Novel substituted heterocyclic compound serving as VAV1 protein target degradation agent

Abstract

Disclosed in the present invention is a novel substituted heterocyclic compound having VAV1 target degradation activity. Specifically disclosed is a compound serving as a VAV1 target degradation agent and having the structure of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isotopic substituent or isomer of the compound. The compound can be used for preventing or treating diseases related to VAV1 targets or signaling pathways.

Description

Novel substituted heterocyclic compounds as VAV1 protein target degraders

[0001] The present application claims the priority of:

[0002] The priority of the prior application with the patent application number 2024110227104, entitled "Novel substituted heterocyclic compounds as VAV1 protein target degraders", filed on July 29, 2024, with the State Intellectual Property Office of China;

[0003] The priority of the prior application with the patent application number 2025100173723, entitled "Novel substituted heterocyclic compounds as VAV1 protein target degraders", filed on January 6, 2025, with the State Intellectual Property Office of China;

[0004] The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0005] The present application belongs to the field of medicinal chemistry, and specifically includes novel substituted heterocyclic compounds with the degradation of human oncogene VAV1 protein target, compositions containing such compounds and methods of using such compounds for the preparation of drugs for treating or preventing diseases related to the disorder of VAV1 protein signaling pathway. BACKGROUND

[0006] VAV family proteins including VAV1, VAV2, VAV3 belong to the guanine nucleotide exchange factor (GEF) proteins of the Rho family of GTPases, which are involved in a variety of cellular processes. Its activation leads to rearrangement of the actin cytoskeleton and changes in transcriptional pathways, and is closely related to a variety of physiological and pathological processes, such as hematopoietic system, T cell and B cell development and activation, etc. The activation of Vav1 also stimulates the MAPK signaling cascade, which can lead to cancer by enhancing cell mitotic properties. MAPK functions are related to a variety of biological processes, such as cell proliferation, differentiation, death, migration, invasion and inflammation. In recent years, it has been found that VAV is closely related to the occurrence and development of a variety of diseases such as tumors, autoimmunity, and inflammation. In the field of tumors, wild-type VAV1 has recently been found to be associated with mammalian malignancies, including neuroblastoma, melanoma, pancreatic cancer, lung cancer and breast cancer, as well as B-cell chronic lymphocytic leukemia. Among the 95 tumor specimens of pancreatic ductal adenocarcinoma (PDA) examined, more than 50% also found Vav1. And compared with Vav1-negative tumor patients, Vav1-positive tumor patients have a poorer survival prognosis; among the 78 cancer cell lines examined, 42% of the cell lines, 46% of the cell lines were found to have abnormal expression of Vav1 in 57 human primary cancer specimens, and abnormal expression of Vav1 was found in breast cancer, ovarian cancer and prostate cancer.

[0007] In the field of autoimmunity and inflammation, such as neuronal injury and cerebral ischemia, reperfusion injury, Vav1 is overexpressed, mainly in microglia, and its silencing can inhibit microglial activation and reduce inflammation by inhibiting NLRP3-mediated inflammatory factor release. Knockout of Vav1 can reduce cerebral infarction and neuronal injury in middle cerebral artery occlusion reperfusion rats. Therefore, VAV1 is a very potential target for various tumors, autoimmunity or inflammation related diseases. SUMMARY

[0008] The purpose of the present application is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer and isotopically substituted product thereof,

[0009] wherein,

[0010] Z is independently selected from a carbonyl or oxacyclopropyl, oxacyclobutyl structure;

[0011] Ring A and D are independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole or structure;

[0012] Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0013] R1 is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with alkyl or carboxyl alternative, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0014] R2is independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0015] R3and R4may be the same or different and are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a member selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl substituted;

[0016] L1, L2, L3are each independently selected from the group consisting of nothing, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene, an alkyne;

[0017] Y optionally independently represents =O or =NR d7 ;

[0018] Q is optionally independently selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0019] each R d1 , R d2 , R d3 , R d4 , R d5 , Rd7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0020] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0021] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0022] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0023] n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0024] t is any integer selected from 0, 1, or 2;

[0025] p can be any integer selected from 0, 1, or 2;

[0026] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (IA-1) or Formula (IA-2),

[0027] wherein,

[0028] X is independently selected from C(R d1 ) or N;

[0029] Ring A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or

[0030] Ring B is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure;

[0031] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH, and -NH2, -COOH, or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl, or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with C

[0032] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C​1-10 alkylsulfonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfonyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0033] R3and R4may be the same or different, each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0034] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2)-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0035] Y can represent either =O or =NR independently. d7 ;

[0036] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0037] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0038] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0039] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0040] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0041] n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0042] t is any integer selected from 0, 1, or 2;

[0043] p can be any integer selected from 0, 1, or 2;

[0044] In one aspect of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute or isomer has a structure of formula (IB-1) or formula (IB-2).

[0045] in,

[0046] Each can independently represent a single bond or a double bond;

[0047] Z can be selected independently from carbonyl or oxetine propyl or oxetine butyl structures;

[0048] X is arbitrarily and independently selected from C(R)d1 ) or N;

[0049] Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged ring structure; preferably a benzene, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole, furan, pyrrole, thiophene, pyridine, isothiazole or structure;

[0050] Ring C is independently selected from a monocyclic or polycyclic structure of 3 to 8 carbon atoms, optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged ring structure;

[0051] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with C

[0052] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0053] R3and R4may be the same or different, each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, selected from C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0054] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5)-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), a double bond, a triple bond;

[0055] Y represents, independently and optionally, =O or =NR d7 ;

[0056] Q is selected, independently and optionally, from a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group or a 3-18 membered saturated or partially saturated heterocyclyl group, which cycloalkyl or heterocyclyl group can be fused, spiro or bridged; and a hydrogen on Q is optionally substituted with one to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups of cycloalkyl or heterocyclyl groups;

[0057] Each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, and are selected, independently and optionally, from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein the C1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group; 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group; 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0058] said hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0059] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0060] m is any integer selected from 0, 1, 2, 3 and 4;

[0061] n is any integer selected from 0, 1, 2, 3 and 4;

[0062] t is any integer selected from 0, 1 or 2;

[0063] p is any integer selected from 0, 1 or 2;

[0064] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted or isomer thereof, has the structure of Formula (IC),

[0065] wherein,

[0066] ring D is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, annulated, spirocyclic or bridged cyclic structure; preferably benzene, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole, furan, pyrrole, thiophene, pyridine, isothiazole or structure;

[0067] X1, X2are any independently selected from C(R d1 ) or N;

[0068] Y is any independently selected from NR d1 , O or S;

[0069] Z is independently selected from carbonyl or oxiranyl, oxetanyl structure;

[0070] Ring B is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged structure;

[0071] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0072] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH and -NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0073] R3and R4may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH and -NH2, -COOH or from C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0074] L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4)P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), a double bond, a triple bond;

[0075] Q is independently selected from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogens on Q are optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0076] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C3-10 C1-C6alkyl substituted with 1 to 3 heterocycloalkyl groups; 3-10 heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C1-C6alkyl; 3-10 saturated or partially substituted groups substituting saturated cycloalkyl or heterocyclyl groups;

[0077] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0078] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0079] m is any integer selected from 0, 1, 2, 3, and 4;

[0080] n is any integer selected from 0, 1, 2, 3, and 4;

[0081] t is any integer selected from 0, 1, or 2;

[0082] p is any integer selected from 0, 1, or 2;

[0083] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, having the structure of Formula (ID-1) or Formula (ID-2),

[0084] wherein,

[0085] X, X1, X2are any independently selected from C(R d1 ) or N;

[0086] Z is any independently selected from carbonyl or oxacyclopropyl, oxacyclobutyl structure;

[0087] Ring B is any independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure can be any independently selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring, or bridged ring structure;

[0088] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl group, -CN, -OH, -SH, and -NH2, -COOH or selected from C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkoxy, C1-C6heteroalkyl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocycloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl substituted with C1-C6alkyl, C3-C8cycloalkyl, or C3-C8heterocycloalkyl; 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl, or C 3-10 heterocycloalkyl substituted with C 1-10alkyl, C 3-10 cycloalkyl, C 2-10 heteroalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl-substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0089] R2is optionally and independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0090] R3and R4may be the same or different and are optionally and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl-substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom(s) to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a member selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0091] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), alkene, alkyne;

[0092] Y optionally independently represents =O or =NR d7 ;

[0093] Q is optionally independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0094] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0095] said hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0096] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0097] m is any integer selected from 0, 1, 2, 3 and 4;

[0098] n is any integer selected from 0, 1, 2, 3 and 4;

[0099] t is any integer selected from 0, 1 or 2;

[0100] p is an integer selected from 0, 1 or 2;

[0101] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of (IE-1) or (IE-2),

[0102] wherein,

[0103] Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole or structure;

[0104] Z is independently selected from a carbonyl or an oxiranyl, oxetanyl structure;

[0105] X and X1are independently selected from C(R d1 ) or N;

[0106] Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0107] R1is independently selected from hydrogen, deuterium, halogen, a sulfur pentafluoride group, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with C

[0108] R3and R4may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0109] Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro or bridged; and the hydrogens on Q are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0110] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0111] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0112] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0113] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0114] t is any integer selected from 0, 1, or 2;

[0115] p can be any integer selected from 0, 1, or 2;

[0116] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute or isomer thereof has a structure of formula (IF-1), formula (IF-2) or formula (IF-3).

[0117] in,

[0118] Z can be selected independently from carbonyl or oxetine propyl or oxetine butyl structures;

[0119] Ring A is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridged ring structures; preferably, it is a benzene ring, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole ring, furan ring, pyrrole ring, thiophene ring, pyridine ring, isothiazole, or... structure;

[0120] Ring B is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0121] R1 is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfide, -CN, -OH, -SH and -NH2, -COOH or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3- 10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes, dialkylphosphoryl groups, cycloalkylphosphoryl groups, or Q groups;

[0122] R2 is arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C3-10 cycloalkylsulfonyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C

[0123] R3and R4may be the same or different, each independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0124] Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro or bridged ring structure; and the hydrogen on Q is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted group saturated cycloalkyl or heterocyclyl;

[0125] each R d1 , R d2 , R d3 , Rd4 R d5 R d7 R d8 R d9 R 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl; or R 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl; or R 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0126] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0127] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0128] m is any integer selected from 0, 1, 2, 3 and 4;

[0129] n is any integer selected from 0, 1, 2 or 3;

[0130] t is any integer selected from 0, 1 or 2;

[0131] p is any integer selected from 0, 1 or 2;

[0132] In one aspect of the application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (IH-1), Formula (IH-2), or Formula (IH-3),

[0133] wherein,

[0134] Z is independently selected from a carbonyl or oxiranyl, oxetanyl structure;

[0135] Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged ring structure; preferably a benzene, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole, furan, pyrrole, thiophene, pyridine, isothiazole, or structure;

[0136] Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged ring structure;

[0137] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH, and -NH2, -COOH, or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl, or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with an alkyl, or carboxyl replacement, dialkylphosphoryl, cycloalkylphosphoryl, or Q group;

[0138] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10alkylcarbonyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylcarbonyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0139] R3and R4may be the same or different, each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, substituted by C 1-10 alkyl, and substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkyloxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0140] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(Rd2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond;

[0141] Y represents, independently at each occurrence, =O or =NR d7 ;

[0142] Q is selected, independently at each occurrence, from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and a hydrogen on Q is optionally substituted with one to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups of a saturated or partially substituted cycloalkyl or heterocyclyl;

[0143] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 , or R d9 may be the same or different, and are selected, independently at each occurrence, from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, CHeteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0144] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0145] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0146] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0147] n is any integer selected from 0, 1, 2 or 3;

[0148] t is any integer selected from 0, 1, or 2;

[0149] p can be any integer selected from 0, 1, or 2;

[0150] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute or isomer thereof has a structure of formula (IJ-1), formula (IJ-2) or formula (IJ-3).

[0151] in,

[0152] Z can be selected independently from carbonyl or oxetine propyl or oxetine butyl structures;

[0153] X and X1 are arbitrarily and independently selected from CR2 or N;

[0154] Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spirocyclic ring, or a bridged ring structure;

[0155] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH, and -NH2, -COOH, or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl, or C 3-10 heterocycloalkyl, C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl, or a Q group;

[0156] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0157] R3and R4may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10alkyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0158] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(Rd1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0159] Y can represent either =O or =NR independently. d7 ;

[0160] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0161] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0162] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0163] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0164] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0165] n is any integer selected from 0, 1, 2 or 3;

[0166] t is any integer selected from 0, 1, or 2;

[0167] p can be any integer selected from 0, 1, or 2;

[0168] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute or isomer thereof has a structure of formula (IK-1) or formula (IK-2).

