclyl and a 6 to 10 membered fused bicyclic heterocyclyl. More preferably, a 7-10 membered spiro bicyclic heterocyclic group having ring carbon atoms and 1 to 4 ring heteroatoms selected from N, O and S is included. More preferably, a 9-14 membered bicyclic or tricyclic bridged, spiro heterocyclic or fused heterocyclic group having ring carbon atoms and 1 to 4 ring heteroatoms selected from N, O and S is included. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. In some embodiments, a 4-12 membered heterocyclic group is preferred, which is a 4-12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms selected from N, O and S; in some embodiments, a 3-10 membered heterocyclic group is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms selected from N, O and S. In some embodiments, it is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms selected from N, O and S. Preferably, in some embodiments, 3-8 membered is a 3-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms selected from N, O and S; preferably, 3-7 membered heterocyclyl is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O and S; preferably, 3-6 membered heterocyclyl is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O and S; preferably, 4-8 membered heterocyclyl is a 4-8 membered heterocyclyl having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O and S; The present invention further comprises a 4- to 8-membered non-aromatic ring system having ring heteroatoms selected from N, O and S; more preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3, preferably 1 to 2, ring heteroatoms selected from N, O and S; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O and S; more preferably a 4- to 5-membered heterocyclyl, which is a 4- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 2 ring heteroatoms selected from N, O and S.Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, where the point of attachment is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiirane. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, oxazolidinyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, thiepanyl, heterocycloheptatrienyl, oxepinyl, oxaspiro[3.3]heptanyl, and thiepanyl. Exemplary 7-membered heterocyclyls containing two heteroatoms include, but are not limited to, azazepanyl, oxathiepanyl, and thiazepanyl nitrogen. Exemplary 5-membered heterocyclyls fused to a phenyl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinone. Exemplary 6-membered heterocyclyls fused to a phenyl ring (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "5- to 14-membered heteroaryl" refers to a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-5, 1-4, 1-3, or 1-2 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. In some embodiments, heteroaryl bicyclic ring systems are 9-10 membered bicyclic heteroaryl groups containing 1-5 ring heteroatoms selected from N, O, and S. Preferred heteroaryl groups also include ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 10-membered heteroaryls are preferred, which are 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-5 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryls are particularly preferred, which are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms selected from N, O, and S. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered 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 one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] "Oxo" refers to =0.

[0035] "-CN" refers to a -C≡N group.

[0036] "-OR'" refers to an alkoxy group, wherein R' represents H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl as defined above.

[0037] Unless otherwise stated, "optionally substituted" means that the group is unsubstituted or substituted by one or more (e.g., 12, 3, 4, or 5) substituents listed for the group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group is unsubstituted. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, or 1 to 5 substituents. When multiple substituents are present, each substituent is independently selected unless otherwise stated.

[0038] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0039] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0040] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NRbb 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0041] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0042] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0043] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc)2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0044] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0045] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、 -N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ffCO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(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, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0046] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0047] R ffEach of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0048] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(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 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6Alkyl, -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 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0049] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb)R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0050] Other definitions

[0051] As used herein, the term "Cbl-b" refers to a Cbl-b protein. The term also includes naturally occurring Cbl-b variants, including splice variants or allelic variants. The term also includes non-naturally occurring Cbl-b variants, such as recombinant Cbl-b proteins or truncated variants thereof, which generally retain the binding ability of naturally occurring Cbl-b or naturally occurring Cbl-b variants (e.g., the ability to bind to an E2 enzyme).

[0052] As used herein, "proliferation" refers to the proliferation of cells. Increased proliferation includes the production of a greater number of cells relative to a baseline value. Decreased proliferation includes the production of a decreased number of cells relative to a baseline value. In some embodiments, the cells are immune cells, such as T cells, and increased proliferation is desired. In some embodiments, the cells are cancer cells and decreased proliferation is desired.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0054] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0055] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0056] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0057] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0058] "Disease," "disorder," and "condition" are used interchangeably herein.

[0059] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0060] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0061] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0062] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form.

[0063] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0064] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0065] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0066] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0067] The term "metabolite" refers to substances including products produced during the metabolism of the compounds of the present invention in the body, including intermediate metabolites and terminal metabolites.

[0068] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0069] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0070] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0071] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0072] As used herein, "excipients" include pharmaceutically acceptable excipients, carriers, vehicles, or stabilizers that are non-toxic to cells or mammals exposed thereto at the dosages and concentrations employed. Typically, a physiologically acceptable excipient is a buffered aqueous solution.

[0073] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0074] Detailed Description of the Invention

[0075] In one embodiment, the present invention relates to a compound of formula (A), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0076] Indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring;

[0077] Symbol A represents carbon (C), C (R a ) or nitrogen (N);

[0078] Symbol B represents C(R b )、C(R b )(R b '), N(R b ), N, O or S;

[0079] Symbol D represents C(R d )、C(R d )(R d '), N(R d ) or N;

[0080] Symbol E represents C(R e )、C(R e )(R e '), N(R e ) or N;

[0081] Symbol F represents C(R f )、C(R f )(R f '), N(R f ), N, O or S;

[0082] Symbol Q represents C(R q )、C(R q )(R q '), N(R q ), N, O or S;

[0083] Alternatively, the symbols B and D together with the substituents thereon, or the symbols D and E together with the substituents thereon, form a group selected from the group consisting of: C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0084] Each occurrence of R1 is independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups;

[0085] Each occurrence of R2 is independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups;

[0086] R a Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0087] R b Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0088] R b 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0089] Or, R b and R b 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0090] R d Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0091] R d 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0092] Or, R d and R d 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0093] R e Selected from H, halogen, CN, oxo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0094] R e 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0095] Or, R e and R e 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0096] R f Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0097] R f 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0098] Or, R f and R f 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0099] R q Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0100] R q 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0101] Or, R q and R q 'Together with the carbon atom to which it is connected, it forms an oxo, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0102] Each occurrence of R8 is independently selected from NR'R", C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with 1-3 R9 substituents;

[0103] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0104] R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0105] X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O;

[0106] Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O;

[0107] When there is a single bond between X and Y and X and Y do not form a ring, X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O; and Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O;

[0108] When there is a double bond between X and Y and X and Y do not form a ring, X is N or C (R x1 ); and Y is N or C(R y1 );

[0109] R x1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0110] R x2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0111] Or, R x1 and R x2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0112] R y1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0113] R y2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0114] Or, R y1 and R y2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0115] When X and Y are cyclic together, they form a C6-C 10 Aryl, 5-14 membered heteroaryl, C 5-15 Cycloalkyl and 4-15 membered heterocyclic group, which is optionally substituted by r R 10 Substituent substitution;

[0116] L is selected from a covalent bond, -O-, -S- and -NR'-, or L is a C1-C6 alkylene group, one or more methylene units of which are optionally and independently replaced by -O-, -C(O)- or -S-;

[0117] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6Substituents of haloalkyl groups;

[0118] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0119] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0120] m is 0, 1, 2, 3, 4 or 5;

[0121] p is 0, 1, 2, 3, 4, or 5;

[0122] r is 0, 1, 2, 3, 4, or 5;

[0123] x is 1, 2, 3, or 4;

[0124] y is 1, 2, 3, or 4.

[0125] In a further embodiment, the present invention is directed to a compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0126] It indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring.

[0127] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (II):

[0128] Indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring;

[0129] The symbol G represents a covalent bond, C(R g )、C(R g )(R g '), N(R g ), N, O or S;

[0130] The symbol H represents a covalent bond, C(R h )、C(R h )(R h '), N(R h ), N, O or S;

[0131] The symbol J represents a covalent bond, C(R j )、C(R j )(R j '), N(R j ), N, O or S;

[0132] The symbol K represents a covalent bond, C(R k )、C(R k )(R k '), N(R k ), N, O or S;

[0133] R g Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0134] R g 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0135] Or, R g and R g 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0136] R h Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0137] R h 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0138] Or, R h and R h 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0139] R j Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0140] R j 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0141] Or, R j and R j 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0142] R k Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0143] R k 'Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0144] Or, R k and R k 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 groups selected from H, halogen, CN, oxo, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0145] Any pair of G and H, H and J, J and K together with the substituents thereon form a group selected from the following: phenyl, a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-6 cycloalkyl and 3-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; other groups are as defined for formula A.

[0146] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (III):

[0147] It indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring.

[0148] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (IV):

[0149] It indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring.

[0150] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0151] Wherein, ring B is a phenyl group or a 5-6 membered heteroaryl group.

[0152] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0153] Wherein, ring B and its substituents are selected from:

[0154] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0155] Wherein, ring B and its substituents are selected from

[0156] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0157] wherein R2 is independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups;

[0158] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0159] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0160] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0161] p is 1, 2, or 3.

[0162] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0163] Wherein, ring B and its substituents are selected from:

[0164] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0165] Wherein, when X is a covalent bond and Y is C(R y1 )(R y2 )hour,

[0166] R y1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -L-R8;

[0167] R y2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -L-R8;

[0168] Or, R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0169] Each occurrence of R8 is independently selected from NR'R", C 3-15 Cycloalkyl, C6-C 10Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with 1-3 R9 substituents;

[0170] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0171] L is selected from a covalent bond, -O-, -S- and -NR'-, or L is a C1-C6 alkylene group, one or more methylene units of which are optionally and independently replaced by -O-, -C(O)- or -S-;

[0172] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0173] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0174] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0175] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0176] When X is a covalent bond, Y is selected from the following groups:

[0177] Preferably, the group together with the substituents thereon forms a group selected from the group consisting of:

[0178] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0179] When X and Y are cyclic, they form a C6-C 10 Aryl, preferably phenyl, which is optionally substituted by r R 10 Substituent substitution,

[0180] R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0181] r is 1, 2 or 3.

[0182] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0183] Wherein, when X and Y are together to form a ring, they together form a 5-6 membered heteroaryl, preferably pyrazolyl, which is optionally substituted by r R 10 Substituent substitution,

[0184] R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0185] r is 1, 2 or 3.

[0186] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0187] Wherein, when X and Y form a ring together, they together form a C3-C6 cycloalkyl, a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, which is optionally substituted by r R 10 Substituent substitution,

[0188] R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0189] r is 1, 2 or 3.

[0190] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0191] X is N(R x1 ) or C(R x1 )(R x2 );

[0192] Y is N(R y1 ) or C(R y1 )(R y2 );

[0193] The condition is that one of X and Y is N(R x1 ) or N(R y1 ), and X and Y together form a group selected from the following: a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, which is optionally substituted by r substituents R 10 replace,

[0194] R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0195] r is 1, 2 or 3.

[0196] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0197] Where X is (C(R x1 )(R x2 )) x , Y is C(R y1 )(R y2 ),

[0198] R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0199] R x1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0200] R x2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0201] x is 1, 2, 3, or 4.

[0202] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0203] in, and the substituents thereon together form a group selected from the following:

[0204] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0205] wherein ring C is a 5- to 10-membered heteroaryl group or a 3- to 10-membered heterocyclic group.

[0206] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0207] Wherein, ring C is selected from:

[0208] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0209] Wherein, ring C together with the substituents thereon is:

[0210] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0211] in,

[0212] Symbol A is C,

[0213] Symbol B is C(R b );

[0214] Symbol F is N(R f ),

[0215] R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0216] R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0217] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0218] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0219] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0220] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0221] in,

[0222] Symbol A is C,

[0223] Symbol B is N;

[0224] Symbol F is N(R f ),

[0225] R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 3-10 membered heterocyclic groups.

[0226] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0227] in,

[0228] Symbol A is N,

[0229] Symbol B is C(R b );

[0230] Symbol F is C(R f ),

[0231] R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0232] R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0233] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0234] R" is independently selected from H, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0235] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0236] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0237] in,

[0238] Symbol A is N,

[0239] Symbol B is C(R b )(R b ');

[0240] Symbol F is N(R f ),

[0241] R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0242] R b 'Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10Cycloalkyl and 3-10 membered heterocyclic groups;

[0243] R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0244] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0245] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0246] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0247] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: wherein, Selected from the following groups:

[0248] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: wherein, and the substituents thereon together form a group selected from the following:

[0249] in, Indicates the connection point with the adjacent ring B.

[0250] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VI):

[0251] R g Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0252] R h Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0253] R j Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0254] R k Selected from H, halogen, CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0255] A, B, F, R1, X, Y, L, R8, R' and R" are as defined for formula (A).

[0256] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of Formula (VI-1), Formula (VI-2), Formula (VI-3) or Formula (VI-4):

[0257] R b Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0258] R b 'Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0259] R f Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably H.

[0260] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

[0261] X is a covalent bond;

[0262] Y is C(R y1 )(R y2 ),

[0263] R y1 and R y2 Together with the attached carbon atom, it forms C 3-6cycloalkyl, 6-10 membered bicycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S or 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0264] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0265] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0266] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0267] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0268] R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 a cycloalkyl ring, a 7-10 membered bicycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N and O, or a 7-10 membered bicyclic spiroheterocyclic group containing 1-4 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of a haloalkyl group.

[0269] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0270] R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 cycloalkyl ring, 7-10 membered bicyclic spirocycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of a haloalkyl group.

[0271] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0272] R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 Cycloalkyl group, 7-10 membered bicyclic spirocycloalkyl group, 4-6 membered oxamonocyclic heterocyclic group or 7-10 membered oxabicyclic spiroheterocyclic group, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen and C 1-6 The substituent of the alkyl group, preferably, R y1 and R y2 Together with the attached carbon atom, it forms

[0273] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0274] When X and Y together form C6-C 10 Aryl, preferably phenyl, which is optionally substituted by r R 10 Substituent substitution,

[0275] R 10 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably F;

[0276] r is 1 or 2;

[0277] Preferably, X and Y together form a group selected from:

[0278] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0279] Wherein, when X and Y together form a 5-6 membered heteroaryl, preferably pyrazolyl, which is optionally substituted by r R 10 Substituent substitution,

[0280] R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-4 Alkyl, more preferably methyl;

[0281] r is 1 or 2;

[0282] Preferably, X and Y together form a group selected from:

[0283] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0284] Wherein, when X and Y together form a C3-C6 cycloalkyl, a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, it is optionally substituted by r R 10 Substituent substitution,

[0285] R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0286] r is 1 or 2.

[0287] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0288] X is N(R x1 ) or C(R x1 )(R x2 );

[0289] Y is N(R y1 ) or C(R y1 )(R y2 );

[0290] The condition is that one of X and Y is N(R x1 ) or N(R y1 ), and X and Y together form a group selected from the following: a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic spiro heterocyclic group, which is optionally substituted by r substituents R 10 replace,

[0291] R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0292] r is 1 or 2;

[0293] Preferably, X and Y together form a group selected from:

[0294] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0295] Where X is (C(R x1 )(R x2 ))x , Y is C(R y1 )(R y2 ),

[0296] R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0297] R x1 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0298] R x2 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0299] x is 1 or 2;

[0300] Preferably, X and Y together form

[0301] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

[0302] Each occurrence of R1 is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S;

[0303] R g Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR'R", -OR', 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0304] R h Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR'R", -OR', 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0305] R j Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR'R", -OR', 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0306] R k Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0307] Each occurrence of R8 is independently selected from NR'R", C 3-10 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with 1-3 R9 substituents;

[0308] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0309] L is C1-C6 alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)- or -S-;

[0310] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0311] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0312] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0313] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

[0314] Each occurrence of R1 is independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0315] R g Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0316] R h Selected from H, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0317] R j Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0318] R k Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8;

[0319] Each occurrence of R8 is independently selected from NR'R", C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, which are optionally substituted with 1-3 R9 substituents;

[0320] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR';

[0321] L is a C1-C6 alkylene group;

[0322] R' is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 heteroatoms selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0323] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-6Cycloalkyl and 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 heteroatoms selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0324] Or R' and R" together with the nitrogen atom form a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with 1-3 heteroatoms selected from H, C 1-6 Alkyl and C 1-6 Substituents of a haloalkyl group.

[0325] In a further embodiment, the present invention relates to a compound of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:

[0326] R1 is selected from H and C 1-6 Alkyl, preferably C 1-4 an alkyl group, preferably a methyl group;

[0327] R g Selected from H, F, Br, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl;

[0328] R h is selected from H and halogen, preferably F;

[0329] R j selected from H and -L-R8;

[0330] R k selected from H and -L-R8;

[0331] R8 is independently selected at each occurrence from NR'R" and a 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, which is optionally substituted with 1-3 R9 substituents;

[0332] Each occurrence of R9 is independently selected from H and C 1-4 Alkyl, preferably methyl;

[0333] R' is independently selected from H, C 1-4 alkyl, 4-6 membered cycloalkyl and 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O, said cycloalkyl and heterocyclic group are optionally substituted with 1-2 heteroatoms selected from H and C 1-4 Substituents of alkyl groups;

[0334] R" is independently selected from H, C 1-4 alkyl, 4-6 membered cycloalkyl and 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O, said cycloalkyl and heterocyclic group are optionally substituted with 1-2 heteroatoms selected from H and C 1-4 Substituents of alkyl groups;

[0335] Alternatively, R' and R" together with the nitrogen atom form a 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O, the heterocyclic group being optionally substituted with 1-2 heteroatoms selected from H and C 1-4 Substituents of alkyl groups;

[0336] L is a C1-C2 alkylene group.

[0337] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VII):

[0338] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VII-1), formula (VII-2) or formula (VII-3):

[0339] R g Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0340] R j Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0341] R k Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0342] R b Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0343] R f Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0344] Each occurrence of R8 is independently selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, which are optionally substituted with 1-3 R9 substituents;

[0345] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR';

[0346] L is C1-C6 alkylene, preferably C1-C4 alkylene, more preferably C1-C2 alkylene;

[0347] R' is independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

[0348] R" is independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl 5-10 membered heteroaryl and 3-10 membered heterocyclic group; or, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0349] In a further embodiment, the present invention relates to a compound of formula (VII-1), formula (VII-2) or formula (VII-3) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0350] X is a covalent bond;

[0351] Y is C(R y1 )(R y2 ),

[0352] R y1 and R y2 Together with the attached carbon atom, it forms C 3-6cycloalkyl ring, 7-10 membered bicycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S or 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0353] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0354] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0355] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of a haloalkyl group.

[0356] In a further embodiment, the present invention relates to a compound of formula (VII-1), formula (VII-2) or formula (VII-3) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0357] R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 cycloalkyl ring, 7-10 membered bicyclic spirocycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of a haloalkyl group.

[0358] In a further embodiment, the present invention relates to a compound of formula (VII-1), formula (VII-2) or formula (VII-3) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0359] R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 cycloalkyl ring, 7-10 membered bicyclic spirocycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of a haloalkyl group.

[0360] In a further embodiment, the present invention relates to a compound of formula (VII-1), formula (VII-2) or formula (VII-3) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0361] R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 Cycloalkyl ring, 7-10 membered bicyclic spirocycloalkyl, 4-6 membered oxamonocyclic heterocyclic group or 7-10 membered oxabicyclic spiroheterocyclic group, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen and C 1-6 The substituent of the alkyl group, preferably, R y1 and R y2 Together with the attached carbon atom, it forms More preferably

[0362] In a further embodiment, the present invention is directed to a compound of formula (VIII), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

[0363] in,

[0364] Indicates whether the bond is a single bond or a double bond;

[0365] Symbol U is C(R 2d ) or nitrogen (N);

[0366] R1 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0367] R 2a Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3- 15-membered cycloalkyl and 3-15-membered heterocyclyl;

[0368] R 2b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups;

[0369] R 2c Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups;

[0370] R 2d Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic groups;

[0371] R bSelected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0372] R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0373] R g Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0374] R h Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0375] R j Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0376] R k Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Halogenated alkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0377] X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O;

[0378] Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O;

[0379] When there is a single bond between X and Y and X and Y do not form a ring, X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O; and Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O;

[0380] When there is a double bond between X and Y and X and Y do not form a ring, X is N or C (R x1 ); and Y is N or C(R y1 );

[0381] R x1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0382] R x2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0383] Or, R x1 and R x2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0384] R y1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0385] R y2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0386] Or, R y1 and R y2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0387] When X and Y are cyclic together, they form a C6-C 10 Aryl, 5-14 membered heteroaryl, C 5-15 Cycloalkyl and 4-15 membered heterocyclic group, which is optionally substituted by r R 10 Substituent substitution;

[0388] L is selected from a covalent bond, -O-, -S- and -NR'-, or L is a C1-C6 alkylene group, one or more methylene units of which are optionally and independently replaced by -O-, -C(O)- or -S-;

[0389] Each occurrence of R8 is independently selected from NR'R", C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with 1-3 R9 substituents;

[0390] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0391] R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0392] R' is independently selected from H, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-C6-C 10 Aryl, -L'-5-14 membered heteroaryl, -L'-C 3-15 Cycloalkyl and -L'-3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0393] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-C6-C 10 Aryl, -L'-5-14 membered heteroaryl, -L'-C 3-15 Cycloalkyl and -L'-3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0394] Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0395] L' is a covalent bond or a C1-C6 alkylene group, wherein one or more methylene units in the C1-C6 alkylene group are optionally and independently replaced by -O-, -C(O)-, or -S-;

[0396] r is 0, 1, 2, 3, 4, or 5;

[0397] x is 1, 2, 3, or 4;

[0398] y is 1, 2, 3, or 4.

[0399] In a further embodiment, the present invention relates to a compound of formula (VIII), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is of formula (VIII-1) or formula (VIII-2):

[0400] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0401] in,

[0402] X is a covalent bond;

[0403] Y is C(R y1 )(R y2 ),

[0404] Among them, R y1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0405] R y2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6haloalkyl, NR'R" and -OR' substituents;

[0406] Or, R y1 and R y2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0407] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, L'-5-6 membered heteroaryl, L'-C 3-10 Cycloalkyl and L'-3-10 membered heterocyclic group, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0408] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, L'-phenyl, L'-5-6 membered heteroaryl, L'-C 3-10 Cycloalkyl and L'-3-10 membered heterocyclic group, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0409] Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0410] L' is a covalent bond or a C1-C6 alkylene group,

[0411] The other groups are as defined for formula (VIII).

[0412] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0413] in,

[0414] X is a covalent bond;

[0415] Y is C(R y1 )(R y2 ),

[0416] Among them, R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 cycloalkyl ring, 7-10 membered bicyclic spirocycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl and OR' substituents;

[0417] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl,

[0418] The other groups are as defined for formula (VIII).

[0419] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0420] in,

[0421] X is a covalent bond;

[0422] Y is C(R y1 )(R y2 );

[0423] Among them, R y1 and R y2 Together with the attached carbon atom, it forms C 4-6Cycloalkyl ring, 7-10 membered bicyclic spirocycloalkyl, 4-6 membered oxamonocyclic heterocyclic group or 7-10 membered oxabicyclic spiroheterocyclic group, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, C 1-6 Alkyl, cyano substituted C 1-6 Alkyl and OR' substituents,

[0424] R' is C 1-6 alkyl;

[0425] Preferably, R y1 and R y2 Together with the attached carbon atom, it forms More preferably

[0426] The other groups are as defined for formula (VIII).

[0427] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0428] in,

[0429] X is (C(R x1 )(R x2 )) x ,

[0430] Y is C(R y1 )(R y2 ),

[0431] Among them, R x1 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0432] R x2 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H;

[0433] R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents;

[0434] x is 1 or 2;

[0435] R' at each occurrence is independently selected from H and C 1-6 alkyl;

[0436] R" is selected from H and C 1-6 alkyl;

[0437] Preferably, X and Y together form

[0438] The other groups are as defined for formula (VIII).

[0439] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0440] in,

[0441] X is N(R x1 ) or C(R x1 )(R x2 );

[0442] Y is N(R y1 ) or C(R y1 )(R y2 );

[0443] The condition is that one of X and Y is N(R x1 ) or N(R y1 ), and X and Y together form a group selected from the following: a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic spiro heterocyclic group, which is optionally substituted by r substituents R 10 replace,

[0444] R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0445] r is 1 or 2;

[0446] Preferably, X and Y together form a group selected from:

[0447] The other groups are as defined for formula (VIII).