[0169] in,

[0170] Z can be selected independently from carbonyl or oxetine propyl or oxetine butyl structures;

[0171] Ring A is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridged ring structures; preferably, it is a benzene ring, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole ring, furan ring, pyrrole ring, thiophene ring, pyridine ring, isothiazole, or... structure;

[0172] Ring B is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0173] R1 is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfide, -CN, -OH, -SH and -NH2, -COOH or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl-substituted C 1-10 alkyl, C 3-10 cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0174] R2is optionally independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0175] R3and R4may be the same or different and are optionally independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl-substituted C 1-10 alkyl, and substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0176] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), alkene, alkyne;

[0177] Y optionally independently represents =O or =NR d7 ;

[0178] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0179] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0180] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0181] said halogen is independently selected from F, Cl, Br, I and isotopes thereof;

[0182] m is an integer selected from 0, 1, 2, 3 and 4;

[0183] n is an integer selected from 0, 1, 2 or 3;

[0184] t is an integer selected from 0, 1 or 2;

[0185] p is an integer selected from 0, 1 or 2;

[0186] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (IL-1), Formula (IL-2), or Formula (IL-3),

[0187] wherein,

[0188] Z is independently selected from a carbonyl or an oxiranyl, oxetanyl structure;

[0189] X, X1, X3, are independently selected from CR2or N;

[0190] Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure is independently selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0191] R1is independently selected from hydrogen, deuterium, halogen, a sulfur pentafluoride group, -CN, -OH, -SH and -NH2, -COOH or is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0192] R2is independently selected from hydrogen, deuterium, halogen, CN, a sulfur pentafluoride group, OH, SH and NH2, -COOH, C 1-10 alkyl, C2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0193] R3and R4may be the same or different, each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, substituted by C 1-10 alkyl, and substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a member selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0194] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0195] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0196] The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0197] The halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0198] m is any integer selected from 0, 1, 2, 3 and 4;

[0199] n is any integer selected from 0, 1, 2 or 3;

[0200] t is any integer selected from 0, 1 or 2;

[0201] p is any integer selected from 0, 1 or 2;

[0202] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted or isomer thereof, has a structure of Formula (IM-1) or Formula (IM-2),

[0203] wherein,

[0204] Z is any independently selected from carbonyl or oxiranyl, oxetanyl structure;

[0205] Ring A is any independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged structure; preferably benzene, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole, furan, pyrrole, thiophene, pyridine, isothiazole or structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged structure;

[0206] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substituents, dialkylphosphoryl, cycloalkylphosphoryl or Q groups;

[0207] R2is independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0208] R3and R4may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, by C 3-10 cycloalkyl or C 3-10 C substituted by C 1-10 alkyl, and by C 3-10 cycloalkyl, C 3-10 C substituted by C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally replaced by selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0209] Q is optionally and independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged ring structure; and hydrogen on Q is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0210] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, and are each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0211] said hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0212] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0213] m is any integer selected from 0, 1, 2, 3 and 4;

[0214] n is any integer selected from 0, 1, 2 or 3;

[0215] t is any integer selected from 0, 1 or 2;

[0216] p is any integer selected from 0, 1 or 2;

[0217] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted or isomer thereof, has a structure of formula (IN-1) to (IN-4),

[0218] wherein,

[0219] Z is any independently selected from carbonyl or oxiranyl, oxetanyl structure;

[0220] Ring A is any independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; preferably benzene ring, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole ring, furan ring, pyrrole ring, thiophene ring, pyridine ring, isothiazole or structure;

[0221] Ring B is any independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure;

[0222] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0223] R2is optionally independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0224] R3and R4may be the same or different and are optionally independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0225] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), alkene, alkyne;

[0226] Y optionally independently represents =O or =NR d7 ;

[0227] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0228] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0229] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0230] said halogen is independently selected from F, Cl, Br, I and isotopes thereof;

[0231] m is independently selected from an integer of 0, 1, 2, 3 and 4;

[0232] n is independently selected from an integer of 0, 1, 2 or 3;

[0233] t is independently selected from an integer of 0, 1 or 2;

[0234] p is independently selected from an integer of 0, 1 or 2;

[0235] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has a structure of formula (IO-1) to (IO-2),

[0236] wherein,

[0237] Z is independently selected from a carbonyl or an oxiranyl, oxetanyl structure;

[0238] Ring D is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole or structure;

[0239] Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0240] R1is independently selected from hydrogen, deuterium, halogen, a pentafluorosulfanyl group, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0241] R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0242] R3and R4may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a member selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0243] L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene, an alkyne;

[0244] Y optionally independently represents =O or =NR d7 ;

[0245] Q is optionally and independently selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0246] each R d1 , R d2 , R d3 , Rd4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0247] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0248] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0249] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0250] n is any integer selected from 0, 1, 2 or 3;

[0251] t is any integer selected from 0, 1, or 2;

[0252] p can be any integer selected from 0, 1, or 2;

[0253] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotope substitution, or isomer thereof, has a structure of Formula (IP-1) to (IP-2),

[0254] wherein,

[0255] Z is independently selected from carbonyl or oxiranyl, oxetanyl structure;

[0256] Ring D is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annelated ring, spirocyclic ring, or bridged ring structure; preferably benzene ring, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole ring, furan ring, pyrrole ring, thiophene ring, pyridine ring, isothiazole, or structure;

[0257] Ring B is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annelated ring, spirocyclic ring, or bridged ring structure;

[0258] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH, and -NH2, -COOH, or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl, or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with alkyl, or carboxyl replacement, dialkylphosphoryl, cycloalkylphosphoryl, or Q group;

[0259] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0260] R3 and R4 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3 or R4 atoms together with their attached atoms to form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0261] L1, L2, and L3 are each independently selected from non-existent, single-bond, and -C(R) d1 (R) d2)-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0262] Y can represent either =O or =NR independently. d7 ;

[0263] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0264] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted group saturated cycloalkyl or heterocyclyl is substituted by;

[0265] the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0266] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0267] m is any integer selected from 0, 1, 2, 3 and 4;

[0268] n is any integer selected from 0, 1, 2 or 3;

[0269] t is any integer selected from 0, 1 or 2;

[0270] p is any integer selected from 0, 1 or 2;

[0271] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has a structure of formula (1-I),

[0272] wherein A is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure can be any independently selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annulated ring, spirocyclic ring or bridged ring structure;

[0273] each R1may be the same or different, and is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or is selected from C1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes, dialkyl phosphoryl groups, cycloalkyl phosphoryl groups, or -L1-Q; or any two adjacent R1 groups together with their attached atoms to form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C. 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 The cycloalkyl group is substituted; furthermore, the hydrogen on R1 is optionally preferably replaced by one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 Substituents of the substituents;

[0274] R2 is arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10Cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkylacyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogens on R2are optionally replaced with 1 to multiple groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1- 6alkyl)2, oxo, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 Alkoxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 Cycloalkyl;

[0275] R3, R4, R5may be the same or different, each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, substituted with C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, and substituted with C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 1-10 Heteroalkyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3, R4or R5together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally replaced with groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, =0, and saturated or partially saturated C 3-6cycloalkyl-substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups independently selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl-substituted, and C

[0276] each R7may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted, C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted, C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted, C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted, C 3-10 heterocyclyl is optionally substituted with 1 to 3 groups independently selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted group saturated cycloalkyl or heterocyclyl is substituted with;

[0277] L1is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -

[0278] C(=NR d5)-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-,

[0279] S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (= d1 )(R d2 ), an olefinic,

[0280] acetylenic bond;

[0281] Q is independently selected from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0282] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; and C 3-10 heterocyclyl; wherein the C 1-10alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted with C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0283] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0284] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0285] m is any integer selected from 0, 1, 2, 3 and 4;

[0286] n is any integer selected from 0, 1, 2, 3, 4 and 5.

[0287] In one aspect of the present application, the compound or its pharmaceutically acceptable salt, isotopically substituted or isomer thereof, has the structure of formula (1-IA-1 or formula 1-IA-2),

[0288] wherein,

[0289] any independently represents single or double bond;

[0290] A is any independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure can be any independently selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annulated ring, spirocyclic ring or bridged ring structure;

[0291] X1and X2are any independently selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(Rd1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=X)–, -OS(=X)-, -S(=O)2, C(R d1 ) or N;

[0292] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, pentafluoride sulfide, -CN, -OH, -SH and -NH2, -COOH or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes, dialkyl phosphoryl groups, cycloalkyl phosphoryl groups, or -L1-Q; or any two adjacent R1 groups together with their attached atoms to form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C. 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 The cycloalkyl group is substituted; furthermore, the hydrogen on R1 is optionally preferably replaced by one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR.d8 R d9 substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C

[0293] R2is optionally and independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogen on R2is optionally substituted by one to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, oxo, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted by one to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -CF3, -OH, -OCH3, -OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0294] each R3may be the same or different and is optionally and independently from each other selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0295] L1is independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), a double bond, a triple bond;

[0296] Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogens on Q are optionally substituted with 1 to 4 groups independently selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0297] Each R7may be the same or different, and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl-substituted C 3-10 alkyl, or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 1-10 heterocyclyl; wherein the C 2- alkyl, C 10 alkenyl, or C 1-10 alkynyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl-substituted C 3-10 alkyl, or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with 1 to 4 groups independently selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C d1 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0298] Each R d2 , R d3 , R d4 , R d5 , R d7 , R d8 , R d9They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0299] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0300] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0301] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0302] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0303] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0304] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute, or isomer thereof has a structure of formula (1-IB-1 or 1-IB-2).

[0305] in,

[0306] Arbitrary stands for a single or double bond independently;

[0307] X is arbitrarily selected from N or CR1;

[0308] X1and X2are arbitrarily selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), -C(=S)-, -S(=O)-, -(R d4 )P(=X)-, -OS(=X)-, -S(=O)2, C(R d1 ) or N;

[0309] Each R1may be the same or different, selected independently from each other from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 alkyl substituted with C 3-10 cycloalkyl or C 1-10 heterocycloalkyl, C 3-10 alkyl substituted with C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10alkyl, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to multiple groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR d8 R d9 ; and R2is independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C

[0310] R2is independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein a hydrogen on R2is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, oxo, and saturated or partially saturated C 3-6cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally further substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl substituted;

[0311] each R3may be the same or different and is independently of each other selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or is selected from C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl, or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl, and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl substituted;

[0312] L1is independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(Rd2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0313] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0314] Each R7 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2- 10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocyclyl is optionally substituted with 1 to several substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0315] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different and are each independently of one another selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocyclyl is optionally substituted with 1 to several substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0316] The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0317] The halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0318] m is any integer selected from 0, 1, 2, 3 and 4;

[0319] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0320] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0321] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (1-IC),

[0322] wherein,

[0323] X is any independently selected from N or CR1;

[0324] Each R1may be the same or different, and is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate substituted with alkyl, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 5 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; and further R1 hydrogen is optionally substituted with 1 to 5 groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR d8 R d9 substituted with 1 to 5 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C

[0325] R2 is optionally and independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein R2 hydrogen is optionally substituted with 1 to 5 groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, oxo, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to 5 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0326] each R3 can be the same or different, and is optionally and independently of each other selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or selected from C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, by C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0327] L1is independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1(R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0328] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0329] Each R7 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2- 10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0330] Each R d1 Rd2 R d3 R d4 R d5 R d7 R d8 R d9 R 1-10 R 2-10 R 1-10 R 1-10 R 1-10 R 2-10 R 3-10 R 3-10 R 3-10 R 1-10 R 3-10 R 3-10 R 3-10 R 1-10 R 2-10 R 1-10 R 1-10 R 1-10 R 2-10 R 3-10 R 3-10 R 3-10 R 1-10 R 3-10 R 3-10 R 3-10 R 3-10 R R

[0331] R R

[0332] R R

[0333] m n

[0334] n n

[0335] p p

[0336] provided that when and only when R2is hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, or Br, then at least one of R1and R3is present and is sulfurboryl, dialkylphosphinoyl, or cycloalkylphosphinoyl.