[0448] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0449] in,

[0450] is a double bond, and X and Y together form a C3-C6 cycloalkyl ring, which is optionally substituted by r substituents R 10 replace,

[0451] R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0452] r is 1 or 2;

[0453] Preferably, X and Y together form a group selected from:

[0454] The other groups are as defined for formula (VIII).

[0455] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0456] in,

[0457] R k Selected from:

[0458] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is of formula (IX),

[0459] in,

[0460] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0461] R 2a Selected from H, halogen, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR' and C 3-10 Cycloalkyl;

[0462] R g Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0463] R k Selected from H, phenyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0464] L is a C1-C6 alkylene group;

[0465] R8 is selected from NR'R", C 3-10 Cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with 1-3 R9 substituents;

[0466] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0467] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0468] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0469] Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0470] L' is a covalent bond or a C1-C6 alkylene group.

[0471] In a further embodiment, the present invention relates to a compound of formula (IX), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0472] in,

[0473] R1 is selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0474] R 2a Selected from H, NR'R", -OR' and C 3-6 Cycloalkyl;

[0475] R g Selected from H, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0476] R k selected from H and -L-R8;

[0477] L is a C1-C6 alkylene group;

[0478] R8 is NR'R";

[0479] R' is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0480] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0481] Alternatively, R' and R" together with the nitrogen atom form a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0482] L' is a covalent bond or a C1-C6 alkylene group.

[0483] In a further embodiment, the present invention relates to a compound of formula (IX), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0484] in,

[0485] R1 is C 1-4 an alkyl group, preferably a methyl group;

[0486] R 2a is H;

[0487] R g is halogen, preferably F;

[0488] R k for -L-R8;

[0489] L is a C1-C4 alkylene group;

[0490] R8 is NR'R";

[0491] R' is H;

[0492] R" is selected from C 1-6 Alkyl and -L'-C 3-7 Cycloalkyl, the cycloalkyl is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of alkyl groups;

[0493] Alternatively, R' and R" together with the nitrogen atom form a 5-6 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of alkyl groups;

[0494] L' is a covalent bond or a C1-C4 alkylene group.

[0495] In a further embodiment, the present invention relates to a compound of formula (VIII), formula (VIII-1) or formula (VIII-2), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is of formula (X),

[0496] in,

[0497] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0498] R 2a Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR' and C 3-10 Cycloalkyl;

[0499] R g Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0500] R k Selected from H, phenyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8;

[0501] L is a C1-C6 alkylene group;

[0502] R8 is selected from NR'R", C 3-10 Cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with 1-3 R9 substituents;

[0503] Each occurrence of R9 is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR';

[0504] R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated alkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0505] R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0506] Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups;

[0507] L' is a covalent bond or a C1-C6 alkylene group.

[0508] In a further embodiment, the present invention is directed to a compound of formula (X), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0509] in,

[0510] R1 is selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0511] R 2a Selected from H, NR'R", -OR' and C 3-6 Cycloalkyl;

[0512] R g Selected from H, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0513] R k selected from H and -L-R8;

[0514] L is a C1-C6 alkylene group;

[0515] R8 is NR'R";

[0516] R' is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0517] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0518] Alternatively, R' and R" together with the nitrogen atom form a 3-10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-3 groups selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0519] L' is a covalent bond or a C1-C6 alkylene group.

[0520] In a further embodiment, the present invention is directed to a compound of formula (X), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

[0521] in,

[0522] R1 is C 1-4 an alkyl group, preferably a methyl group;

[0523] R 2a Selected from NR'R", -OR' and C 3-5 Cycloalkyl;

[0524] R g is halogen, preferably F;

[0525] R k for -L-R8;

[0526] L is a C1-C4 alkylene group;

[0527] R8 is NR'R";

[0528] R' at each occurrence is independently selected from H and C 1-4 alkyl;

[0529] R" is selected from C 1-4 Alkyl and -L'-C 3-7 Cycloalkyl, the cycloalkyl is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of alkyl groups;

[0530] Or R' and R" together with the nitrogen atom form a 5-6 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of alkyl groups;

[0531] L' is a covalent bond.

[0532] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from:

[0533] In a further embodiment, the present invention relates to a compound as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from:

[0534] In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

[0535] In one embodiment, the present invention relates to a method for treating or preventing a disease or condition associated with Cbl-b activity, comprising administering to a subject in need thereof a compound of the present invention or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of the present invention that is a Cbl-b inhibitor.

[0536] In one embodiment, the present invention relates to the use of a compound of the present invention, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of the present invention, for the preparation of a medicament for treating or preventing a disease or condition associated with Cbl-b activity.

[0537] In one embodiment, the present invention relates to the use of a compound of the present invention or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of the present invention, in the preparation of a medicament for the treatment of cancer.

[0538] In one embodiment, the present invention relates to a compound of the present invention, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of the present invention, for use in treating or preventing a disease or condition associated with Cbl-b activity.

[0539] In one embodiment, the present invention relates to a compound of the present invention or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of the present invention for use in the treatment of cancer.

[0540] Uses and methods

[0541] The present invention provides Cbl-b inhibitors for use as therapeutically active substances. The present invention provides Cbl-b inhibitors for use in treating or preventing diseases or conditions associated with Cbl-b activity. Furthermore, the present invention provides Cbl-b inhibitors for use in treating cancer. The present invention further provides the use of Cbl-b extracts in the preparation of medicaments for treating or preventing diseases or conditions associated with Cbl-b activity. The present invention also provides the use of Cbl-b inhibitors in the preparation of medicaments for treating cancer.

[0542] Furthermore, the present invention provides therapeutic methods, medicaments, and uses comprising a Cbl-b inhibitor as part of a combination therapy for treating cancer involving one or more of an immune checkpoint inhibitor, an anti-tumor agent, and radiation therapy.

[0543] In some embodiments of the methods of treatment, medicaments and uses of the present invention, the cancer is a hematological cancer, such as lymphoma, leukemia, or myeloma. In other embodiments of the methods of treatment, medicaments and uses of the present invention, the cancer is a non-hematological cancer, such as sarcoma, carcinoma or melanoma.

[0544] Hematological cancers include, but are not limited to, one or more leukemias, such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL); one or more chronic leukemias, including, but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); other hematological cancers or hematological diseases, including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse Large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, follicular small cell lymphoma or follicular large cell lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemias" are a variety of hematologic disorders that are united by ineffective production (or dysplasia) of myeloid blood cells.

[0545] Non-hematological cancers include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0546] In some cases, the effectiveness of a Cbl-b inhibitor in treating a disease or condition (e.g., cancer) is determined by evaluating clinical outcomes (e.g., reduction in tumor size or number, and / or survival rate). In certain embodiments, "treating cancer" comprises evaluating the efficacy of a Cbl-b inhibitor in treating a disease or condition (e.g., cancer) according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), such as (see, e.g., Eisenhauere et al., Eur J Cancer, 45: 228-247, 88

[0547] In some embodiments, the present invention provides a method for treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering to a subject an effective amount of a Cbl-b inhibitor provided herein or a composition thereof to treat the cancer responsive to inhibition of Cbl-b activity. In some embodiments, the cancer is a hematological cancer or a non-hematological cancer as described herein.

[0548] In some embodiments, the present invention provides a method for inhibiting abnormal cell proliferation (eg, hyperplasia), comprising administering to a subject an effective amount of a Cbl-b inhibitor provided herein or a composition thereof to inhibit abnormal cell proliferation in the subject.

[0549] In some embodiments, the present invention provides a method for inhibiting Cbl-b activity, comprising administering to a subject an effective amount of a Cbl-b inhibitor provided herein or a composition thereof to inhibit Cbl-b activity in the subject.

[0550] In some embodiments, for example, in modulating an immune response in an individual in need thereof (e.g., an individual with T cell dysfunction), treating a disease or disorder in an individual (e.g., cancer or abnormal cell proliferation in an individual), and / or inhibiting Cbl-b activity in an individual, the appropriate dosage of the active agent will depend on the type of condition, disease, or disorder to be treated (as defined above), the severity and course of the condition, disease, or disorder, whether the agent is administered for preventive or therapeutic purposes, previous therapy, the subject's clinical history and response to the Cbl-b inhibitor, and the judgment of the attending physician.

[0551] The Cbl-b inhibitor or composition thereof is suitably administered to the individual once or over a series of treatments. In some embodiments, the treatment comprises multiple administrations of the Cbl-b inhibitor or composition, wherein the intervals between administrations can vary. For example, the interval between the first administration and the second administration is about 1 month, and the interval between subsequent administrations is about 3 months. In some embodiments, the Cbl-b inhibitor of the present invention is administered in a fixed dose. In some embodiments, the Cbl-b inhibitor of the present invention is administered to the individual in a fixed dose based on the individual's body weight (e.g., mg / kg).

[0552] In some embodiments of the present invention, the cancer is a hematological cancer. For example, the hematological cancer can be lymphoma, leukemia, or myeloma. In other embodiments of the present invention, the cancer is a non-hematological cancer. In particular, the non-hematological cancer can be carcinoma, sarcoma, or melanoma.

[0553] In some embodiments, the Cbl-b inhibitor is co-administered with one or more additional therapeutic agents or another therapeutic intervention simultaneously or sequentially in any order. For example, in some therapeutic regimens of the present invention, both the Cbl-b inhibitor and the modified immune cells are administered to a mammalian subject in need thereof, wherein the Cbl-b inhibitor is a compound described above, or any variant thereof. Thus, in some embodiments, the therapeutic regimen comprises both adoptive cell therapy and chemotherapy.

[0554] The present invention provides a method for treating cancer, comprising administering an effective amount of a Cbl-b inhibitor to a subject having cancer, and administering an effective amount of an additional therapeutic agent to the subject. The present invention also provides a method for treating a subject having cancer, comprising administering an effective amount of a Cbl-b inhibitor to the subject, and administering an effective amount of an additional therapeutic agent to the subject. In addition, the present invention provides a method for increasing an anti-cancer immune response, comprising administering an effective amount of a Cbl-b inhibitor to a subject having cancer, and administering an effective amount of an additional therapeutic agent to the subject. The present invention also provides a method for treating cancer, comprising administering an effective amount of a Cbl-b inhibitor to a subject having cancer, wherein the subject has received or is receiving an effective amount of an additional therapeutic agent.

[0555] In some embodiments of the aforementioned methods, the Cbl-b inhibitor and the additional therapeutic agent are administered sequentially in either order. As used herein, the terms "sequentially," "continuously," and "sequentially" refer to administering the Cbl-b inhibitor after administering the additional therapeutic agent, or administering the additional therapeutic agent after administering the Cbl-b inhibitor.

[0556] The present invention relates to combinations of Cbl-b inhibitors with the following additional therapeutic agents:

[0557] Immune checkpoint inhibitors. In some embodiments, the inhibitory checkpoint molecule is selected from the group consisting of: PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT, TIM3 (CD366), and VISTA. In certain embodiments, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule, and the at least one inhibitory checkpoint molecule is selected from the group consisting of PD-1 (CD279), PD-L1 (CD274) and CTLA-4 (CD152).

[0558] Immune checkpoint inhibitors can be biomolecules. For example, immune checkpoint inhibitors may comprise antibodies or their antigen-binding fragments. The antibody or fragment may be a monoclonal antibody (mAb), a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in certain embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antibody or fragment is a bispecific antibody. In some embodiments, the antigen-binding fragment comprises one of the group consisting of Fab, Fab'-SHF (ab') 2, sCFv, and Fv fragments.

[0559] In some embodiments, the at least one inhibitory checkpoint molecule comprises PD-1. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, and biosimilars thereof. In one embodiment, the anti-PD-1 antibody is pembrolizumab CMk-3475, which is marketed by Merck & Co. In one embodiment, the anti-PD-1 antibody is nivolumab (BMS-936558 or MDX-1106, marketed by Bristol-Myers Squibb as OPDIVOR). In one embodiment, the anti-PD-1 antibody is cemiplimab (REGN2810, Regeneron). In some embodiments, the immune checkpoint inhibitor is a variant of pembrolizumab, nivolumab, or cemiplimab.