[0337] In one aspect of the application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (1-ID-1 or 1-ID-2),

[0338] wherein,

[0339] each R1is the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, sulfurboryl, -CN, -OH, -SH, and -NH2, -COOH, or a C

[0340] X1and X2are each independently selected from the group consisting of -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), -C(=S)-, -S(=O)-, -(R d4 )P(=X)-, -OS(=X)-, -S(=O)2, C(R d1 ), or N;

[0341] each R1may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, sulfurboryl, -CN, -OH, -SH, and -NH2, -COOH, or a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 alkyl substituted with C 3-10 cycloalkyl or C 1-10 heterocycloalkyl, C 3-10Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes, dialkyl phosphoryl groups, cycloalkyl phosphoryl groups, or -L1-Q; or any two adjacent R1 groups together with their attached atoms to form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C. 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 The cycloalkyl group is substituted; furthermore, the hydrogen on R1 is optionally preferably replaced by one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 Substituents of the substituents;

[0342] R2 is arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogen on R2 is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC1-6 alkyl, -N(C 1- 6alkyl), =0, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally further substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, -CN, -CF3, -OH, -OCH3, -OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0343] each R3may be the same or different and is independently of the other(s) selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH2, -COOH, or from C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, from C 3-10 cycloalkyl, or C 3- 10 C substituted with heterocycloalkyl 1-10 alkyl, and from C 3-10 cycloalkyl, C 3-10 C substituted with heterocycloalkyl 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl, and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atom(s) to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, -CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl), =0, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, -CN, -CF3, -OH, -OCH3, -OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0344] L1is independently selected from absent, a single bond, -C(R d1 )(R d2)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond;

[0345] Q is independently selected from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogens on Q are optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0346] each R7may be the same or different, and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein said C 3-10 alkyl, C 1-10 2- 10 ​alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0347] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different and are each independently of one another selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10saturated or partially substituted group saturated cycloalkyl or heterocycloalkyl is substituted by a substituent;

[0348] said hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0349] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0350] m is any integer selected from 0, 1, 2, 3 and 4;

[0351] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0352] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0353] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (1-IE),

[0354] wherein,

[0355] each R1may be the same or different, each being independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted or replaced by alkyl, dialkylphosphoryl, cycloalkylphosphoryl or -L1-Q; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a substituent selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to 3 groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR d8 R d9 ; and

[0356] R2is optionally independently selected from CN, SF5, dialkylphosphoryl, cycloalkylphosphoryl;

[0357] each R3may be the same or different and is optionally independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or selected from C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl, or C 3- 10 heterocycloalkyl, C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl, and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and a hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0358] L1is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), a double bond, a triple bond;

[0359] Q is optionally and independently selected from the group consisting of a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and a hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups of saturated cycloalkyl or heterocyclyl;

[0360] each R7may be the same or different, and is optionally and independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10C1-C6-alkyl substituted by a heterocycloalkyl group 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C1-C6-alkyl substituted by a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C1-C6-alkyl substituted by a heterocycloalkyl group 3-10 heterocyclyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0361] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different and are independently of each other selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C1-C6-alkyl substituted by a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C1-C6-alkyl substituted by a heterocycloalkyl group 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C1-C6-alkyl substituted by a cycloalkyl group 1-10 alkyl or C 3-10 cycloalkyl, C3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0362] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0363] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0364] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0365] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0366] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0367] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute or isomer has a structure of formula (1-IF).

[0368] in,

[0369] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, pentafluoride sulfide, -CN, -OH, -SH and -NH2, -COOH or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes, dialkyl phosphoryl groups, cycloalkyl phosphoryl groups, or -L1-Q; or any two adjacent R1 groups together with their attached atoms to form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C. 1-6 Alkyl, C 1-6alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally further substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to 3 groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR d8 R d9 of the substituents;

[0370] R2is optionally independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein a hydrogen on R2is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, and saturated or partially saturated C 1- cycloalkyl substituted, and C 3-6 alkyl and C 1-6 alkoxy is optionally further substituted with 1 to 3 groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 1-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to 3 groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR 3-6 of the substituents;

[0371] Each R3may be the same or different, and is independently of one another selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3, R4or R5together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0372] L1is independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(Rd3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0373] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0374] Each R7 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2- 10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C3-10 heterocyclyl is optionally substituted with 1 to 3 groups independently selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0375] R a and R b may be the same or different and are each independently of the other selected from hydrogen, deuterium, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl; or R a and R b are linked together with the atom to which they are attached to form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to 3 groups independently selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0376] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different and are each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group; 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group; 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C substituted with a cycloalkyl group; 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 C substituted with a heterocycloalkyl group; 3-10 heterocyclyl optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0377] the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0378] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0379] m is any integer selected from 0, 1, 2, 3, and 4;

[0380] n is any integer selected from 0, 1, 2, 3, 4, and 5;

[0381] p is any integer selected from 0, 1, 2, 3, 4, and 5.

[0382] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (2-I),

[0383] wherein,

[0384] X is any independently selected from C(R d1 ) or N;

[0385] A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0386] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0387] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH and -NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0388] R3and R4may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10alkyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0389] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(Rd1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds;

[0390] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0391] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C.3-10 saturated or partially substituted group saturated cycloalkyl or heterocyclyl substituted by;

[0392] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0393] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0394] m is any integer selected from 0, 1, 2, 3 and 4;

[0395] n is any integer selected from 0, 1, 2, 3 and 4;

[0396] t is any integer selected from 0, 1 or 2.

[0397] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted or isomer thereof, has the structure of Formula (2-IA),

[0398] wherein,

[0399] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted by C 1-10 alkyl, C 3-10 cycloalkyl substituted by C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted by C

[0400] R2is any independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10alkylsulfonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0401] R3and R4may be the same or different, each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, substituted by C 1-10 alkyl, and substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted by C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0402] L1, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(Rd1 )-, -C(R d2 )(R d1 )-, -C(R d2 )(R d3 )-, -C(R d4 )(R d5 )-, -C(R d6 )(R d7 )-, -C(R d3 )(R d4 )-, -C(R d1 )(R d2 )-, -C(R d1 )(R d2 )-, -C(R d1 )(R d2 )-, -C(R d1 )(R d2 )-, -C(R 3-10 )(R Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogens on Q are optionally substituted with 1 to 4 substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C d1 1-4 alkyl, C d2 1-4 alkenyl, C d3 1-4 alkynyl, C d4 1-4 alkoxy, C d5 1-4 alkylacyl, C d7 1-4 alkylsulfonyl, C d8 1-4 heteroalkyl, C d9 1-4 cycloalkyl, C

[0403] Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogens on Q are optionally substituted with 1 to 4 substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C

[0404] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 , or R d9 may be the same or different, and are each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 1-4 alkyl, C 2-10 1-4 alkenyl, C 1-10 1-4 alkynyl, C 1-10 1-4 alkoxy, C 1-10 1-4 alkylacyl, C 2-10 1-4 alkylsulfonyl, C 3-10 1-4 heteroalkyl, C 3-10 1-4 cycloalkyl, C 3-10 1-4 heterocycloalkyl, C 1-10alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted with C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0405] the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0406] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0407] m is any integer selected from 0, 1, 2, 3 and 4;

[0408] n is any integer selected from 0, 1, 2, 3 and 4;

[0409] t is any integer selected from 0, 1 or 2.

[0410] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (2-IB),

[0411] wherein,

[0412] any independently represents a single or double bond;

[0413] X1, X2, X3are any independently selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), -C(=S)-, -S(=O)-, -(R d4 )P(=X)-, -OS(=X)-, -S(=O)2, C(R d1 ) or N;

[0414] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate substituted with C

[0415] R2is optionally independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0416] R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, selected from the group consisting of C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0417] L1, L2, L3are each independently selected from the group consisting of absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5)-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)- d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), a double bond, a triple bond;

[0418] Q is independently selected from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups of saturated cycloalkyl or heterocyclyl;

[0419] Each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10alkyl acyl, C 1-10 alkyl sulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0420] the hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0421] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0422] m is any integer selected from 0, 1, 2, 3 and 4;

[0423] n is any integer selected from 0, 1, 2, 3 and 4;

[0424] t is any integer selected from 0, 1 or 2.

[0425] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (2-IC),

[0426] wherein,

[0427] X1and X2are any independently selected from C(R d1 ) or N;

[0428] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0429] R2is independently selected from hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0430] R4is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyloxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally replaced by a member selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0431] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), alkene, alkyne;

[0432] Q is optionally and independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0433] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , Rd8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0434] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0435] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0436] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0437] n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.

[0438] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt, isotopic substitute or isomer has a structure of formula (2-ID).

[0439] in,

[0440] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group;

[0441] R2is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0442] R3, R4may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10C1-C6alkyl substituted by 1 to 3 groups independently selected from halo, -CN, -OH, -OR 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted by 1 to 3 groups independently selected from halo, -CN, -OH, -OR 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halo, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 3 groups independently selected from hydrogen, deuterium, halo, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated 3-6 cycloalkyl;

[0443] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(Rd2 ), olefinic bonds, and alkyne bonds;

[0444] Q is arbitrarily and independently selected from 6-10 aryl, 5-8 heteroaryl, 3-18 saturated or partially saturated cycloalkyl, or 3-18 saturated or partially saturated heterocyclic groups, wherein the cycloalkyl or heterocyclic group can be a fused ring, spiro ring, or bridged ring structure; and the hydrogen on Q is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0445] Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0446] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0447] said halogen is independently selected from F, CI, Br, I, and isotopes thereof;

[0448] m is independently selected from an integer from 0, 1, 2, 3, and 4;

[0449] n is independently selected from an integer from 0, 1, 2, 3, and 4;

[0450] t is independently selected from an integer from 0, 1, or 2.

[0451] In an aspect of the application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (2-IE),

[0452] wherein,

[0453] R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH, and -NH2, -COOH, or is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3- 10 cycloalkyl, or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl substituted with alkyl, or carboxyl replacement, dialkylphosphoryl, cycloalkylphosphoryl, or Q group;

[0454] R2is independently selected from hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0455] R3and R4may be the same or different, each independently of the other selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, selected from C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0456] L1, L2, L3are each independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(Rd4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), a double bond, a triple bond;

[0457] Q is independently selected from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups of the saturated cycloalkyl or heterocyclyl;

[0458] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 , or R d9 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted with C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0459] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0460] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0461] m is any integer selected from 0, 1, 2, 3 and 4;

[0462] n is any integer selected from 0, 1, 2, 3 and 4;

[0463] t is any integer selected from 0, 1 or 2.

[0464] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has a structure of Formula (2-IF-1 or 2-IF-2),

[0465] wherein,

[0466] any independently represents a single or double bond;

[0467] X1, X3 are any independently selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(Rd1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=X)–, -OS(=X)-, -S(=O)2, C(R d1 ) or N;

[0468] R1 is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfide, -CN, -OH, -SH and -NH2, -COOH or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3- 10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes, dialkylphosphoryl groups, cycloalkylphosphoryl groups, or Q groups;

[0469] R2 is arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl;

[0470] R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0471] L1, L2, L3are each independently selected from the group consisting of absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3)C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond;

[0472] Q is independently selected from a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-18 membered saturated or partially saturated cycloalkyl, or a 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and the hydrogens on Q are optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0473] each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 , or R d9 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl; C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by;

[0474] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0475] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0476] m is any integer selected from 0, 1, 2, 3 and 4;

[0477] n is any integer selected from 0, 1, 2, 3 and 4;

[0478] t is any integer selected from 0, 1 or 2.