[0560] In some embodiments, the at least one inhibitory checkpoint molecule comprises PD-L1. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof. In one embodiment, the anti-PD-L1 antibody is atezolizumab (available from Genentech, Inc. as In one embodiment, the anti-PD-L1 antibody is avelumab (marketed as BAVENCIO® by Merck Serono, Inc. and Pfizer, Inc.). In one embodiment, the anti-PD-L1 antibody is durvalumab (MEDI4736, marketed as In some embodiments, the immune checkpoint inhibitor is a variant of atezolizumab, avelumab, or durvalumab.

[0561] In some embodiments, the at least one inhibitory checkpoint molecule comprises CTLA-4. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of ipilimumab, tremelimumab, and biosimilars thereof. In one embodiment, the anti-CTLA4 antibody is ipilimumab (MDX-010 or BMS-734016, available from Bristol-Myers Squibb for In one embodiment, the anti-CTLA4 antibody is tremelimumab (ticilimumab, CP-675, 206, developed by AstraZeneca). In some embodiments, the immune checkpoint inhibitor is ipilimumab or a variant of tremelimumab.

[0562] In some embodiments, the monoclonal antibody is a "variant" antibody comprising heavy and light chain sequences identical to those in a "reference" antibody, except that 3, 2, or 1 conservative amino acid substitutions are made at positions outside the light chain CDRs and / or 6, 5, 4, 3, 2, or 1 conservative amino acid substitutions are made at positions outside the heavy chain CDRs (e.g., the variant positions are all located in the framework region or constant region). In other words, the reference antibody and the variant antibody both comprise the same CDR sequence but differ from each other by having conservative amino acid substitutions at no more than 3 or 6 other positions in their full-length light and heavy chain sequences, respectively. The variant antibody is substantially identical to the reference antibody in terms of its binding affinity for the inhibitory checkpoint molecule and the ability to block binding of the inhibitory checkpoint molecule to its ligand.

[0563] In other embodiments, the immune checkpoint inhibitor may comprise an immunoadhesin comprising an inhibitory checkpoint molecule binding domain of one of its ligands fused to a constant region (e.g., the Fc region of an immunoglobulin molecule).

[0564] In another aspect, the present invention also relates to a combination of a Cbl-b inhibitor and an anti-tumor agent. The anti-tumor agent comprises a cytotoxic antibiotic selected from the group consisting of ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, aclarubicin, epirubicin, daunorubicin, doxorubicin, and dactinomycin.

[0565] The anti-tumor agent comprises a plant alkaloid selected from the group consisting of trabectedin, cabazitaxel, paclitaxelpoliglumex, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, vintafolide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine.

[0566] The anti-tumor agent includes an antimetabolite selected from the group consisting of: floxuridine, trifluridine, tegafur, fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nelarabine, clofarabine, fludarabine, cladribine, tioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate.

[0567] The anti-tumor agent includes an alkylating agent selected from the group consisting of dacarbazine, temozolomide, pipobroman, mitobronitol, etoglucid, uracil mustard, ranimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, and carbomer. carboquone, triaziquone, thiotepa, mannosulfan, treosulfan, busulfan, bendamustine, prednimustine, trofosfamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide.

[0568] The anti-tumor agent also includes other anti-tumor agents selected from the following: platinum compounds (ATC code L01XA), methylhydrazine (ATC code L01XB), sensitizers (ATC code LO1XD), protein kinase inhibitors (ATC code L01XE), and other anti-tumor agents (ATC code L01XA).

[0569] Platinum compounds are suitable antitumor agents that can be used in the methods, medicines, and uses of the present invention. In some embodiments, the platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatin.

[0570] In another embodiment, the present invention also provides a combination therapy of a Cbl-b inhibitor and radiation therapy

[0571] The present invention provides a method for treating cancer, comprising administering an effective amount of a Cbl-b inhibitor to a subject suffering from cancer, and administering an effective amount of radiation therapy to the subject. The present invention also provides a method for treating a subject suffering from cancer, comprising administering an effective amount of Cbl-b to the subject, and administering an effective amount of radiation therapy to the subject. In addition, the present invention provides a method for increasing an anti-cancer immune response, comprising administering an effective amount of a Cbl-b inhibitor to a subject suffering from cancer, and administering an effective amount of radiation therapy to the subject. The present invention also provides a method for treating cancer, comprising administering an effective amount of a Cbl-b inhibitor to a subject suffering from cancer, wherein the subject has received or is currently receiving an effective amount of radiation therapy.

[0572] In some embodiments, the radiation therapy is external beam radiation therapy. In other embodiments, the radiation therapy is internal beam radiation therapy. In some embodiments, the radiation therapy is ablative radiation therapy.

[0573] In some embodiments, the combination therapy regimens of the present invention comprise administration of a Cbl-b inhibitor, radiation therapy, and one or both of an immune checkpoint inhibitor and an anti-tumor agent.

[0574] Drug administration

[0575] The compound provided by the present invention or its pharmaceutical composition can be administered by many ways, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0576] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0577] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0578] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0579] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.

[0580] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0581] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art.

[0582] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0583] The compounds of the present invention may also be administered by transdermal means.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0584] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0585] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0586] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which are composed of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin.

[0587] Also can use two or more kinds of the combination of compound and composition disclosed in the present invention.The two or more kinds of compounds or compositions can be mixed together and administered together shortly before administration.The two or more kinds of compounds or compositions can be administered simultaneously by the same route of administration or by different routes of administration.The two or more kinds of compounds or compositions can be administered sequentially by the same route of administration or by different routes of administration.In one embodiment, the kit form can include two or more kinds of compounds or compositions as a separate form of compound or composition, with printed or electronic instructions for administering with a mixture of compounds or compositions, administering simultaneously with a separate compound or composition, or administering sequentially with a separate compound or composition.When three or more kinds of compounds or compositions are used, they can be administered as a mixture of compounds or compositions, as a separate compound or composition for simultaneous administration, as a separate compound or composition for sequential administration, as a separate compound or composition for sequential administration, as a separate compound or composition for which two or more kinds of compounds or compositions can be administered simultaneously, and the rest can be administered sequentially before or after simultaneous administration, or as a separate compound or composition for administration in any other possible combination of mixed administration, simultaneous administration and sequential administration.

[0588] In one aspect, the compounds disclosed herein can be in purified form, and the present invention discloses compositions comprising the compounds in purified form. The present invention provides compositions comprising the compounds disclosed herein or their salts, such as compositions of substantially pure compounds. In some embodiments, the compositions comprising the compounds disclosed herein or their salts are in substantially pure form. In one variation, "substantially pure" refers to a composition that contains no more than 35% impurities, wherein the impurities represent compounds other than the compound (or compounds, if a combination of compounds is used) administered in the composition, or salts or solvates of the compound (or compounds, if a combination is used). The weight of any added vehicle, carrier, or excipient is not included in such calculations, and the added vehicle, carrier, or excipient is not considered an impurity. For example, a composition of a substantially pure compound selected from the compounds shown in Table 1 or Table 2 refers to a composition that contains no more than 35% impurities, wherein the impurities represent compounds other than the compound or its salt or solvate. In one variation, the present invention provides a composition of a substantially pure compound or its salt or solvate, wherein the composition contains no more than 25% impurities. In another variation, the present invention provides a composition of a substantially pure compound or its salt or solvate, wherein the composition contains no more than 20% impurities. In yet another variation, the present invention provides a composition of a substantially pure compound or its salt or solvate, wherein the composition contains no more than 10% impurities. In a further variation, the present invention provides a composition of a substantially pure compound or its salt or solvate, wherein the composition contains no more than 5% impurities. In another variation, the present invention provides a composition of a substantially pure compound, or a salt or solvate thereof, wherein the composition contains no more than 3% impurities. In yet another variation, the present invention provides a composition of a substantially pure compound, or a salt or solvate thereof, wherein the composition contains no more than 1% impurities. In a further variation, the present invention provides a composition of a substantially pure compound, or a salt or solvate thereof, wherein the composition contains no more than 0.5% impurities. In other variations, a composition of a substantially pure compound is one that contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity. Impurities can be compounds in a different stereochemical form than the desired stereochemical form. For example, a composition of a substantially pure (S)-compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% of the (R) form of the compound. Alternatively, "enantiomeric excess (ee)," as used herein, refers to a dimensionless molar ratio that describes the purity of a chiral substance containing, for example, a single stereocenter. For example, an enantiomeric excess of zero would indicate a racemate (e.g., milk, a 50:50 mixture of enantiomers, or no excess of one enantiomer relative to the other).As a further example, an enantiomeric excess of 99 would represent an almost stereopure enantiomer compound (i.e., one enantiomer is in large excess relative to the other). Percent enantiomeric excess, %ee = ([(R-compound] - [(S)-compound] / ([(R)-compound] + [(S)-compound]) x 100, where the (R)-compound > (S)-compound; or %ee = ([(S)-compound] - [(R)-compound] / ([(S)-compound] + [(R)-compound]) x 100, where the (S)-compound > (R)-compound. Additionally, as used herein, "diastereomeric excess (de)" refers to a compound that contains more than one stereoisomer. The diastereomeric excess is a dimensionless molar ratio of the purity of a chiral substance at the center of the diastereomeric center. For example, a diastereomeric excess of zero would represent an equimolar mixture of diastereomers. As a further example, a diastereomeric excess of 99 would represent a nearly stereopure diastereomeric compound (i.e., one diastereomer is in large excess relative to the other diastereomer). Diastereomeric excess can be calculated using methods similar to ee. As will be appreciated by those skilled in the art, de is typically reported as percent de (%de). %de can be calculated in a manner similar to %ee.

[0589] It should be understood that the embodiments and implementations described in the present invention are for illustrative purposes only, and various modifications / modifications or changes / variations made thereto by those skilled in the art are to be included within the spirit and scope of this application and the scope of the appended claims.

[0590] Chemical synthesis part

[0591] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. This application has been described in detail herein, and its specific embodiment mode is also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All solvents used in this application are commercially available and can be used without further purification. The initial compound raw materials used in this application for synthesis are commercially available or can be prepared by the methods of the prior art.

[0592] Example 1

[0593] Synthesis of intermediate 1-1

[0594] SM1a (25 g, 0.11 mol) and 1,3-dibromo-2-methylpropane (23.6 g, 0.11 mol) were dissolved in N,N-dimethylformamide (100 mL). Sodium hydride (8.8 g, 60%, 0.22 mol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride solution (100 mL) was added to the reaction system at 0°C to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1) to obtain compound 1-1 as a colorless oil (20 g, yield: 65%). LCMS (ESI) m / z: 283 / 285.

[0595] Synthesis of intermediate 1-2

[0596] Compound 1-1 (20 g, 0.07 mol) was dissolved in ethanol (100 mL), and hydrazine hydrate (11.2 g, 0.35 mol) was added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, and water (60 mL) was slowly added to the reaction system. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-2 (25 g) as a colorless oil, which was used directly in the next step as a crude product. LCMS (ESI) m / z: 283 / 285.

[0597] Synthesis of intermediates 1-3

[0598] Compound 1-2 (25 g) was dissolved in methanol (100 mL), and methyl isothiocyanate (19.7 g, 0.27 mol) was added to the reaction system. The mixture was stirred at room temperature for 16 hours under nitrogen. 4 M sodium hydroxide solution (14.4 g, 0.36 mol) was then added to the reaction system, and the reaction system was stirred at 65°C for 3 hours. The reaction was cooled to 0°C, and dilute hydrochloric acid was slowly added dropwise to the reaction system to adjust the pH of the system to 5-6. The mixture was extracted with dichloromethane (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-3 (28 g) as a white solid, which was used directly in the next step as a crude product. LCMS (ESI) m / z: 338 / 340.

[0599] Synthesis of intermediate 1-4-P1

[0600] Compound 1-3 (28 g) was dissolved in dichloromethane (300 mL). Acetic acid (45 mL) and hydrogen peroxide (23 mL, 30%) were added at 0°C. The mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution was slowly added dropwise to the reaction system at 0°C to adjust the pH of the reaction system to 10-12. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 20:1) to obtain compound 1-4 (10 g) as a colorless oil.

[0601] Compound 1-4 (10 g) was purified by HPLC (column: Gemini-C18, 150 x 21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), gradient: 5-30%) to afford compound 1-4-P1 (4.5 g, 45% yield) as a colorless oil. LCMS (ESI) m / z: 306 / 308.

[0602] Synthesis of intermediates 1-5

[0603] Compound 1-4-P1 (200 mg, 0.66 mmol), pinacol diboronate (419 mg, 1.65 mmol), potassium acetate (226 mg, 2.31 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (108 mg, 0.132 mmol) were dissolved in dioxane (10 mL) and reacted at 90°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 10:1) to obtain compound 1-5 (120 mg, yield: 45%) as a brown oil. LCMS (ESI) m / z: 354.

[0604] Synthesis of intermediates 1-6

[0605] SM1b (1 g, 3.77 mmol), (S)-3-methylpiperidine hydrochloride (610 mg, 4.52 mol), and N,N-diisopropylethylamine (1.46 g, 11.34 mmol) were dissolved in tetrahydrofuran (20 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added portionwise with stirring at room temperature. The reaction system was stirred at room temperature for 16 hours. The reaction temperature was cooled to 0°C and quenched with saturated sodium bicarbonate solution (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 15:1) to afford compound 1-6 (1.05 g, yield: 80%) as a colorless oil. LCMS (ESI) m / z: 349 / 351.

[0606] Synthesis of intermediates 1-7

[0607] Compound 1-6 (1 g, 2.87 mmol) was dissolved in tetrahydrofuran (10 mL), palladium on carbon (200 mg) was added, and the gas was replaced three times with a hydrogen balloon. The mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered and concentrated to afford a yellow solid compound 1-7 (700 mg) as a crude product, which was used directly in the next reaction. LCMS (ESI) m / z: 271.

[0608] Synthesis of intermediates 1-8

[0609] Compound 1-7 (700 mg) was dissolved in 48% hydrobromic acid (20 mL). The reaction system was stirred at 80°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 10:1) to obtain compound 1-8 (380 mg) as a brown oil. LCMS (ESI) m / z: 257.

[0610] Synthesis of intermediates 1-9

[0611] Compound 1-8 (380 mg, 1.48 mmol) was dissolved in acetic acid (10 mL), and 70% concentrated nitric acid (0.64 mL, 14.8 mmol) and bromine (0.08 mL, 1.62 mmol) were added. Silver nitrate (377 mg, 2.22 mmol) was slowly added to the mixture with stirring at room temperature. The mixture was stirred at room temperature for 12 hours. Ice water (10 mL) and 1M sodium hydroxide (40 mL) were slowly added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 15:1) to afford compound 1-9 (35 mg, yield: 7.1%) as a colorless oil. LCMS (ESI) m / z: 335 / 337.

[0612] Synthesis of compound 1

[0613] Compound 1-9 (35 mg, 0.1 mmol), 1-5 (42 mg, 0.12 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (7 mg, 0.01 mmol), and potassium carbonate (41 mg, 0.3 mmol) were dissolved in 4 mL of a mixture of dioxane and water (v / v = 5:1). The mixture was stirred at 100°C under nitrogen for 8 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 15:1). The crude product was purified by high-performance liquid chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), gradient: 20-40%) to afford compound 1 (17 mg, yield: 33.8%) as a white solid. LCMS (ESI) m / z: 482.

[0614] 1 H NMR (400MHz, DMSO-d6) δppm: 12.08 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.69 (d, J = 7. 2Hz,1H),7.61(d,J=7.7Hz,1H),7.50-7.25(m,3H),7.16(t,J=7.6Hz,1H),3.84(s,2H),3.22(s, 3H),2.88(d,J=3.8Hz,2H),2.78(d,J=9.4Hz,2H),2.56-2.54(m,3H),2.00-1.98(m,1H),1.79-1 .59(m,4H),1.52-1.48(m,1H),1.09(d,J=5.3Hz,3H),0.95-0.93(m,1H),0.85(d,J=6.2Hz,3H).

[0615] The following examples were synthesized in the same manner as above:

[0616] The synthesis of the following compounds is described in Example 1:

[0617] Example 28

[0618] Synthesis of Intermediate 28-1

[0619] SM28a (10 g, 68.03 mmol), iodine granules (20.7 g, 81.50 mmol), and 70% aqueous tert-butyl hydroperoxide (43.7 g, 339.89 mmol) were dissolved in acetonitrile (100 mL), and the reaction system was stirred at 80°C for 16 hours. After cooling to room temperature, the pH of the reaction system was adjusted to 9 with saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated sodium sulfite solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 8:1) to obtain 28-1 (10.7 g, 57.6%) as a yellow solid. MS m / z (ESI): 274.

[0620] Synthesis of intermediate 28-2

[0621] 28-1 (10.7 g, 39.19 mmol) was dissolved in dichloromethane (200 mL). Meta-chloroperbenzoic acid (13.56 g, 78.38 mmol) was added portionwise with stirring at 0°C. The reaction system was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction system, and the pH of the reaction system was adjusted to 9-10 with 1N aqueous sodium hydroxide at 0°C. The mixture was extracted with dichloromethane (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 2:1) to obtain 28-2 (5.0 g, 44.1% yield) as a yellow solid. MS m / z (ESI): 290.

[0622] Synthesis of intermediate 28-3

[0623] 28-2 (5.0 g, 17.30 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (536 mg, 0.87 mmol), silver hexafluoroantimonate (1.19 g, 3.47 mmol), and sodium acetate (284 mg, 3.46 mmol) were dissolved in trifluoroethanol (90 mL). N-bromosuccinimide (4.0 g, 22.47 mmol) was added with stirring at room temperature. The reaction system was stirred at 50°C for 16 hours. The reaction system was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 4:1) to obtain 28-3 (1.4 g, 21.9% yield) as a yellow solid. MS m / z (ESI): 368.

[0624] Synthesis of intermediate 28-4

[0625] 28-3 (1.4 g, 3.80 mmol) was dissolved in 30 mL of a mixture of dichloromethane and water (V / V = 1:1). Sodium hydroxide (304 mg, 7.60 mmol) was added, and benzoyl chloride (643 mg, 4.56 mmol) was added dropwise with stirring at 0°C. The reaction system was stirred at room temperature for 1 hour. After the reaction, the precipitated solid was collected by filtration, and the filter cake was washed with water (5 mL × 3) and dried to give the crude product 28-4 (750 mg) as an off-white solid. MS m / z (ESI): 368.

[0626] Synthesis of intermediate 28-5

[0627] 28-4 (600 mg, 1.63 mmol), intermediate 1-5 (692 mg, 1.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (119 mg, 0.16 mmol), and potassium carbonate (450 mg, 3.26 mmol) were dissolved in 12 mL of a mixture of dioxane and water (V / V = 5:1). The reaction system was stirred at 80°C under nitrogen for 2 hours. After cooling to room temperature, the reaction system was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 12:1) to give the brown solid product 28-5 (560 mg, 73.5% yield). MS m / z (ESI): 467.

[0628] Synthesis of intermediate 28-6

[0629] 28-5 (300 mg, 0.64 mmol), SM28b (462 mg, 1.28 mmol), and bistriphenylphosphine palladium dichloride (90 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction system was stirred at 85°C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, 2N hydrochloric acid solution (10 mL) was added to the reaction system, and the reaction system was stirred at room temperature for another hour. The pH of the reaction system was then adjusted to 9-10 with saturated sodium carbonate solution. The reaction system was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 10:1) to obtain 28-6 (170 mg, 61.5% yield) as a yellow solid. MS m / z (ESI): 431.

[0630] Synthesis of compound 28

[0631] Compound 28-6 (140 mg, 0.33 mmol), cyclopentylamine (56 mg, 0.66 mmol), tetraethyl titanate (226 mg, 0.99 mmol), and triethylamine (133 mg, 1.32 mmol) were dissolved in 1,2-dichloroethane (4 mL), and the reaction system was stirred at 80°C for 16 hours. After cooling to room temperature, methanol (4 mL) was added to the reaction system, and sodium borohydride (63 mg, 1.66 mmol) was then added portionwise while stirring at room temperature. After the addition was complete, the reaction system was stirred at room temperature for 3 hours. Water (20 mL) was added dropwise to the reaction system, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 9:1) to give a crude yellow solid. The crude product was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm mobile phase: ACN-H2O (0.05% FA), gradient: 15-40%) to give 28 as a white solid (25 mg, yield 15.4%), MS m / z (ESI): 500.

[0632] 1 H NMR (400MHz, DMSO-d6) δppm: 8.25 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.57 (d, J = 7.7Hz, 1H), 7.44-7.26 (m, 3H), 6.94 (t, J = 9.0Hz, 1H), 4 .23-4.14(m,1H),3.19(s,3H),2.88-2.75(m,3H),2.51(d,J=6.4Hz,3H),1.80-1.50(m,4H),1.44-1.22(m,7H),1.05(d,J=4.8Hz,3H).

[0633] Example 29 and Example 30

[0634] Compound 28 was subjected to chiral separation (chromatographic column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm, mobile phase: 40% IPA (NH 4 OH 0.2%), flow rate: 40 mL / min, RT1: 4.80 min, RT2: 5.95 min, column temperature: 40°C) to give a white solid P1, MS m / z (ESI): 500.

[0635] 1H NMR (400MHz, DMSO-d6) δppm: 8.28 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.61 (d, J = 7.7Hz, 1H), 7.48-7.29 (m, 3H), 6.98 (dd, J = 9.8, 8.3Hz, 1H), 4.27-4 .18(m,1H),3.22(s,3H),2.92-2.81(m,3H),2.54(d,J=6.6Hz,3H),1.83- 1.73(m,1H),1.72-1.53(m,3H),1.50-1.26(m,7H),1.09(d,J=4.9Hz,3H).

[0636] White solid P2, MS m / z (ESI): 500.

[0637] 1 H NMR (400MHz, DMSO-d6) δppm: 8.28 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.61 (d, J=7.8Hz, 1H), 7.48-7.29 (m, 3H), 6.98 (dd, J=9.8, 8.3Hz, 1H), 4.27-4 .18(m,1H),3.22(s,3H),2.92-2.82(m,3H),2.54(d,J=6.5Hz,3H),1.83- 1.73(m,1H),1.72-1.53(m,3H),1.50-1.25(m,7H),1.09(d,J=4.8Hz,3H).

[0638] The following examples were synthesized in the same manner as above:

[0639] Example 51

[0640] Synthesis of Intermediate 51-1

[0641] Compound SM51a (23.6 g, 145.68 mmol) and dimethyl carbonate (26.22 g, 291.36 mmol) were dissolved in 400 mL of tetrahydrofuran. The reaction system was cooled to -78°C, and a 2M solution of lithium diisopropylamide in tetrahydrofuran (218.5 mL, 437 mmol) was added dropwise under nitrogen. The reaction system was stirred at -78°C for 2 hours. After completion of the reaction, saturated ammonium chloride solution (20 mL) was added dropwise to quench the reaction mixture. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 20:1) to afford 51-1 (13.5 g, 42.1% yield) as a yellow solid. MS m / z (ESI): 220.

[0642] Synthesis of Intermediate 51-2

[0643] A mixture of 51-1 (13.5 g, 61.36 mmol) and 1,3-dibromo-2-methylpropane (15.83 g, 73.63 mmol) was added to N,N-dimethylformamide (200 mL). The reaction mixture was then cooled to 0°C and 60% sodium hydride (4.91 g, 122.72 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Water (200 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The aqueous phase was adjusted to pH 3-4 with 4M hydrochloric acid to produce a white solid. The filter cake was collected by filtration and dried to give the crude product 51-2 (5 g) as a white solid. MS m / z (ESI): 260.