[0479] In some embodiments of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, wherein Z is preferably a carbonyl, oxetanyl structure; most preferably C=O;

[0480] In some embodiments of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, wherein R2 is preferably hydrogen, deuterium, halogen, CN, SF5, OH, or C 1-10 alkyl; most preferably Cl;

[0481] In one embodiment of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, wherein ring A is preferably a benzene ring, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole ring, furan ring, pyrrole ring, thiophene ring, pyridine ring, isothiazole or structure;

[0482] In one embodiment of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, wherein ring D is preferably a benzene ring, benzofuran, benzopyrrole, benzodihydrofuran, benzodihydropyrrole, thiazole ring, furan ring, pyrrole ring, thiophene ring, pyridine ring, isothiazole or structure;

[0483] In one aspect of the present application, the compound or its pharmaceutically acceptable salt, isotope substitute or isomer thereof, wherein ring B is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which is optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annelated ring, spiro ring or bridged ring structure; preferably benzene ring, pyridine ring, thiazole ring, isothiazole ring or thiophene ring, pyrimidine, pyridazine, piperidine, piperazine, pyrazole, imidazole, oxazole, morpholine, pyrrole, tetrahydropyrrole, furan, tetrahydrofuran, piperidone and the following structures: Most preferably,

[0484] In one aspect of the present application, the compound or its pharmaceutically acceptable salt, isotope substitute or isomer thereof, has the structure of formula (II),

[0485] wherein T is a single bond or -L1-L2-L3-, L1 is connected with ring A; ring A, B, R1, R2, R3, L1, L2, L3, p, t independently have the definitions described above;

[0486] According to an embodiment of the present application, ring A is selected from C6aryl, 9-10 membered heteroaryl, 3-6 membered heterocyclyl 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl;

[0487] B is selected from a single bond or C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl;

[0488] T is selected from a single bond or -L1-L2-L3-, L1 is connected with ring A; L1 is selected from CH2, O, NH; L2 is selected from C(=O), C(=S), S(=O)2; L3 is selected from CH2, O, NH;

[0489] each R1, R2, R3 is the same or different, independently H, CN, oxo (=O), halogen, C 1-10 alkyl, C 1-10 alkoxy, -P(=O)(C 1- 10 alkyl)(C 1-10 alkyl);

[0490] p is selected from 0, 1 or 2;

[0491] t is selected from 0, 1 or 2.

[0492] According to an embodiment of the present application, ring A is selected from C6aryl, 9-10 membered heteroaryl, 3-6 membered heterocyclyl

[0493] According to embodiments of the present application, ring A is selected from phenyl, benzofuranyl, thienyl, thiazolyl, indolyl, azetidinyl;

[0494] According to embodiments of the present application, ring A is selected from * is attached to the ring at the * end;

[0495] According to embodiments of the present application, is selected from * is attached to the ring at the * end;

[0496] According to embodiments of the present application, is selected from * is attached to the ring at the * end.

[0497] According to embodiments of the present application, B is selected from a single bond, phenyl;

[0498] According to embodiments of the present application, B is selected from a single bond,

[0499] According to embodiments of the present application, is selected from -P(=0)(C 1-6 alkyl)(C 1-6 alkyl), According to embodiments of the present application, is selected from

[0500] According to embodiments of the present application, each R1, R2, R3is the same or different, independently of one another, H, CN, oxo (=0), halogen, C 1-6 alkyl, C 1-6 alkoxy, -P(=0)(C 1-6 alkyl)(C 1-6 alkyl).

[0501] According to embodiments of the present application, each R1is the same or different, independently of one another, selected from H, oxo (=0), halogen; for example, selected from H, oxo (=0), F, Cl,

[0502] According to embodiments of the present application, R2is selected from H, CN, halogen; for example, selected from H, CN, Cl.

[0503] According to embodiments of the present application, each R3is the same or different, independently of one another, selected from H, halogen; for example, selected from H, F.

[0504] In one aspect of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a corresponding isomer, isotope substitute thereof, is a novel compound selected from the structures disclosed in the examples.

[0505] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds represented by Formula (I), a pharmaceutically acceptable salt, solvate, enantiomer, and isotope substitute thereof.

[0506] According to an embodiment of the present application, the pharmaceutical composition is formulated to be administered by a route selected from the group consisting of oral, injection, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural.

[0507] According to an embodiment of the present application, the pharmaceutical composition is preferably administered orally.

[0508] The oral dosage form is not particularly limited, and any oral dosage form well known in the art can be used, preferably including tablets, capsules, suspensions, or oral solutions, and the like oral dosage forms known in the art.

[0509] According to an embodiment of the present application, the pharmaceutical composition can further comprise a pharmaceutically acceptable excipient selected from at least one of the group consisting of, but not limited to, a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a humectant, a pH adjusting agent, a solubilizer or a co-solubilizer, an osmotic pressure adjusting agent. Those skilled in the art can easily determine how to select the corresponding excipient and its corresponding amount according to the needs of the specific dosage form.

[0510] According to an embodiment of the present application, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0511] Another object of the present application is to provide the use of the above-mentioned compound in the preparation of a medicament for preventing and / or treating a disease related to the VAV1 target or signal pathway. The disease related to the VAV1 target or signal pathway includes, but is not limited to, cancer, metabolic disease, autoimmune disease, inflammatory disease, and the like.

[0512] The present application also provides the use of the compound represented by Formula (I), a pharmaceutically acceptable salt, solvate, enantiomer, and isotope substitute thereof, and the pharmaceutical composition in preventing and / or treating a disease related to the VAV1 signal pathway. The disease related to the VAV1 signal pathway has the definition described above.

[0513] The present application also provides a method for preventing and / or treating a disease related to VAV1 signal pathway, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compounds represented by formula (I), pharmaceutically acceptable salts, solvates, enantiomers and isotopically substituted compounds thereof, or administering to a patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition. The disease related to VAV1 signal pathway has the definition described above.

[0514] In some embodiments, the patient is a mammal, preferably a human.

[0515] Technical effects

[0516] The present inventors have unexpectedly found that a part of the novel structure of heterocyclic compounds or fragments has high-efficiency CRBN binding ability, and based on the combination of this part of the compounds or fragments, a degradation agent for VAV1 target is obtained, and further, the novel heterocyclic compounds substituted with part of the structure of formula (I) of the present application not only have significant VAV1 degradation activity, but also have better anti-proliferation, anti-inflammatory, and good pharmacokinetic properties (including longer T1 / 2, higher exposure), bioavailability, safety, and other properties, and are more suitable as candidate drugs for preventing or treating diseases related to VAV1 target or signal pathway.

[0517] Definitions and explanations:

[0518] C 1-10 selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 ; C 2-10 selected from C2, C3, C4, C5, C6, C7, C8, C9, and C 10 ; C 3-10 selected from C3, C4, C5, C6, C7, C8, C9, and C 10 ;

[0519] The term "alkyl" as used herein is to be understood as meaning a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms, also denoted as "C 1-20 alkyl". For example, "C 1-10 alkyl" denotes a straight-chain and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-8 alkyl" denotes a straight-chain and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6"Alkyl" denotes straight-chained and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 -dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and the like or their isomers.

[0520] The term "3 to 18 carbon atoms monocyclic or polycyclic structure" encompasses all kinds of monocyclic or polycyclic structures having 3 to 18 carbon atoms (while other heteroatoms can be contained) the number of carbon atoms in the monocyclic or polycyclic structure can be selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or ranges formed by any combination of these point values. The monocyclic or polycyclic structure can be arbitrarily selected from the group consisting of aromatic, heteroaromatic, aliphatic, heterocyclic, annelated, spiro or bridged ring structures; wherein aromatic, heteroaromatic, aliphatic, heterocyclic, annelated, spiro or bridged ring are defined below.

[0521] The term "alkenyl" is to be understood as meaning straight-chain or branched- chain hydrocarbon radicals which contain one or more double bonds and have 2 to 20 carbon atoms, preferably "C 2-10 alkenyl". C 2-10 The term "alkenyl" is to be understood as meaning straight-chain or branched- chain hydrocarbon radicals which contain one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 alkenyl". C 2-10 The term "alkenyl" is to be understood as meaning straight-chain or branched- chain hydrocarbon radicals which contain one or more double bonds and have 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. C 2-6 alkenyl), 2 or 3 carbon atoms (i.e. C 2-3alkenyl). It is to be understood that in case the alkenyl group comprises more than one double bond, the double bonds can be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0522] The term "alkynyl" is to be understood as meaning a straight-chain or branched hydrocarbon group which contains one or more triple bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkynyl". The term "C 2-10 alkynyl" is to be understood as preferably meaning a straight-chain or branched hydrocarbon group which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C 2-8 alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C 2-6 alkynyl"), 2 or 3 carbon atoms ("C 2-3The term "alkynyl" denotes a saturated or partially unsaturated group consisting of 1 to 20 carbon atoms and at least one triple bond. In some embodiments, the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0523] The term "heteroalkyl" denotes a saturated or partially unsaturated group consisting of 1 to 20 carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from O, N, S or P and isotopes thereof, wherein the N, S or P atom is optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-10 heteroalkyl, C 1-6Heteroalkyl. The heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, e.g., as an alkoxy, alkylthio, alkylamino, ether group. Examples of heteroalkyl include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and up to two heteroatoms can be consecutive, e.g., -CH2-NH-OCH3. The term "1 to multiple" as used herein means 1 or more, e.g., 1, 2, 3, 4, 5 or more.

[0524] The term "aliphatic ring", "carbocyclic" or "cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the carbocyclic ring can comprise 3 to 20 carbon atoms, preferably C 3-12 Cycloalkyl, comprising 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably C 3-10 Cycloalkyl, C 3-6 Cycloalkyl, comprising 3 to 6 carbon atoms. The carbocyclic ring can be monocyclic or polycyclic, which can be a saturated cycloalkyl or can optionally comprise one, two or more double and / or triple bonds in its ring, thereby forming so-called cycloalkenyl or cycloalkynyl groups. In case of carbocyclic rings with multiple rings, these rings can form spiro, fused and bridged ring structures. Non-limiting examples of monocyclic carbocyclic rings include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl and the like; non-limiting examples of polycyclic carbocyclic rings include, e.g., decalinyl or isobornyl.

[0525] The term "aryl" or "aromatic ring" means: it is to be understood as preferably denoting an aromatic or partially aromatic monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which can be a single aromatic ring or multiple aromatic rings fused together, preferably "C 6-14 Aryl". The term "C 6- 14 Aryl" is to be understood as preferably denoting an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0526] The term "spirocyclic" refers to a ring system in which two rings share a single cyclic atom, and it may contain aliphatic rings, heterocyclic rings, aromatic rings, or heteroaromatic rings as described above.

[0527] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms, and it may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as described above.

[0528] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms, and it may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as described above.

[0529] The term "heterocyclo" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are heteroatoms or groups selected from N, O, NH, S, S(O) or S(O)2, but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remainder of which are carbon. Preferred are 3- to 12-membered heterocyclo groups comprising 3 to 12 ring atoms, one to four of which are heteroatoms (e.g., one, two, three, and four); more preferred are 3- to 6-membered heterocyclo groups comprising 3 to 6 ring atoms (e.g., three, four, five, six). The heterocyclo group can be attached to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom (if present) or the oxygen or sulfur atom (particularly in the case of onium salts). The heterocyclo group can include fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclo groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl, and the like, preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclo groups include spirocyclic, fused ring, and bridged ring heterocyclo groups, and can also be benzo-fused heterocyclo groups such as dihydroisoquinolinyl. The heterocyclo group can be bicyclic, non-limiting examples of which include hexahydrocyclopenta[c]pyrrol-2(lH)-yl, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl. The heterocyclo group can also be partially unsaturated, i.e., it can contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[l,4]thiazinyl.

[0530] The heterocyclo group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, haloalkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0531] As used herein, the term "heteroaryl / heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. The heteroaryl group is preferably 5- to 10-membered (e.g., 5-, 6-, 7-, 8-, 9- or 10-membered), more preferably 5- or 6-membered. Non-limiting examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like, as well as benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, as well as benzo derivatives thereof, such as quinolinyl, quinazolinyl, isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like, as well as benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl and / or phenoxazinyl and the like.

[0532] The heteroaryl / heteroaromatic ring can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0533] Unless otherwise indicated, the heterocyclyl, heteroaryl or heteroaromatic ring includes all possible isomeric forms thereof, such as positional isomers. Thus, for some illustrative, non-limiting examples, forms substituted or bonded at one, two or more of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) can be included, including pyrid-2-yl, pyrid-2-ylidene, pyrid-3-yl, pyrid-3-ylidene, pyrid-4-yl and pyrid-4-ylidene; thienyl or thienylidene including thien-2-yl, thien-2-ylidene, thien-3-yl and thien-3-ylidene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl and the like.

[0534] The term "pharmaceutically acceptable", as used herein, pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0535] The term "pharmaceutically acceptable salt" means a salt of a compound of this application which is found to be pharmaceutically acceptable, i.e., water or oil-soluble or dispersible, non-toxic, and efficacious for the treatment of conditions for which compounds of this application are indicated. Salts of the compounds of this application can be obtained by contacting the compounds having the specific substituents discovered in this application with a sufficient amount of a relatively nontoxic acid or base, in either pure solution or in a suitable inert solvent. Base addition salts can be obtained by contacting a neutral form of such compounds in either pure solution or in a suitable inert solvent with a sufficient amount of a base to produce the salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. Acid addition salts can be obtained by contacting a neutral form of such compounds in either pure solution or in a suitable inert solvent with a sufficient amount of an acid to produce the salt. Examples of pharmaceutically acceptable acid addition salts include mineral acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, boric acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; also salts of amino acids such as arginine and the like, and salts of organic acids like gluconic acid, and the like (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of this application contain both basic and acidic functionalities as a result of which, two salt forms can exist, i.e., either a base or an acid addition salt.

[0536] Preferably, the salt is contacted with a base or acid in conventional manner to reisolate the parent compound, thus regenerating the neutral form of the compound. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt forms are equivalent to the parent form of the compound for purposes of the present application.

[0537] As used herein, "pharmaceutically acceptable salts" are meant to include derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acid or organic acid salts of base groups such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts of a wide variety of organic and inorganic acids, such as Na salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, and the like. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids and bases, such as 2-acetoxybenzoic acid, 2-hydroxyethansulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonates, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyl, hydantoin, isethionic acid, lactic acid, lactose, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and p-toluenesulfonic acid, and the like, and salts of the above-mentioned acids with bases such as Na, potassium, magnesium, calcium, and the like, or amines, diethylamine, triethylamine, ethanolamine, and the like.

[0538] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acid or base moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, are preferred.

[0539] In addition to salt forms, the compounds provided herein can also take the form of a prodrug. Prodrugs of the compounds described herein are readily converted by chemical or physiological action into the compounds of the present application. Additionally, prodrugs can be converted to the compounds of the present application by chemical or physiological processes in vivo.

[0540] Certain compounds of the present application can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present application. Certain compounds of the present application can exist in multiple crystalline or amorphous forms.

[0541] The term "solvate" as used herein refers to an association or complex of one or more solvent molecules and a compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Thus, the term "hydrate" refers to the complex where the solvent molecule is water.

[0542] Certain compounds of the present application can possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all intended to be within the scope of the present application.

[0543] The graphical representation of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. Unless otherwise stated, the absolute configuration of a stereo center is represented by a wedge and hash bond. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include the E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0544] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures of those

[0545] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or by chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, diastereomeric salts with an appropriate optically active acid or base are formed, and the pure enantiomer is recovered by fractional crystallization or chromatography of the diastereomeric mixture, followed by recovery of the pure enantiomer. In addition, separation of the enantiomers and diastereomers is often accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0546] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14C). All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0547] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetable and mineral, ointment bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, and the like. Their formulation is well known to those skilled in the art of cosmetics or topical pharmaceuticals. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0548] When any variable (e.g., R) occurs more than one time in a compound, its definition in each occurrence is independent of the other. Thus, for example, if a group is substituted with 0-2 R, then said group can optionally be substituted with up to two R, and at each occurrence R is selected independently. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0549] When a bond to a substituent can cross to an adjacent atom in a ring, the substituent can be bonded to either atom in the ring. When a recited substituent is not specified to be connected to a chemical structure general formula by a particular atom, the substituent can be bonded through any atom thereof. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0550] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0551] The present application is now further described by the examples. The examples given below are for illustrative purposes only and are not meant to limit the scope of the present application. The compounds of the present application can be prepared using many known methods in the art of organic synthesis. The examples of the present application can be synthesized using the methods described below, as well as known synthetic methods in the art of organic synthesis chemistry, or by improved methods based thereon. Preferred methods include, but are not limited to, the methods described below.

[0552] Unless otherwise specified, all solvents used in the present application are commercially available and used without further purification. The reactions are generally carried out under an inert atmosphere of nitrogen using anhydrous solvents. Nuclear magnetic resonance spectra are measured on a Bruker-Avance-400 (400 mhz) spectrometer and chemical shifts are reported in δ (ppm). Mass spectra are measured with Agilent 1200 series (plus 6110 / and 1956A) LC / MS or Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) operating in positive and negative modes.

[0553] The abbreviations used are as follows: aq is aqueous solution; TLC is thin layer chromatography; RT is room temperature; MeOH is methanol; EtOH is ethanol; EtOAc is ethyl acetate; THF is tetrahydrofuran; eq is equivalent; CDI is carbonyldiimidazole; DCM is dichloromethane; PE is petroleum ether; DIAD is diisopropyl azodicarboxylate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; CBz is carbobenzyloxy; BOC is tert-butyloxycarbonyl; HOAc is acetic acid; Ms is methanesulfonyl; NMP is N-methylpyrrolidinone; DMAP is 4-(dimethylamino)pyridine; Boc2O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; DIPEA is diisopropylethylamine; SOCl2 is thionyl chloride; CS2 is carbon disulfide; TsOH is 4-toluenesulfonic acid; MTBE is tert-butyl methyl ether; FA is formic acid; ACN is acetonitrile; i-PrOH is 2-propanol.

[0554] The compounds can be named manually or using ChemDraw® The catalog name of the supplier can be used if commercially purchased. TLC or LC-MS is generally used to determine whether the reaction is completed. DETAILED DESCRIPTION

[0555] In order to explain the present application in more detail, the following examples are given, but the scope of the present application is not limited thereto.

[0556] Example 1, Synthesis of 3-(2,6-dioxopiperidin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile (Compound 1):

[0557] 1) Synthesis of 1-(4-bromophenyl)pyridin-2(1H)-one

[0558] A solution of (4-bromophenyl)boronic acid (3.0 g, 14.9 mmol), pyridin-2(lH)-one (1.70 g, 17.9 mmol), copper acetate (2.71 g, 14.9 mmol) and triethylamine (4.53 g, 44.8 mmol, 6.24 mL) in 1,2-dichloroethane (5 mL) was purged with oxygen three times, then stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0~80% elution) to give l-(4-bromophenyl)pyridin-2(lH)-one (1.6 g, 6.33 mmol, yield: 42%), LCMS m / z: 250 [M+H] + ;

[0559] 1 HNMR (400 MHz, DMSO-d6) δ = 7.75-7.67 (m, 2H), 7.67-7.60 (m, 1H) 7.51 (ddd, J = 9.2, 6.8, 2.0 Hz, 1H), 7.44-7.34 (m, 2H), 6.48 (d, J = 9.2 Hz, 1H), 6.32 (dt, J = 6.8, 1.2 Hz, 1H).

[0560] 2) Synthesis of l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one

[0561] A solution of l-(4-bromophenyl)pyridin-2(lH)-one (500 mg, 2.00 mmol), 4,4,4',4',5,5',5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (588 mg, 2.2 mmol), Pd(dppf)Cl2(146 mg, 199 umol), potassium acetate (588 mg, 6 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen three times, then stirred at 80 °C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0~100% elution) to give l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one (500 mg, 1.53 mmol, yield: 76%), LCMS m / z: 298 [M+H] + ;

[0562] 1H NMR (400 MHz, DMSO-d6) δ = 7.79 (d, J = 7.6 Hz, 2H), 7.64-7.60 (m, 1H), 7.54-7.47 (m, 1H), 7.42 (d, J = 7.6 Hz, 2H), 6.48 (d, J = 9.2 Hz, 1H), 6.32 (t, J = 6.8 Hz, 1H), 1.31 (S, 12H).

[0563] 3) Synthesis of 3-bromo-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile

[0564] A solution of 2,6-dibromobenzonitrile (2.4 g, 9.20 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H) (3.00 g, 10.1 mmol), Pd(dppf)Cl2 (672 mg, 918 umol) and potassium phosphate (5.84 g, 27.5 mmol) in N,N-dimethylformamide (60 mL) was heated to 100 °C under nitrogen protection and stirred for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to give 3-bromo-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile (820 mg, 2.33 mmol, yield: 25%), LC-MS m / z: 351 [M+H] + .

[0565] 4) Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile

[0566] A solution of 3-bromo-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile (320 mg, 0.920 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (417 g, 1.0 mmol), Pd(dppf)Cl2(67 mg, 91 umol) and potassium phosphate (584 mg, 2.75 mmol) in N,N-dimethylformamide (6 mL) was heated at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0~100%) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile (206 mg, 0.36 mmol, yield: 40%) LC-MS m / z: 562 [M+H] + .

[0567] 5) Synthesis of 3-(2,6-dioxopiperidin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile

[0568] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile (206 mg, 0.36 mmol) in EA (50 mL) was added Pd / C (206 mg) and Pd(OH)2(206 mg) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature under H2atmosphere for 16 h. The reaction mixture was filtered through a pad of celite and the filter cake was washed with EA (50 mL). The filtrate was concentrated under reduced pressure to give 3-(2,6-dioxopiperidin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-2-carbonitrile (44 mg, 0.11 mmol, yield: 32%) LCMS m / z: 384 [M+H] + .

[0569] Example 2, Synthesis of 3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione and its isomers (compounds 2-1 and 2-2):

[0570] 1) Synthesis of (4-bromophenyl)dimethyl phosphine oxide:

[0571] To a solution of 1-bromo-4-iodobenzene (1.00 g, 3.53 mmol, 1.0 eq) in dioxane (10 mL) was added TEA (1.07 g, 10.59 mmol, 3.0 eq), dimethyl phosphine oxide (275 mg, 3.53 mmol, 1.0 eq), Pd2(dba)3(323 mg, 0.35 mmol, 0.1 eq) and XantPhos (204 mg, 0.35 mmol, 0.1 eq) at room temperature. The mixture was stirred at 100 °C under N2atmosphere for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with H2O (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EA from 100:1 to 10:1, Rf= 0.4, PE:EA = 1:1, 254 nm) to give (4-bromophenyl)dimethyl phosphine oxide (600 mg, 2.58 mmol, yield: 72.8%) as a yellow solid. RT: 1.650 min, M / Z = 235.0 [M+H] + .

[0572] 2), 3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione:

[0573] To a solution of (4-bromophenyl)dimethyl phosphine oxide (200 mg, 0.86 mmol, 1.0 eq), 3-(2-chloro-3-(4.4.4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (452 mg, 1.29 mmol, 1.5 eq) and K3PO4(547 mg, 2.58 mmol, 3.0 eq) in dioxane / H2O (10 mL / 2 mL) was added Pd(dppf)Cl2(66 mg, 0.09 mmol, 0.1 eq). The reaction was stirred at 100 °C under nitrogen atmosphere for 16 hours. LCMS showed the reaction was completed. The reaction was poured into water (100 mL) and extracted with EA (100 mL x 2), the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE from 0% to 50%, Rf= 0.4, PE:EA = 1:1, 254 nm) to give 3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (100 mg, 0.26 mmol, yield: 30.9%) as a white solid. RT = 1.270 min, LCMS: m / z = 376.0 [M+H] +

[0574] 3) Synthesis of (S)-3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidine- 2,6-dione or the enantiomer and (R)-3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'- biphenyl]-3-yl)piperidine-2,6-dione or the enantiomer

[0575] Compound 3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidine-2,6- dione (100 mg, 0.26 mmol) was purified by SFC (System: Waters SFC 150; Column name: Chiralpak IC, 250*30mm 10pm; Mobile phase A: Supercritical CO2; Mobile phase B: IPA (+0.1% 7.0 mol / 1 ammonia in MEOH), A:B = 60:40; Wavelength: 214 nm; Flow rate: 120 mL / min; Column temperature: RT; Back pressure: 100 bar, Injection: 6.0 mL; Cycle time: 8.21 min) to obtain two isomers: Compound 2-1 and Compound 2-2. Compound 2-1 : Peak 1 Chiral HPLC: 3.545 min; (33.50 mg, 0.089 mmol, yield: 33.50%), RT: 6.652 min, M / Z = 376.1 [M+H]

[0576] Compound 2-1 : Peak 1 Chiral HPLC: 3.545 min; (33.50 mg, 0.089 mmol, yield: 33.50%), RT: 6.652 min, M / Z = 376.1 [M+H] + .

[0577] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.86 (dd, J = 11.2, 8.0 Hz, 2H), 7.56 (dd, J = 8.4, 2.0 Hz, 2H), 7.47 - 7.38 (m, 2H), 7.35 (dd, J = 6.8, 2.4 Hz, 1H), 4.36 (dd, J = 12.4, 5.2 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.64 - 2.53 (m, 1H), 2.35 - 2.31 (m, 1H), 2.12 - 2.00 (m, 1H), 1.70 (d, J = 13.2 Hz, 6H).

[0578] 31 P NMR (162 MHz, DMSO-d6) δ 32.299

[0579] Compound 2-2: Peak 2 Chiral HPLC: 4.637 min; (34.61 mg, 0.092 mmol, yield: 34.61 %), RT: 6.647 min, M / Z = 376.1 [M+H] + .