[0644] Synthesis of Intermediate 51-3

[0645] 51-2 (5 g, 19.23 mmol), 4-methylthiosemicarbazide (2.02 g, 19.23 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (14.61 g, 38.46 mmol), and N,N-diisopropylethylamine (4.96 g, 38.46 mmol) were dissolved in 100 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. The mixture was concentrated, ethyl acetate (200 mL) was added, and the mixture was washed with water (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 20:1) to give the crude product 51-3 (7 g) as a yellow solid. MS m / z (ESI): 347.

[0646] Synthesis of Intermediate 51-4

[0647] 51-3 (7 g, 20.23 mmol) was dissolved in 50 mL of a mixed solvent of methanol and water (V / V = 1:1), and sodium hydroxide (1.62 g, 40.46 mmol) was added. The mixture was reacted at 50°C for 4 hours. After cooling to room temperature, 6 M hydrochloric acid was added dropwise at 0°C until the pH of the reaction solution reached 5-6. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product 51-4 (5 g) as a yellow oil. MS m / z (ESI): 329.

[0648] Synthesis of Intermediate 51-5

[0649] 51-4 (5 g, 15.24 mmol) was dissolved in 50 mL of dichloromethane. Acetic acid (9.12 g, 152 mmol) and hydrogen peroxide (4.3 g, 38 mmol, 30%) were added at 0°C and allowed to react at room temperature for 2 hours. 2M sodium hydroxide solution was added dropwise at 0°C to adjust the pH of the reaction solution to 9-10. The solution was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 15:1) to obtain a crude white solid product 51-5 (1.7 g). The crude product was then purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm mobile phase: ACN-H2O (0.05% FA), gradient: 15-40%) to obtain P1 (51-5, 550 mg) as a white solid. MS m / z (ESI): 297.

[0650] Synthesis of Intermediate 51-6

[0651] Compound 51-5 (200 mg, 0.67 mmol), potassium cyclopropyltrifluoroborate (99 mg, 0.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (49 mg, 0.067 mmol), and potassium carbonate (185 mg, 1.34 mmol) were dissolved in 10 mL of a mixture of dioxane and water (V / V = 5:1). The reaction system was stirred at 100°C under nitrogen for 4 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 20:1) to afford 51-6 (80 mg, 39.6% yield) as a white solid. MS m / z (ESI): 303.

[0652] Synthesis of Intermediate 51-7

[0653] SM51b (1.0 g, 5.26 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to 0°C under nitrogen. A 2 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (5.26 mL, 10.53 mmol) was added and the mixture was allowed to react at 0°C for 30 minutes. Methyl 3,3-dimethoxypropionate (1.17 g, 7.89 mmol) was then added and allowed to react at room temperature for 16 hours. The mixture was quenched by dropwise addition of saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 3:1) to afford 51-7 (1.2 g, 75.0% yield) as a pale yellow solid. MS m / z (ESI): 306.

[0654] Synthesis of Intermediate 51-8

[0655] 51-7 (1.2 g, 3.93 mmol) was dissolved in 10 mL of dichloromethane, and 20 mL of concentrated sulfuric acid was added dropwise to the solution. The dichloromethane was removed under reduced pressure and the mixture was allowed to react at 50°C for 1 hour. After cooling to room temperature, the reaction solution was added dropwise to 30 mL of ice water and filtered. The filter cake was washed with water (30 mL) and dried to afford 51-8 as a light yellow solid (500 mg, 52.5% yield). MS m / z (ESI): 242.

[0656] Synthesis of Intermediate 51-9

[0657] 51-8 (500 mg, 2.07 mmol), potassium (S)-trifluoro[(3-methyl-1-piperidinyl)methyl]borate (909 mg, 4.15 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (325 mg, 0.414 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (395 mg, 0.828 mmol) and potassium carbonate (571 mg, 4.14 mmol) were dissolved in 5 mL of a mixed solvent of dioxane and water (V / V=4:1) and reacted at 100°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 12:1) to give a light yellow solid 51-9 (200 mg, yield 44.1%), MS m / z (ESI): 275.

[0658] Synthesis of Intermediate 51-10

[0659] 51-9 (200 mg, 0.91 mmol) and potassium bromate (184 mg, 1.10 mmol) were dissolved in 6 mL of a mixture of hydrobromic acid and water (V / V = 5:1) and reacted at 120°C for 3 hours in a sealed tube. After cooling to room temperature, 6 M sodium hydroxide solution was added dropwise until the reaction solution had a pH of 9-10. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 3:1) to afford 51-10 (50 mg, 15.6%) as a yellow solid. MS m / z (ESI): 353.

[0660] Synthesis of compound 51

[0661] 51-10 (120 mg, 0.34 mmol), pinacol diboron (259 mg, 1.02 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.034 mmol), and potassium acetate (100 mg, 1.02 mmol) were dissolved in 10 mL of dioxane, and the reaction system was stirred at 60°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, and 51-6 (80 mg, 0.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19 mg, 0.026 mmol), potassium carbonate (72 mg, 0.52 mmol), and water (1 mL) were added to the reaction solution. The reaction system was stirred at 100°C under nitrogen for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 10:1) to give a yellow solid. The crude product was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 um mobile phase: ACN-H2O (0.05% FA), gradient: 10-40%) to give 51 as a white solid (8.39 mg, yield 5.96%). MS m / z (ESI): 541.

[0662] 1H NMR (400MHz, DMSO-d6) δppm: 12.45 (s, 1H), 8.76 (s, 1H), 8.34 (s, 1H), 8.28 (d, J = 1.4Hz, 1H), 7.41(dd,J=8.1,5.9Hz,1H),7.26(d,J=1.4Hz,1H),7.09-6.95(m,1H),3.82(s,2H),3.23(s, 3H),3.00-2.71(m,4H),2.66-2.53(m,3H),2.25-2.11(m,1H),2.08-1.92(m,1H),1.82-1.57 (m,4H),1.52-1.48(m,1H),1.10(d,J=5.3Hz,3H),1.05-0.90(m,5H),0.85(d,J=6.1Hz,3H).

[0663] The following examples were synthesized in the same manner as above:

[0664] Biological activity test

[0665] Test Example 1 Cbl-b activity test

[0666] Experimental purpose: To test the inhibitory activity of compounds on the interaction between Cbl-b protein and UbcH5B-Ub.

[0667] Experimental Methods: Experiments were performed in 384-well plates (Perkin Elmer). The reaction buffer was prepared as follows: 50 mM HEPES (Life Technologies), 5 mM MgCl2 (Sigma), 100 mM NaCl (Sigma), 0.01% Triton X-100 (Sigma), pH 7. Twenty nL of a three-fold serial dilution of compound (final concentrations of 50 μM to 2.54 nM, starting at 50 μM, 10-point distribution, with the tenth point at 2.54 nM) was dispensed into the 384-well plate using an Echo555 (LabCyte). UBE1 (UBA1), FLAG-tag recombinant (BPS), Biotin-Ubiquitin (Thermo), UbcH5b, His-Tag (Human) recombinant (BPS), and CBL-B, GST-Tag (Human) recombinant (BPS) were mixed in a buffered reaction solution: 1 μL Biotin-Ubiquitin (50 ng / μL) + 1 μL UBE1 (25 ng / μL) + 1 μL UBCH5b (220 ng / μL) + 2.5 μL Human CBL-B, GST-tag (3 ng / μL) + 2 μL reaction buffer. After mixing, 7.5 μL of the mixture was added to each well and centrifuged at 1000 rpm for 1 minute. 2.5 μL ATP (40 μM) was added and the cells were centrifuged again at 1000 rpm for 1 minute. The cells were incubated at 25°C for 3 hours. 10 μL of detection solution (MAb Anti GST-Tb cryptate (Cisbio, 1:200) and Streptavidin-XL665 (Cisbio, 1:200)) was added to the reaction plate and incubated at 25°C for 1 hour. The FRET signal (665 / 620) was read on a PHERAstar FSX multifunctional microplate reader (BMG). IC was calculated using IDBS XLfit. 50 .

[0668] As shown in the examples, the compounds showed IC 50 Values ​​are within the following range: A indicates IC 50 Less than 10nM, B represents IC 50 Between 10-100 nM, C represents IC 50 Between 100-1000 nM, D represents IC 50 Greater than 1000nM.

[0669] Table 1. In vitro enzymatic activity results of the compounds

[0670] Experimental Example 2: Jurkat activation experiment

[0671] Experimental purpose: To test the effect of compounds on the activation of IL-2 release in Jurkat cells

[0672] Experimental method: Prepare 1.026x10 6 To a 1 μg / mL Jurkat cell suspension, anti-CD3 human OKT3 (eBioscience, 16-0037-85) was added to the cell suspension and mixed thoroughly. 195 μL of the cell suspension was transferred to a 96-well cell culture plate (Corning, 3599). Five μL of a three-fold serial dilution of the compound (final concentrations of 10 μM to 1.52 nM, starting at 10 μM, and 3-fold dilutions were performed over nine steps, with the ninth step being 1.52 nM) was added to the plate. The cells were incubated in a 37°C cell culture incubator for 24 hours. The supernatant was collected and IL-2 release was assayed using a Human IL-2 DuoSet ELISA kit (R&D Systems, DY202). The absorbance at 450 nm was measured using an EnVision multi-function microplate reader (Perkin Elmer). IDBS XLfit was used to fit the standard curve and determine the IL-2 content of the samples. The original IL-2 concentration of the samples was normalized to the average value of the DMSO group, and the dose-response curve was drawn and the EC was calculated. 50 .

[0673] Test Example 3 Cbl-b activity experiment

[0674] Experimental purpose: To test the inhibitory activity of compounds on the interaction between Cbl-b protein and BODIPY-Ub-UbcH5B.

[0675] Experimental Methods: Untagged Ub (in-house) was incubated with UbcH5B (aa 1-147, C85K, in-house) and UBA1 (in-house) at 19°C for 24 hours to prepare BODIPY-Ub-UbcH5B (aa 1-147, in-house, C85K). BODIPY-Ub-UbcH5B was aliquoted and stored at -80°C. Cbl-b activity was assayed in 384-well plates. 150 nL of a three-fold serial dilution of compound (final concentrations of 10 μM to 0.5 nM, starting at 10 μM, followed by three-fold dilutions, 10 steps, and 10 steps at 0.5 nM) was incubated with 5 μL of biotinylated AVI-Cbl-b (aa 36-427, in-house) protein at a final concentration of 3.5 nM for 1 hour at room temperature (25°C). The reaction buffer was 50 mM HEPES pH 7.5 (Gibco), 50 mM NaCl (Sigma), 0.01% Triton X-100 (Sigma), 0.01% BSA 1mM DTT (Sigma). 5μL Src mixture (30nM Src (Sino Biological), 500μM ATP (Promega), 5000μM MgCl2 (Sigma)) was added to the reaction plate and incubated at room temperature for 2 hours. 5μL detection solution (1nM streptavidin-Terbium (Cisbio), 200nM Fluorescein-BODIPY-Ub-UbcH5B (in-house), 300nM EDTA (Sigma), 0.01% BSA) was added to the reaction plate. ) and incubated at room temperature for 1 hour. HTRF signals (520 / 615) were read on EnVision (Perkin Elmer). IC was calculated using IDBS XLfit. 50 .

[0676] As shown in the examples, the compounds showed IC 50 Values ​​are within the following range: A indicates IC 50 Less than 10nM, B represents IC 50 Between 10-100 nM, C represents IC 50 Between 100-1000 nM, D represents IC 50 Greater than 1000nM.