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.86 (dd, J = 11.2, 8.0 Hz, 2H), 7.56 (dd, J = 8.4, 2.0 Hz, 2H), 7.47 - 7.38 (m, 2H), 7.35 (dd, J = 6.8, 2.4 Hz, 1H), 4.36 (dd, J = 12.4, 5.2 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.64 - 2.53 (m, 1H), 2.35 - 2.31 (m, 1H), 2.12 - 2.00 (m, 1H), 1.70 (d, J = 13.2 Hz, 6H).

[0581] 31 P NMR (162 MHz, DMSO-d6) δ 32.299.

[0582] Example 3, synthesis of 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzofuran-4- yl)phenyl)piperidine-2,6-dione and its isomers (Compound 3-1 and Compound 3-2):

[0583] 1) Synthesis of 1-bromo-3-(bromomethyl)-2-chlorobenzene:

[0584] To a solution of 1-bromo-2-chloro-3-methylbenzene (30.00 g, 147.93 mmol, 1.0 eq) in CCl4(300 mL) was added NBS (26.33 g, 147.99 mmol, 1.0 eq), BPO (3.60 g, 14.79 mmol, 1.0 eq) at room temperature. The reaction solution was stirred at 110 °C for 16 hours. TLC (PE / EA = 20 / 1) showed new product. The reaction solution was quenched with H2O (500 mL), extracted with EA (200 mL x 2). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 1-bromo-3-(bromomethyl)-2-chlorobenzene (50.00 g, 176.06 mmol, crude) as a white solid.

[0585] 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.12 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 4.61 (s, 2H).

[0586] 2) Synthesis of 2-(3-bromo-2-chlorophenyl)acetonitrile

[0587] To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (49.00 g, 172.54 mmol, 1.0 eq) in DCM (800 mL) was added TMSCN (34.16 g, 345.08 mmol, 2.0 eq), TBAF (90.07 g, 345.08 mmol, 2.0 eq) at room temperature. The reaction was stirred at room temperature for 16 h. TLC (PE:EA = 10:1, Rf = 0.6, 254 nm) showed the reaction was completed. The reaction was quenched with H2O (1000 mL), extracted with EA (500 mL x 3). The combined organic layers were washed with saturated brine (500 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (19.00 g, 82.61 mmol, yield: 47.8%) as a white solid.

[0588] 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.12 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 4.61 (s, 2H).

[0589] 3) Synthesis of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate

[0590] To a solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (19.00 g, 82.61 mmol, 1.0 eq) in THF (200 mL) was added tert-butyl acrylate (21.15 g, 165.22 mmol, 2.0 eq) and MeONa (6.69 g, 123.92 mmol, 1.5 eq) at 0 °C. The reaction was stirred at room temperature for 2 h. TLC (PE:EA = 10:1, Rf = 0.6, 254 nm) showed the reaction was completed. The reaction was quenched with H2O (500 mL), extracted with EA (300 mL x 3). The combined organic layers were washed with saturated brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (13.00 g, 36.31 mmol, yield: 43.8%) as a white solid.

[0591] 1 H NMR (400 MHz, DMSO-d6) d 7.83 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 4.63 (t, J = 6.8 Hz, 1H), 2.43-2.33 (m, 2H), 2.18-2.12 (m, 2H), 1.39 (s, 9H).

[0592] 4) Synthesis of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione

[0593] To a solution of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (12.5 g, 34.82 mmol, 1.0 eq) in AcOH (200 mL) was added H2SO4 (16.38 g, 167.14 mmol, 4.8 eq) at room temperature. The reaction was stirred at 90 °C for 16 h. TLC (PE:EA = 10:1, Rf = 0.6, 254 nm) showed the reaction was completed. The reaction was quenched with H2O (500 mL), extracted with EA (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (9.00 g, 29.70 mmol, yield: 85.3%) as a white solid.

[0594] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.72 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.38 (dd, J = 7.6, 1.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 4.32 (dd, J = 12.4 Hz, 5.2 Hz, 3H), 2.83-2.74 (m, 1H), 2.57-2.51 (m, 1H), 2.38-2.27 (m, 1H), 2.04-1.98 (m, 1H).

[0595] 5) Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboran-2-yl)phenyl)piperidine- 2,6-dione

[0596] A solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (1.50 g, 4.95 mmol, 1.0 eq), B2(pin)2(2.51 g, 9.90 mmol, 2.0 eq) and K(OAc)2(1.46 g, 14.85 mmol, 3.0 eq) in dioxane (20 mL) was added Pd(dppf)Cl2(723 mg, 0.99 mmol, 0.2 eq). The reaction was stirred at 100 °C under nitrogen atmosphere for 16 h. LCMS showed the reaction was completed. The reaction mixture was poured into water (200 mL), extracted with EA (200 mL x 2), the combined organic layers were washed with saturated brine (150 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE from 0% to 50%, Rf = 0.4, PE:EA = 1:1, 254 nm) to give the product 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboran-2-yl)phenyl)piperidine-2,6-dione (1.00 g, 2.86 mmol, yield: 57.4%) as a yellow solid. RT = 1.669 min. LCMS: m / z = 367.1 [M+H] + .

[0597] 6) Synthesis of 1,4-dibromo-2-(2,2-dimethoxyethoxy)benzene

[0598] To a solution of 2,5-dibromophenol (10.0 g, 39.68 mmol, 1.0 eq) in DMF (200 mL) was added 2-bromo-1,1-dimethoxyethane (13.41 g, 79.36 mmol, 2.0 eq), K2CO3(10.95 mg, 79.36 mol, 2.0 eq), Nal (596 mg, 3.97 mmol, 0.1 eq) at room temperature. The reaction was stirred at 100 °C for 16 h. TLC (PE:EA = 10:1, Rf = 0.6, 254 nm) showed the reaction was completed. The reaction was quenched with H2O (700 mL), extracted with EA (400 mL x 3). The combined organic layers were washed with saturated brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 1,4-dibromo-2-(2,2-dimethoxyethoxy)benzene (14.0 g, 41.18 mmol, crude) as a white solid.

[0599] 1 H NMR (400 MHz, DMSO-d6) d 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 4.70 (t, J = 5.2 Hz, 1H), 4.10 (d, J = 5.2 Hz, 2H), 3.38 (s, 6H).

[0600] 7) Synthesis of 4,7-dibromobenzofuran

[0601] To a solution of 1,4-dibromo-2-(2,2-dimethoxyethoxy)benzene (14.00 g, 41.18 mmol, 1.0 eq) in chlorobenzene (200 mL) was added PPA (14.00 g) at room temperature. The reaction was stirred at 130 °C for 3 h. TLC (PE:EA = 10:1, Rf = 0.7, 254 nm) showed the reaction was completed. The reaction was quenched with H2O (500 mL), extracted with EA (500 mL x 3). The combined organic layers were washed with saturated brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE = 100%, PE:EA = 10 / 1, Rf = 0.7, 254 nm) to give the product 4,7-dibromobenzofuran (9.00 g, 32.60 mmol, yield: 79.2%) as a white solid.

[0602] 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H).

[0603] 8) Synthesis of 1-(4-bromobenzofuran-7-yl)pyridin-2(lH)-one

[0604] To a solution of 4,7-dibromobenzofuran (4.00 g, 15.87 mmol, 1.0 eq) in DMF (100 mL) was added pyridin-2(lH)-one (5.36 g, 31.74 mmol, 2.0 eq), K2CO3 (4.38 mg, 31.74 mol, 2.0 eq), Cul (302 mg, 1.59 mmol, 0.1 eq) at room temperature. The reaction was stirred at 150 °C for 4 h. TLC (PE:EA = 10:1, Rf = 0.6, 254 nm) showed the reaction was completed. The reaction was quenched with H2O (500 mL), extracted with EA (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 1-(4-bromobenzofuran-7-yl)pyridin-2(lH)-one (400 mg, 1.38 mmol, yield: 8.7%) as a white solid.

[0605] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H).

[0606] 9) Synthesis of 3-(2-chloro-3-(7-(2-oxopyridin-l(2H)-yl)benzofuran-4-yl)phenyl)piperidine- 2,6-dione and its isomers (Compound 3-1 and Compound 3-2)

[0607] A solution of 1-(4-bromobenzofuran-7-yl)pyridin-2(1H)-one (300 mg, 1.04 mmol, 1.0 eq), 3-(2-chloro-3-(4.4.5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (546 mg, 1.56 mmol, 1.5 eq) and K3PO4 (661 mg, 3.12 mmol, 3.12 mmol / L, 3.0 eq) in dioxane / H2O (10 mL / 2 mL) was added Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.1 eq). The reaction was stirred at 100 °C under nitrogen atmosphere for 16 h. LCMS showed the reaction was completed. The reaction was poured into water (100 mL), extracted with EA (100 mL x 2), the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE as 0% to 50%, Rf = 0.4, PE:EA = 1:1, 254 nm) to give 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzofuran-4-yl)phenyl)piperidine-2,6-dione (100 mg, 0.23 mmol, yield: 22.2%) as a white solid. RT = 8.768 min, LCMS: m / z = 433.1 [M+H] + .

[0608] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzofuran-4-yl)phenyl)piperidine-2,6-dione (100 mg, 0.23 mmol) was purified by SFC (System: Waters SFC 150; Column name: Chiralpak IC; Column size: 250*30mm 10pm; Mobile phase A: Supercritical CO2; Mobile phase B: EtOH (+0.1% 7.0 mol / l ammonia in MEOH), A:B = 55:45; Wavelength: 214 nm; Flow rate: 120 mL / min; Column temperature: RT; Back pressure: 100 bar, Injection: 3.5 mL; Cycle time: 5.76 min) to give two isomers: Compound 3-1 and Compound 3-2.

[0609] Compound 3-1: Peak 1 Chiral HPLC: 4.291 min; (14.75 mg, 0.034 mmol, yield: 14.75%), RT: 8.164 min, M / Z = 433.1 [M+H] + .

[0610] 1 ​H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 6.8, 1.6 Hz, 1H), 7.60 (ddd, J = 8.8, 6.8, 2.0 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.44 - 7.33 (m, 2H), 6.71 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 9.2 Hz, 1H), 6.39 (td, J = 6.8, 1.2 Hz, 1H), 4.39 (dd, J = 12.4, 5.2 Hz, 1H), 2.87 - 2.74 (m, 1H), 2.62 - 2.53 (m, 1H), 2.44 - 2.32 (m, 1H), 2.18 - 2.05 (m, 1H).

[0611] Compound 3-2: Peak 2 Chiral HPLC: 5.203 min; (13.26 mg, 0.030 mmol, yield: 13.26 %), RT: 8.155 min, M / Z = 433.1 [M+H] + .

[0612] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 6.8, 1.6 Hz, 1H), 7.60 (ddd, J = 8.8, 6.8, 2.0 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.44 - 7.33 (m, 2H), 6.71 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 9.2 Hz, 1H), 6.39 (td, J = 6.8, 1.2 Hz, 1H), 4.39 (dd, J = 12.4, 5.2 Hz, 1H), 2.87 - 2.74 (m, 1H), 2.62 - 2.53 (m, 1H), 2.44 - 2.32 (m, 1H), 2.18 - 2.05 (m, 1H).

[0613] Example 4, Synthesis of 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)benzofuran-4- yl)phenyl)piperidine-2,6-dione and its enantiomers (Compound 4-1 and Compound 4-2):

[0614] 1) Synthesis of 1-(4-bromo-5-fluorobenzofuran-7-yl)pyridin-2(1H)-one

[0615] To a solution of 4-bromo-5-fluoro-7-iodobenzofuran (5.0 g, 14.7 mmol, 1.0 eq) in DMF (100 mL) was added Cul (506 mg, 2.94 mmol, 0.2 eq), pyridin-2(lH)-one (1.4 g, 14.7 mmol, 1.0 eq) and K2CO3(6.08 g, 44.1 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 150 °C under N2atmosphere for 4 h. LCMS showed the reaction was completed. The mixture was quenched with H2O (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA from 100:1 to 1:1, Rf= 0.4, PE:EA = 1:1, 254 nm) to give 1-(4-bromo-5-fluorobenzofuran-7-yl)pyridin-2(lH)-one (420 mg, 1.36 mmol, 9.20% yield) as a yellow solid. Rt= 1.953 min, LCMS: m / z = 308.0 [M+H] + .

[0616] 2), 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-l(2H)-yl)benzofuran-4-yl)phenyl)piperidine- 2,6-dione

[0617] To a solution of 1-(4-bromo-5-fluoro-benzofuran-7-yl)-pyridin-2(1H)-one (400 mg, 1.30 mmol, 1.0 eq) in dioxane (10 mL) was added 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (1.36 g, 3.90 mmol, 5.0 eq), K2CO3 (538 mg, 3.90 mmol, 3.0 eq), Pd(dppf)Cl2 (95 mg, 0.13 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed the reaction was completed. The mixture was quenched with H2O (100 ml), extracted with EA (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA from 100:1 to 1:1, Rf = 0.4, PE:EA = 1:1, 254 nm) to give 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)benzofuran-4-yl)phenyl)piperidine-2,6-dione (100 mg, 0.22 mmol, yield: 17.08%) as a white solid. Rt = 8.275 min, LCMS: m / z = 451.0 [M+H] + .

[0618] 3), (3S)-3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)benzofuran-4-yl)phenyl)piperidine-2,6-dione or its enantiomers (Compound 4-1 and Compound 4-2) synthesis

[0619] Compound 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)benzofuran-4-yl)phenyl)piperidine-2,6-dione (100 mg, 0.22 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Chiralpak IC 250*30mm10μm; mobile phase A: Supercritical CO2; mobile phase B: EtOH, A:B = 55:45; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar, injection: 1.0 mL; cycle time: 7 minutes) to give two isomers: Compound 4-1 and Compound 4-2.

[0620] ​Compound 4-1 : Peak 1 Chiral HPLC: 3.324 min; (8.69 mg, 0.019 mmol, 8.69% yield), RT: 8.280 min, M / Z = 451.1 [M+H] + .

[0621] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.13 (dd, J = 4.4, 2.4 Hz, 1H), 7.83 (dd, J = 6.8, 1.6 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.50 (t, J = 6.4 Hz, 2H), 7.44 (dd, J = 12.4, 8.0 Hz, 1H), 6.74 - 6.68 (m, 1H), 6.58 (d, J = 9.2 Hz, 1H), 6.40 (td, J = 6.8, 1.2 Hz, 1H), 4.40 (dd, J = 12.4, 5.2 Hz, 1H), 2.81 (ddd, J = 18.0, 12.0, 6.0 Hz, 1H), 2.57 (d, J = 16.8 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.16 - 2.05 (m, 1H).

[0622] 19 F NMR (377 MHz, DMSO-d6) δ -120.619.

[0623] Compound 4-2: Peak 2 Chiral HPLC: 4.084 min; (4.53 mg, 0.010 mmol, 4.53% yield), RT: 8.282 min, M / Z = 451.1 [M+H] + .

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.13 (dd, J = 4.4, 2.4 Hz, 1H), 7.83 (dd, J = 6.8, 1.6 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.50 (t, J = 6.4 Hz, 2H), 7.44 (dd, J = 12.4, 8.0 Hz, 1H), 6.74 - 6.68 (m, 1H), 6.58 (d, J = 9.2 Hz, 1H), 6.40 (td, J = 6.8, 1.2 Hz, 1H), 4.40 (dd, J = 12.4, 5.2 Hz, 1H), 2.81 (ddd, J = 18.0, 12.0, 6.0 Hz, 1H), 2.57 (d, J = 16.8 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.16 - 2.05 (m, 1H).

[0625] 19 F NMR (377 MHz, DMSO-d6) δ -120.619.

[0626] Example 5, Synthesis of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7- yl)phenyl)piperidine-2,6-dione and its enantiomers (Compound 5-1 and Compound 5-2):

[0627] 1) Synthesis of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidine- 2,6-dione

[0628] A solution of 1-(7-bromobenzofuran-4-yl)pyridin-2(1H)-one (300 mg, 1.04 mmol, 1.0 eq), 3-(2-chloro-3-(4.4.5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (546 mg, 1.56 mmol, 1.5 eq) and K3PO4 (661 mg, 3.12 mmol, 3.0 eq) in dioxane / H2O (10 mL / 2 mL) was added Pd(dppf)Cl2(73 mg, 0.10 mmol, 0.1 eq). The reaction was stirred at 100 °C under nitrogen atmosphere for 16 h. LCMS showed the reaction was completed. The reaction mixture was poured into water (100 mL), extracted with EA (100 mL x 2), the combined organic layer was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE from 0% to 50%, Rf= 0.4, PE:EA=1:1, 254 nm) to give 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidine-2,6-dione (100 mg, 0.23 mmol, yield: 22.2%) as a white solid. RT = 8.716 min, LCMS: m / z = 433.1 [M+H] + .

[0629] 2) Synthesis of (S)-3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidine- 2,6-dione or enantiomer

[0630] Compound 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidin-2,6-dione (100 mg, 0.23 mmol) was analyzed by SFC (system: Waters SFC 150; column name: Column size: 250*30mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: MEOH (+0.1% 7.0mol / L ammonia in MEOH solution), A:B = 60:40; Wavelength: 214nm; Flow rate: 120mL / min; Column temperature: RT; Back pressure: 100bar; Injection: 3.0mL; Cycle time: 9.23min) Two isomers were obtained after purification: compound 5-1 and compound 5-2.

[0631] Compound 5-1: Peak 1 Chiral HPLC: 3.350 min; (11.82 mg, 0.027 mmol, yield: 11.82%), RT: 8.104 min, M / Z = 433.1 [M+H] + .

[0632] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.05(d,J=2.4Hz,1H),7.77(dd,J=6.8,2.0Hz,1H) ,7.59(ddd,J=8.8,6.8,2.0Hz,1H),7.51-7.45(m,3H),7.41(dd,J=20.0,8.0Hz,2H),6.7 4(d,J=2.4Hz,1H),6.57(d,J=9.2Hz,1H),6.39(td,J=6.8,1.2Hz,1H),4.40(dd,J=12.4, 5.2Hz,1H),2.91-2.77(m,1H),2.62-2.56(m,1H),2.41-2.31(m,1H),2.14-2.04(m,1H).

[0633] Compound 5-2: Peak 2 Chiral HPLC: 4.050 min; (14.10 mg, 0.032 mmol, yield: 14.10%), RT: 8.104 min, M / Z = 433.2 [M+H] + .

[0634] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 6.8, 2.0 Hz, 1H), 7.59 (ddd, J = 8.8, 6.8, 2.0 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.41 (dd, J = 20.0, 8.0 Hz, 2H), 6.74 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 9.2 Hz, 1H), 6.39 (td, J = 6.8, 1.2 Hz, 1H), 4.40 (dd, J = 12.4, 5.2 Hz, 1H), 2.91 - 2.77 (m, 1H), 2.62 - 2.56 (m, 1H), 2.41 - 2.31 (m, 1H), 2.14 - 2.04 (m, 1H).

[0635] Example 6, Synthesis of 1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl (4-chloro-2-fluorophenyl)carbamate and its enantiomer (Compound 6-1 and Compound 6-2):

[0636] 1) Synthesis of 3-(2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione

[0637] To a solution of 3-(2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (200 mg, 0.68 mmol, 1.0 eq) in DCM (2 mL) was added Et3N (0.2 mL, 1.4 mmol, 2.0 eq) and acetyl chloride (0.1 mL, 1.4 mmol, 2.0 eq) at 0 °C. The reaction was stirred at 0 °C for 1 h. LCMS showed the reaction was completed. The reaction was quenched with water (10 mL) and extracted with DCM (20 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (MeOH:DCM = 20 / 1) to give 3-(2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione acetic acid ester (200 mg, 0.68 mmol, yield: 100%) as white solid. Rt = 1.606 min, LCMS: m / z = 313.0 [M+H] + .

[0638] 2) Synthesis of 1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl (4- chloro-2-fluorophenyl)carbamate

[0639] To a solution of 3-(2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (100 mg, 0.34 mmol, 1.0 eq) in THF (5 mL) was added 4-chloro-2-fluoro-1- isocyanobenzene (116 mg, 0.68 mmol, 2.0 eq), TEA (69 mg, 0.68 mmol, 2.0 eq) at room temperature, the reaction mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The mixture was quenched with H2O (100 mL), extracted with EA (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EA from 100:1 to 1:1, Rf=0.4, PE:EA=1:1, 254 nm) to give 1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl (4-chloro-2- fluorophenyl)carbamate (100 mg, 0.21 mmol, yield: 63.1%) as a white solid. Rt=10.336 min, LCMS: m / z = 466.1 [M+H] + .

[0640] 3) Synthesis of (S)-1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl (4- chloro-2-fluorophenyl)carbamate and its enantiomer

[0641] Compound 1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl (4-chloro-2- fluorophenyl)carbamate (100 mg, 0.21 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Chiralpak IC, 250*30mm 10μm; mobile phase A: Supercritical CO2; mobile phase B: IPA, A:B=60:40; wavelength: 214 nm; flow rate: 120 mL / min; column temperature: RT; back pressure: 100 bar, injection: 2.0 mL; cycle time: 8 min) to give two isomers: Compound 6-1 and Compound 6-2.

[0642] ​Compound 6-1 : Peak 1 Chiral HPLC: 1.277 min; compound (S)-1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azabicyclo[3.1 0]hex-3-yl (4-chloro-2- fluorophenyl)carbamate or enantiomer (15.16 mg, 0.032 mmol, yield: 15.16 %), RT: 10.350 min, M / Z = 466.1 [M+H] + .

[0643] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.73 (s, 1H), 7.68 (t, J = 8.8 Hz, 1H), 7.47 (dd, J = 10.8, 2.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 6.8 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.28 - 5.17 (m, 1H), 4.37 (dd, J = 15.2, 6.4 Hz, 2H), 4.19 (dd, J = 12.0, 5.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 2.82 - 2.69 (m, 1H), 2.52 - 2.51 (m, 1H), 2.32 - 2.15 (m, 1H), 2.05 - 1.91 (m, 1H).

[0644] 19 F NMR (377 MHz, DMSO-d6) δ -120.943.

[0645] Compound 6-2: Peak 2 Chiral HPLC: 2.151 min; compound (R)-1-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)azabicyclo[3.1 0]hex-3-yl (4-chloro-2- fluorophenyl)carbamate or enantiomer (20.36 mg, 0.043 mmol, yield: 20.36 %), RT: 8.282 min, M / Z = 451.1 [M+H] + .

[0646] 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.73 (s, 1H), 7.68 (t, J = 8.8 Hz, 1H), 7.47 (dd, J = 10.8, 2.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 6.8 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.28 - 5.17 (m, 1H), 4.37 (dd, J = 15.2, 6.4 Hz, 2H), 4.19 (dd, J = 12.0, 5.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 2.82 - 2.69 (m, 1H), 2.52 - 2.51 (m, 1H), 2.32 - 2.15 (m, 1H), 2.05 - 1.91 (m, 1H).

[0647] 19 F NMR (377 MHz, DMSO-d6) δ -120.943.

[0648] Example 7, Synthesis of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine- 2,6-dione (Compound 7) and its isomers (Compound 7-1 and Compound 7-2):

[0649] 1) Preparation of 1-(5-bromothiophen-2-yl)pyridin-2(lH)-one

[0650] To a mixture of 2-bromo-5-iodothiophene (1.0 g, 3.47 mmol, 1.0 eq) in dioxane (20 mL) was added pyridin-2(lH)-one (362 mg, 3.81 mmol, 1.1 eq), Cul (329 mg, 1.73 mmol, 0.5 eq), (lR,2R)-N,N'-dimethyl-l,2-cyclohexanediamine (245 mg, 1.73 mmol, 0.5 eq) and Cs2CO3(2.25 g, 6.94 mmol, 2.0 eq). The mixture was stirred at 100 °C in a sealed tube for 16 h under nitrogen protection. The mixture was filtered and concentrated, the residue was purified by silica gel (PE:EA = 20:1) to give 1-(5-bromothiophen-2-yl)pyridin-2(lH)-one (210 mg, 0.82 mmol, 23.72% yield) as a brown solid. LCMS: m / z = 256.1 [M+H] +

[0651] 2), 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6- dione (Compound 7)

[0652] To a mixture of 1-(5-bromothiophen-2-yl)pyridin-2(1H)-one (210 mg, 0.82 mmol, 1.0 eq) in dioxane / H2O (5 / 0.5 mL) was added 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (858 mg, 2.46 mmol, 3.0 eq), K3PO4 (521 mg, 2.46 mmol, 3.0 eq), Pd(dppf)Cl2 (60 mg, 0.08 mmol, 0.1 eq) at room temperature, then the mixture was stirred at 100 °C for 16 h under nitrogen. The mixture was filtered and concentrated, the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6-dione (Compound 7) (50.40 mg, 0.126 mmol, 15.34% yield) as a yellow solid, LCMS: m / z = 399.1 [M+H] + .