[0677] Table 2. In vitro enzymatic activity results of the compounds

[0678] Experimental Example 4: Jurkat activation experiment

[0679] Experimental purpose: To test the effect of compounds on the activation of IL2 production in Jurkat cells

[0680] Experimental Methods: Experiments were performed in 96-well plates (Corning). On the day of the experiment, 0.5 μg / mL Anti-CD3 (Biocell) was added to the 96-well plate and incubated at 37°C for 2 hours. Jurkat cells were centrifuged and counted, and the cell density was adjusted to 1×106 cells / mL. 100 μL of cells were then added to the 96-well plate washed with PBS (absin) and then added to the Anti-CD3-containing plate. According to the experimental design, 50 μL of 2 μg / mL Anti-CD28 (Biocell) and 50 μL of diluted compound (final concentrations of 10 μM to 1.5 nM, starting at 10 μM, and three-fold dilutions were performed in 9 wells, with the tenth well being DMSO) were added to each well. The plates were centrifuged and incubated in the incubator for 44 hours. The supernatant was collected by centrifugation and used for the IL-2 ELISA assay. Absorbance signals (450 nm to 570 nm) were converted to doublings. Doublings = sample value / average of control wells. EC was calculated by IDBS XLFit (version 5.3.1.3). 50 .

[0681] As shown in the examples, the compounds showed EC 50 Values ​​are within the following range: A indicates EC 50 Less than 100nM, B indicates EC 50 Between 100-1000 nM, C represents EC 50 Between 1000-10000nM, D represents EC 50 Greater than 10000nM.

[0682] Table 3. Activity results of compounds on Jurkat cells

[0683] Experimental Example 5: IL-2 Release in Human Pan T Cells

[0684] Experimental purpose: To test the activation effect of compounds on IL-2 production by human Pan T cells.

[0685] Experimental Method: The experiment was performed in a 96-well plate (Corning). On the first day of the experiment, 0.5 μg / mL Anti-CD3 (Biocell) was added to the 96-well plate and incubated overnight at 4°C. On the second day of the experiment, PBMCs (Oricell, Z0115) were revived and hPan T cells were isolated using the Pan T Cell Isolation Kit (Miltenyi Biote). The cells were centrifuged and counted, and the cell density was adjusted to 1×106 cells / mL. Then, 100 μL of cells were added to a 96-well plate washed with PBS (absin) and supplemented with Anti-CD3. According to the experimental design, 50 μL of 2 μg / mL Anti-CD28 (Biocell) and 50 μL of diluted compound (final concentrations of 10 μM-1.5 nM, starting concentration of 10 μM, three-fold dilutions, 9 points, and the 10th point was DMSO) were added to each well. After centrifugation, the cell plate was placed in an incubator and incubated for 48 hours. The supernatant was collected by centrifugation and subjected to IL-2 ELISA. The absorbance signal values ​​(450 nm-570 nm) were converted to multiplication factor (DMSO). Multiplication factor = sample value / average of control wells. EC was calculated using IDBS XLFit. 50 .

[0686] As shown in the examples, the compounds showed EC 50 Values ​​are within the following range: A indicates EC 50 Less than 100nM, B indicates EC 50 Between 100-1000 nM, C represents EC 50 Between 1000-10000nM, D represents EC 50 Greater than 10000nM.

[0687] Table 4. Activity results of compounds on human Pan T cells

Claims

1. A compound of formula (A), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: Indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring; Symbol A represents carbon (C), C (R a ) or nitrogen (N); Symbol B represents C(R b )、C(R b )(R b '), N(R b ), N, O or S; Symbol D represents C(R d )、C(R d )(R d '), N(R d ) or N; Symbol E represents C(R e )、C(R e )(R e '), N(R e ) or N; Symbol F represents C(R f )、C(R f )(R f '), N(R f ), N, O or S; The symbol Q represents C(R q )、C(R q )(R q '), N(R q ), N, O or S; Alternatively, the symbols B and D together with the substituents thereon, or the symbols D and E together with the substituents thereon, form a group selected from the group consisting of: C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R1 is independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic group; R2 is independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic group; R a Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R b Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R b ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R b and R b 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR'、C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R d Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R d ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R d and R d 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R e Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R e ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R e and R e 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R f Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R f ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R f and R f 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R q Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R q ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R q and R q 'Together with the carbon atom to which it is attached, it forms an oxo, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Each occurrence of R8 is independently selected from NR'R", C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O; Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O; When there is a single bond between X and Y and X and Y do not form a ring, X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O; and Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O; When there is a double bond between X and Y and X and Y do not form a ring, X is N or C (R x1 ); and Y is N or C (R y1 ); R x1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R x2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; Or, R x1 and R x2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R y1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R y2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; Or, R y1 and R y2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; When X and Y are cyclic together, they form a C6-C 10 Aryl, 5-14 membered heteroaryl, C 5-15 Cycloalkyl and 4-15 membered heterocyclic group, which is optionally substituted by r R 10 Substituent substitution; L is selected from a covalent bond, -O-, -S- and -NR'-, or L is a C1-C6 alkylene group, one or more methylene units of which are optionally and independently replaced by -O-, -C(O)- or -S-; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 3-15 Cycloalkyl and 3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 3-15 Cycloalkyl and 3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; m is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; r is 0, 1, 2, 3, 4, or 5; x is 1, 2, 3, or 4; y is 1, 2, 3, or 4.

2. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (I): It indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring.

3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (II): Indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring; The symbol G represents a covalent bond, C(R g )、C(R g )(R g '), N(R g ), N, O or S; The symbol H represents a covalent bond, C(R h )、C(R h )(R h '), N(R h ), N, O or S; The symbol J represents a covalent bond, C(R j )、C(R j )(R j '), N(R j ), N, O or S; The symbol K represents a covalent bond, C(R k )、C(R k )(R k '), N(R k ), N, O or S; R g Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R g ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R g and R g 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R h Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R h ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R h and R h 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R j Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R j ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R j and R j 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R k Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R k ' is selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Or, R k and R k 'Together with the carbon atom to which it is attached, it forms C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 1-4 selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Substitution by cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Any pair of G and H, H and J, J and K together with the substituents thereon form a group selected from the following: phenyl, a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, C 3-6 Cycloalkyl and 3-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; other groups are as defined in claim 1.

4. A compound according to claim 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (III): It indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring.

5. A compound according to claim 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (IV): It indicates that the ring is an aromatic ring, a partially unsaturated ring or a saturated ring.

6. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring B is phenyl or a 5-6-membered heteroaryl group.

7. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring B and its substituents are selected from:

8. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring B and its substituents are selected from 9. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, R2 is independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 halogen Alkyl, NR'R", -OR', C 3-6 Cycloalkyl and 3-7 membered heterocyclic group; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; p is 1, 2 or 3.

10. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring B and its substituents are selected from:

11. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, When X is a covalent bond, Y is C(R y1 )(R y2 )hour, R y1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -L-R8; R y2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -L-R8; Or, R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 heteroatoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; Each occurrence of R8 is independently selected from NR'R", C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; L is selected from a covalent bond, -O-, -S- and -NR'-, or L is a C1-C6 alkylene group, one or more methylene units of which are optionally and independently replaced by -O-, -C(O)- or -S-; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, C6-C 10 aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, C6-C 10 aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

12. A compound according to claim 11, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: When X is a covalent bond, Y is selected from the following groups: Preferably, the group together with the substituents thereon forms a group selected from the following:

13. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, When X and Y are cyclic together, they form a C6-C 10 Aryl, preferably phenyl, optionally substituted with r R 10 Substituent substitution, R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; r is 1, 2 or 3.

14. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, When X and Y are taken together to form a ring, they together form a 5-6 membered heteroaryl group, preferably a pyrazolyl group, which is optionally substituted by r R 10 Substituent substitution, R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; r is 1, 2 or 3.

15. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, When X and Y are taken together to form a ring, they together form a C3-C6 cycloalkyl, a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, which is optionally substituted by r R 10 Substituent substitution, R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; r is 1, 2 or 3.

16. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: X is N(R x1 ) or C(R x1 )(R x2 ); Y is N(R y1 ) or C(R y1 )(R y2 ); The condition is that one of X and Y is N(R x1 ) or N(R y1 ), and X and Y together form a group selected from: a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, which is optionally substituted by r substituents R 10 replace, R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; r is 1, 2 or 3.

17. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, X is (C(R x1 )(R x2 )) x , Y is C(R y1 )(R y2 ), R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R x1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl; R x2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl; x is 1, 2, 3, or 4.

18. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, and the substituents thereon together form a group selected from the following:

19. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring C is a 5- to 10-membered heteroaryl group or a 3- to 10-membered heterocyclic group.

20. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring C is selected from:

21. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Ring C together with the substituents thereon is:

22. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Symbol A is C, Symbol B is C(R b ); Symbol F is N(R f ), R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

23. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Symbol A is C, The symbol B is N; Symbol F is N(R f ), R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl.

24. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, The symbol A is N, Symbol B is C(R b ); Symbol F is C(R f ), R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 Heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

25. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, The symbol A is N, Symbol B is C(R b )(R b '); Symbol F is N(R f ), R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R b 'Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

26. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: wherein, Selected from the following groups:

27. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: wherein, and the substituents thereon together form a group selected from the following: in, Indicates the connection point with the adjacent ring B.

28. A compound according to claim 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VI): R g Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R h Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R j Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R k Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; A, B, F, R1, X, Y, L, R8, R' and R" are as defined in claim 1.

29. A compound according to claim 28, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VI-1), formula (VI-2), formula (VI-3) or formula (VI-4): R b Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; R b 'Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; R f Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably H.

30. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, X is a covalent bond; Y is C(R y1 )(R y2 ), R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 cycloalkyl, 6-10 membered bicycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

31. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 a cycloalkyl ring, a 7-10 membered bicycloalkyl, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N and O, or a 7-10 membered bicyclic spiroheterocyclic group containing 1-4 heteroatoms selected from N and O, wherein The cycloalkyl ring or spiroheterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group.

32. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 A cycloalkyl ring, a 7-10 membered bicyclic spirocycloalkyl, a 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or a 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group.

33. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 A cycloalkyl group, a 7-10 membered bicyclic spirocycloalkyl group, a 4-6 membered oxamonocyclic heterocyclic group or a 7-10 membered oxabicyclic spiroheterocyclic group, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen and C 1-6 The substituent of the alkyl group, preferably, R y1 and R y2 Together with the attached carbon atom, it forms 34. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, When X and Y together form C6-C 10 Aryl, preferably phenyl, optionally substituted with r R 10 Substituent substitution, R 10 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably F; r is 1 or 2; Preferably, X and Y together form a group selected from:

35. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, When X and Y together form a 5-6 membered heteroaryl, preferably pyrazolyl, which is optionally substituted by r R 10 Substituent substitution, R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-4 Alkyl, more preferably methyl; r is 1 or 2; Preferably, X and Y together form a group selected from:

36. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, When X and Y together form a C3-C6 cycloalkyl, a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic heterocyclic group, it is optionally substituted by r R 10 Substituent substitution, R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; r is 1 or 2.

37. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, X is N(R x1 ) or C(R x1 )(R x2 ); Y is N(R y1 ) or C(R y1 )(R y2 ); The condition is that one of X and Y is N(R x1 ) or N(R y1 ), and X and Y together form a group selected from: a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic spiro heterocyclic group, which is optionally substituted by r substituents R 10 replace, R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; r is 1 or 2; Preferably, X and Y together form a group selected from:

38. A compound according to claim 29, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X is (C(R x1 )(R x2 )) x , Y is C(R y1 )(R y2 ), R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 heteroatoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R x1 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; R x2 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; x is 1 or 2; Preferably, X and Y together form 39. A compound according to any one of claims 29 to 38, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: Each occurrence of R1 is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S; R g Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R", -OR', 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; R h Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R", -OR', 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; R j Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R", -OR', 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; R k Selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; Each occurrence of R8 is independently selected from NR'R", C 3-10 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; L is C1-C6 alkylene, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)- or -S-; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

40. A compound according to any one of claims 29 to 38, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: Each occurrence of R1 is independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R g Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; R h Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; R j Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; R k Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-6 Cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -L-R8; Each occurrence of R8 is independently selected from NR'R", C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, which are optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR'; L is a C1-C6 alkylene group; R' is independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 heteroatoms selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 heteroatoms selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; or R' and R" together with the nitrogen atom form a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted with 1-3 heteroatoms selected from H, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group.

41. A compound according to any one of claims 29 to 38, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein: R1 is selected from H and C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably methyl; R g Selected from H, F, Br, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl; R h is selected from H and halogen, preferably F; R j Selected from H and -L-R8; R k Selected from H and -L-R8; R8 is independently selected at each occurrence from NR'R" and a 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, which is optionally substituted with 1-3 R9 substituents; Each occurrence of R9 is independently selected from H and C 1-4 Alkyl, preferably methyl; R' is independently selected from H, C 1-4 Alkyl, 4-6 membered cycloalkyl and containing 1-2 heteroatoms selected from N and O The 4-6 membered heterocyclic group, the cycloalkyl and heterocyclic groups are optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of the alkyl group; R" is independently selected from H, C 1-4 alkyl, 4-6 membered cycloalkyl and 4-6 membered heterocyclic radical containing 1-2 heteroatoms selected from N and O, the cycloalkyl and heterocyclic radicals are optionally substituted with 1-2 heteroatoms selected from H and C 1-4 Substituents of the alkyl group; Alternatively, R' and R" together with the nitrogen atom form a 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O, the heterocyclic group being optionally substituted with 1-2 heteroatoms selected from H and C 1-4 Substituents of the alkyl group; L is a C1-C2 alkylene group.

42. A compound according to claim 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VII):

43. A compound according to claim 42, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, which is of formula (VII-1), formula (VII-2) or formula (VII-3): R g Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R j Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R k Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R b Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; R f Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; Each occurrence of R8 is independently selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, which are optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR'; L is C1-C6 alkylene, preferably C1-C4 alkylene, more preferably C1-C2 alkylene; R' is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl 5-10 membered heteroaryl and 3-10 membered heterocyclyl; Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

44. A compound according to claim 43, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, X is a covalent bond; Y is C(R y1 )(R y2 ), R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 a cycloalkyl ring, a 7-10 membered bicycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of the haloalkyl group.

45. A compound according to claim 43, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 A cycloalkyl ring, a 7-10 membered bicyclic spirocycloalkyl, a 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or a 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group.

46. ​​A compound according to claim 43, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 A cycloalkyl ring, a 7-10 membered bicyclic spirocycloalkyl, a 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or a 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group.

47. A compound according to claim 43, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 A cycloalkyl ring, a 7-10 membered bicyclic spirocycloalkyl, a 4-6 membered oxamonocyclic heterocyclic group or a 7-10 membered oxabicyclic spiroheterocyclic group, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen and C 1-6 The substituent of the alkyl group, preferably, R y1 and R y2 Together with the attached carbon atom, it forms More preferably 48. A compound of formula (VIII), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof: in, Indicates that the bond is a single bond or a double bond; Symbol U is C(R 2d ) or nitrogen (N); R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R 2a Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C 3- 15-membered cycloalkyl and 3-15-membered heterocyclyl; R 2b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic group; R 2c Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic group; R 2d Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C 3-15 Cycloalkyl and 3-15 membered heterocyclic group; R b Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; R g Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R h Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R j Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; R k Selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR', C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O; Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O; When there is a single bond between X and Y and X and Y do not form a ring, X is a covalent bond, N(R x1 )、(C(R x1 )(R x2 )) x , S or O; and Y is N(R y1 )、(C(R y1 )(R y2 )) y , S or O; When there is a double bond between X and Y and X and Y do not form a ring, X is N or C (R x1 ); and Y is N or C (R y1 ); R x1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R x2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; Or, R x1 and R x2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R y1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R y2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; Or, R y1 and R y2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl ring or 3-10 membered heterocyclyl ring, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; When X and Y are cyclic together, they form a C6-C 10 Aryl, 5-14 membered heteroaryl, C 5-15 Cycloalkyl and 4-15 membered heterocyclic group, which is optionally substituted by r R 10 Substituent substitution; L is selected from a covalent bond, -O-, -S- and -NR'-, or L is a C1-C6 alkylene group, one or more methylene units of which are optionally and independently replaced by -O-, -C(O)- or -S-; Each occurrence of R8 is independently selected from NR'R", C 3-15 Cycloalkyl, C6-C 10 Aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; R 10 Each occurrence is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-C6-C 10 Aryl, -L'-5-14 membered heteroaryl, -L'-C 3-15 Cycloalkyl and -L'-3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -L'-C6-C 10 Aryl, -L'-5-14 membered heteroaryl, -L'-C 3-15 Cycloalkyl and -L'-3-15 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; L' is a covalent bond or a C1-C6 alkylene group, wherein one or more methylene units in the C1-C6 alkylene group are optionally and independently replaced by -O-, -C(O)- or -S-; r is 0, 1, 2, 3, 4, or 5; x is 1, 2, 3, or 4; y is 1, 2, 3, or 4.

49. A compound according to claim 48, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is of formula (VIII-1) or formula (VIII-2):

50. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X is a covalent bond; Y is C(R y1 )(R y2 ), Among them, R y1 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R y2 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; Or, R y1 and R y2 Together with the attached carbon atom, it forms C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the cycloalkyl ring or heterocyclyl ring is optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, phenyl, L'-5-6 membered heteroaryl, L'-C 3-10 Cycloalkyl and L'-3-10 membered heterocyclic group, the phenyl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, L'-phenyl, L'-5-6 membered heteroaryl, L'-C 3-10 Cycloalkyl and L'-3-10 membered heterocyclic group, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; L' is a covalent bond or a C1-C6 alkylene group, Other groups are as defined in claim 48.

51. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X is a covalent bond; Y is C(R y1 )(R y2 ), Among them, R y1 and R y2 Together with the attached carbon atom, it forms C 3-6 A cycloalkyl ring, a 7-10 membered bicyclic spirocycloalkyl, a 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N and O, or a 7-10 membered bicyclic spiro heterocyclic group containing 1-2 heteroatoms selected from N and O, wherein the cycloalkyl ring or spiro heterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl and OR' substituents; R' is selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, Other groups are as defined in claim 48.

52. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X is a covalent bond; Y is C(R y1 )(R y2 ); Among them, R y1 and R y2 Together with the attached carbon atom, it forms C 4-6 a cycloalkyl ring, a 7-10 membered bicyclic spirocycloalkyl, a 4-6 membered oxamonocyclic heterocyclic group or a 7-10 membered oxabicyclic spiroheterocyclic group, wherein the cycloalkyl ring or spiroheterocyclic ring is optionally substituted with 1-3 groups selected from H, halogen, C 1-6 Alkyl, cyano substituted C 1-6 Alkyl and OR' substituents, R' is C 1-6 alkyl; Preferably, R y1 and R y2 Together with the attached carbon atom, it forms More preferably Other groups are as defined in claim 48.

53. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X is (C(R x1 )(R x2 )) x , Y is C(R y1 )(R y2 ), Among them, R x1 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; R x2 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; R y1 and R y2 Together with the attached carbon atom, it forms a C3-C6 cycloalkyl ring, a 4-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or a 6-10 membered bicyclic heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl ring or heterocyclic ring is optionally substituted with 1-3 heteroatoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyano substituted C 1-6 Alkyl, C 1-6 haloalkyl, NR'R" and -OR' substituents; x is 1 or 2; R' at each occurrence is independently selected from H and C 1-6 alkyl; R" is selected from H and C 1-6 alkyl; Preferably, X and Y together form Other groups are as defined in claim 48.

54. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, X is N(R x1 ) or C(R x1 )(R x2 ); Y is N(R y1 ) or C(R y1 )(R y2 ); The condition is that one of X and Y is N(R x1 ) or N(R y1 ), and X and Y together form a group selected from: a 4-6 membered monocyclic heterocyclic group or a 6-10 membered bicyclic spiro heterocyclic group, which is optionally substituted by r substituents R 10 replace, R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; r is 1 or 2; Preferably, X and Y together form a group selected from: Other groups are as defined in claim 48.

55. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, is a double bond, and X and Y together form a C3-C6 cycloalkyl ring, which is optionally substituted by r substituents R 10 replace, R 10 Each occurrence is independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; r is 1 or 2; Preferably, X and Y together form a group selected from: Other groups are as defined in claim 48.

56. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R k Selected from:

57. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is of formula (IX), in, R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; R 2a Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR' and C 3-10 Cycloalkyl; R g Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl; R k is selected from H, phenyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; L is a C1-C6 alkylene group; R8 is selected from NR'R", C 3-10 Cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Or R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; L' is a covalent bond or a C1-C6 alkylene group.

58. A compound according to claim 57, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R1 is selected from C 1-6 Alkyl and C 1-6 Haloalkyl; R 2a Selected from H, NR'R", -OR' and C 3-6 Cycloalkyl; R g Selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R k Selected from H and -L-R8; L is a C1-C6 alkylene group; R8 is NR'R"; R' is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; Alternatively, R' and R" together with the nitrogen atom form a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L' is a covalent bond or a C1-C6 alkylene group.

59. A compound according to claim 57, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R1 is C 1-4 Alkyl, preferably methyl; R 2a is H; R g is halogen, preferably F; R k for-L-R8; L is a C1-C4 alkylene group; R8 is NR'R"; R' is H; R" is selected from C 1-6 Alkyl and -L'-C 3-7 Cycloalkyl, the cycloalkyl is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of the alkyl group; Alternatively, R' and R" together with the nitrogen atom form a 5-6 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of the alkyl group; L' is a covalent bond or a C1-C4 alkylene group.

60. A compound according to claim 48 or 49, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is of formula (X), in, R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; R 2a Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, NR'R", -OR' and C 3-10 Cycloalkyl; R g Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl; R k is selected from H, phenyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and -L-R8; L is a C1-C6 alkylene group; R8 is selected from NR'R", C 3-10 Cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with 1-3 R9 substituents; R9, at each occurrence, is independently selected from H, halogen, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, NR'R" and -OR'; R' is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, -L'-phenyl, -L'-5-10 membered heteroaryl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; Alternatively, R' and R" together with the nitrogen atom form a 5-10 membered heteroaryl or a 3-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-3 groups selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Substituents of haloalkyl groups; L' is a covalent bond or a C1-C6 alkylene group.

61. A compound according to claim 60, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R1 is selected from C 1-6 Alkyl and C 1-6 Haloalkyl; R 2a Selected from H, NR'R", -OR' and C 3-6 Cycloalkyl; R g Selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R k Selected from H and -L-R8; L is a C1-C6 alkylene group; R8 is NR'R"; R' is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-C 3-10 Cycloalkyl and -L'-3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-3 atoms selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; Alternatively, R' and R" together with the nitrogen atom form a 3-10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-3 groups selected from H, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L' is a covalent bond or a C1-C6 alkylene group.

62. A compound according to claim 60, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in, R1 is C 1-4 Alkyl, preferably methyl; R 2a Selected from NR'R", -OR' and C 3-5 Cycloalkyl; R g is halogen, preferably F; R k for-L-R8; L is a C1-C4 alkylene group; R8 is NR'R"; R' at each occurrence is independently selected from H and C 1-4 alkyl; R" is selected from C 1-4 Alkyl and -L'-C 3-7 Cycloalkyl, the cycloalkyl is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of the alkyl group; Or R' and R" together with the nitrogen atom form a 5-6 membered heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted with 1-2 groups selected from H and C 1-4 Substituents of the alkyl group; L' is a covalent bond.

63. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from:

64. A compound according to claim 48, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from:

65. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof.

66. A method for treating or preventing a disease or condition associated with Cbl-b activity, comprising administering a compound of any one of claims 1 to 64 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof as a Cbl-b inhibitor or a composition of claim 65 to a subject in need thereof.

67. Use of a compound of any one of claims 1 to 64, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of claim 65, in the preparation of a medicament for treating or preventing a disease or condition associated with Cbl-b activity.

68. Use of a compound of any one of claims 1 to 64 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a composition of claim 65 in the preparation of a medicament for treating cancer.

69. A compound of any one of claims 1 to 64 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of claim 65, for use in treating or preventing a disease or condition associated with Cbl-b activity.

70. A compound of any one of claims 1-64 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a composition of claim 65 for use in treating cancer.

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