[0653] 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.64-7.24 (m, 6H), 6.64 (d, J = 9.2 Hz, 1H), 6.49 (t, J = 6.8 Hz, 1H), 4.46-4.29 (m, 1H), 2.87-2.75 (m, 1H), 2.61-2.54 (m, 1H), 2.42-2.30 (m, 1H), 2.11-1.99 (m, 1H).

[0654] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6-dione (101 mg, 0.25 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Chiralpak IC 250*30mm 10pm; mobile phase A: Supercritical CO2; mobile phase B: EtOH, A:B = 55:45; wavelength: 214 nm; flow rate: 120 mL / min; column temperature: RT; back pressure: 100 bar, injection: 2.0 mL; cycle time: 7 minutes) to give two isomers: Compound 7-1 and Compound 7-2.

[0655] ​Example 8, Synthesis of 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1H-indol-4- yl)phenyl)piperidine-2,6-dione (Compound 8):

[0656] 1) Preparation of 1-(4-bromo-1H-indol-7-yl)pyridin-2(1H)-one.

[0657] To a solution of 4,7-dibromo-1H-indole (1.00 g, 3.64 mmol, 1.0 eq.) in DMF (25 mL) was added pyridin-2(1H)-one (415 mg, 4.37 mmol, 1.2 eq.), anhydrous potassium carbonate (1.00 g, 7.28 mmol, 2.0 eq.) and cuprous iodide (139 mg, 0.73 mmol, 0.2 eq.) at room temperature, then the mixture was stirred at 150 °C under nitrogen atmosphere for 16 hours. The mixture was filtered and concentrated, the residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 um, 40 g; Mobile Phase A: Water; Mobile Phase B: Acetonitrile; Flow Rate: 50 mL / min; Gradient: 5% B to 80% B in 20 minutes; Detector: 214 nm. Fractions containing the desired product were collected at 46% B) and concentrated under reduced pressure to give Compound 1-(4-bromo-1H-indol-7-yl)pyridin-2(1H)-one (120 mg, 0.42 mmol, 11.4% yield) as a white solid. RT: 1.079 min. LCMS: m / z = 289.0 [M+H] + .

[0658] 2) Preparation of 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1H-indol-4-yl)phenyl)piperidine- 2,6-dione.

[0659] To a solution of 1-(4-bromo-1H-indol-7-yl)pyridin-2(1H)-one (100 mg, 0.35 mmol, 1.0 eq) in 1,4-dioxane / water (5 / 1 mL) was added 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (234 mg, 1.05 mmol, 3.0 eq), potassium phosphate (148 mg, 0.70 mmol, 2.0 eq) and Pd(dppf)Cl2(29 mg, 0.04 mmol, 0.1 eq) at room temperature, then the mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. The mixture was filtered and concentrated, the residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give white solid compound 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1H-indol-4-yl)phenyl)piperidine-2,6-dione (compound 8) (58.22 mg, 0.13 mmol, 39.0% yield), RT: 8.404 min. LCMS: m / z = 432.0 [M+H] + .

[0660] 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.93 (s, 1H), 7.70 (d, J = 6.0 Hz, 1H), 7.60-7.55 (m, 1H), 7.47-7.35 (m, 4H), 7.13-7.07 (m, 2H), 6.56 (d, J = 9.2 Hz, 1H), 6.37-6.34 (m, 1H), 6.18 (s, 1H), 4.40-4.36 (m, 1H), 2.86-2.77 (m, 1H), 2.68-2.66 (m, 1H), 2.45-2.31 (m, 1H), 2.14-2.07 (m, 1H).

[0661] Example 9, synthesis of 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)-1H-indol-4-yl)phenyl)piperidine-2,6-dione (compound 9):

[0662] 1) Preparation of 4,7-dibromo-5-fluoro-1H-indole.

[0663] To a solution of 4,7-dibromo-5-fluoro-1H-indole (1.00 g, 3.41 mmol, 1.0 eq.) in DMF (40 mL) was added pyridine-2(1H)-one (389 mg, 4.09 mmol, 1.2 eq.), anhydrous potassium carbonate (941 mg, 6.82 mmol, 2.0 eq.) and copper(I) iodide (129 mg, 0.68 mmol, 0.2 eq.) at room temperature, then the mixture was stirred at 150 °C under nitrogen atmosphere for 16 hours. The mixture was filtered and concentrated, the residue was purified by reverse phase flash chromatography with the following conditions: Column: spherical C18, 20-40 um, 40 g; Mobile Phase A: water; Mobile Phase B: acetonitrile; Flow rate: 50 mL / min; Gradient: 5% B to 80% B in 20 minutes; Detector: 214 nm. Fractions containing the desired product were collected at 46% B) and concentrated under reduced pressure to give compound 1-(4-bromo-5-fluoro-1H-indol-7-yl)pyridine-2(1H)-one (140 mg, 0.46 mmol, 13.3% yield) as a white solid. RT: 1.109 min. LCMS: m / z = 309.0 [M+H]

[0664] 2) Preparation of 1-(4-bromo-5-fluoro-1H-indol-7-yl)pyridine-2(1H)-one.

[0665] To a solution of 4,7-dibromo-5-fluoro-1H-indole (1.00 g, 3.41 mmol, 1.0 eq.) in DMF (40 mL) was added pyridine-2(1H)-one (389 mg, 4.09 mmol, 1.2 eq.), anhydrous potassium carbonate (941 mg, 6.82 mmol, 2.0 eq.) and copper(I) iodide (129 mg, 0.68 mmol, 0.2 eq.) at room temperature, then the mixture was stirred at 150 °C under nitrogen atmosphere for 16 hours. The mixture was filtered and concentrated, the residue was purified by reverse phase flash chromatography with the following conditions: Column: spherical C18, 20-40 um, 40 g; Mobile Phase A: water; Mobile Phase B: acetonitrile; Flow rate: 50 mL / min; Gradient: 5% B to 80% B in 20 minutes; Detector: 214 nm. Fractions containing the desired product were collected at 46% B) and concentrated under reduced pressure to give compound 1-(4-bromo-5-fluoro-1H-indol-7-yl)pyridine-2(1H)-one (140 mg, 0.46 mmol, 13.3% yield) as a white solid. RT: 1.109 min. LCMS: m / z = 309.0 [M+H] + .

[0666] 3) Preparation of 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)-1H-indol-4-yl)phenyl)piperidine-2,6-dione.

[0667] To a solution of 1-(4-bromo-5-fluoro-1H-indol-7-yl)pyridin-2(1H)-one (90 mg, 0.29 mmol, 1.0 eq) in 1,4-dioxane / water (5 / 1 mL) was added 3-(2-chloro-3-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (194 mg, 0.87 mmol, 3.0 eq), potassium phosphate 123 mg, 0.58 mmol, 2.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg, 0.03 mmol, 0.1 eq) at room temperature, then the mixture was stirred at 100 °C for 4 h under nitrogen atmosphere. The mixture was filtered and concentrated, the residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give white solid compound 3-(2-chloro-3-(5-fluoro-7-(2-oxopyridin-1(2H)-yl)-1H-indol-4-yl)phenyl)piperidine-2,6-dione (compound 9) (23.13 mg, 0.05 mmol, 17.5% yield), LCMS: m / z = 450.0 [M+H] + .

[0668] 1H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 10.94 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.60-7.55 (m, 1H), 7.47-7.41 (m, 4H), 7.18-7.15 (m, 1H), 6.57 (d, J = 9.2 Hz, 1H), 6.38 (t, J = 6.4 Hz, 1H), 6.13-6.10 (m, 1H), 4.41-4.45 (m, 1H), 2.76-2.67 (m, 1H), 2.56-2.54 (m, 1H), 2.34-2.29 (m, 1H), 2.01-1.99 (m, 1H).

[0669] 19F NMR (377 MHz, DMSO-d6): δ -125.99.

[0670] Example 10, synthesis of 3-(2-chloro-3-(2-(2-oxopyridin-1(2H)-yl)thiazol-5-yl)phenyl)piperidine-2,6-dione (compound 10):

[0671] 1) Preparation of 1-(5-bromothiazol-2-yl)pyridin-2(1H)-one.

[0672] To a mixture of 5-bromo-2-iodothiazole (290 mg, 1.03 mmol, 1.0 eq) in 1,4-dioxane (15 mL) was added pyridine-2(lH)-one (98.2 mg, 1.03 mmol, 1.0 eq), Cul (78.6 mg, 0.41 mmol, 0.4 eq), (lR,2R)-N,N'-dimethyl-l,2-cyclohexanediamine (58.2 mg, 0.41 mmol, 0.4 eq) and Cs2CO3(1.0 g, 3.09 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h in a sealed tube under nitrogen. The mixture was filtered and concentrated, the residue was purified by silica gel (PE:EA = 20:1) to give 1-(5-bromothiazol-2-yl)pyridine-2(lH)-one (140 mg, 0.547 mmol, 52.8% yield) as a brown solid. LCMS: m / z = 257.0; 259.0 [M+H]+.

[0673] (5-bromothiazol-2-yl)pyridine-2(lH)-one (140 mg, 0.547 mmol, 52.8% yield). LCMS: m / z = 257.0; 259.0 [M+H]+.

[0674] 2), 3-(2-chloro-3-(2-(2-oxopyridin-l(2H)-yl)thiazol-5-yl)phenyl)piperidine-2,6-dione.

[0675] To a mixture of l-(5-bromothiazol-2-yl)pyridine-2(lH)-one (130 mg, 0.505 mmol, 1.0 eq) in 1,4-dioxane / water (5 / 0.5 mL) was added 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (353 mg, 1.011 mmol, 2.0 eq), potassium phosphate (321 mg, 1.515 mmol, 3.0 eq) and Pd(dppf)Cl2(41 mg, 0.0505 mmol, 0.1 eq) at room temperature, then the mixture was stirred at 100 °C for 4 h under nitrogen. The mixture was filtered and concentrated, the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 3-(2-chloro-3-(2-(2-oxopyridin-l(2H)-yl)thiazol-5-yl)phenyl)piperidine-2,6-dione (98.32 mg, 0.245 mmol, 48.6% yield) as a yellow solid, LCMS: m / z = 400.1 [m+H]+.

[0676] 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.81 (dd, J = 7.2, 1.2 Hz, 1H), 8.04 (s, 1H), 7.77-7.62 (m, 2H), 7.46-7.44 (m, 2H), 6.79 (d, J = 9.2 Hz, 1H), 6.68-6.64 (m, 1H), 4.41-4.36 (m, 1H), 2.86-2.73 (m, 1H), 2.58-2.53 (m, 1H), 2.42-2.32 (m, 1H), 2.07-2.04 (m, 1H).

[0677] Example 11, Synthesis of the following compound

[0678] In a similar manner to the synthesis of the compounds in Examples 1-10, the following compounds were obtained:

[0679] Test Example 1, Detection of VAV1 Target Protein Degradation Activity of Test Substance

[0680] Jurkat cells stably expressing LgBit were introduced with heterologous VAV1 C-terminal Hibit. After cell expansion culture, the cells were adjusted to the appropriate concentration with RPMI1640 medium containing 10% FBS, 1% Penicilin / Streptomycin and 1% Endurazine. The cells were plated at 10 4 Cells / well, 25uL per well, and incubated at 37℃, 5% CO2 for 16 hours. The test compounds were prepared into 10mM stock solution, diluted and added to the cells at 25nL / well (concentration gradient from 10uM down, 3-fold gradient dilution), and incubated for 6 hours and 24 hours. The reading was taken with "LUM plus" enzyme reader, analyzed with Scinamic, and the fluorescence response (R) was calculated according to the following formula: R=100*(S-N) / (P-N). S is the value of the test compound well, and N and P are the average values of the negative and positive wells on each plate, respectively.

[0681] Test Example 2, Detection of VAV1 Target Protein Degradation Activity of Representative Compounds

[0682] The degradation activity of representative compounds on the target VAV1 protein was evaluated by the HiBiT method according to the change in the fluorescence signal intensity of the target point abundance in Jurkat-VAV1-HiBit-KI-1A3 cells.

[0683] 2.1, Instruments and Consumables:

[0684] 2.2, Test Operation:

[0685] a) Jurkat-VAV1-HiBit-KI-1A3 cell strain was cultured at 37℃, 5% CO2 in complete medium (RPMI-1640 + 10% FBS).

[0686] b) Cells in the logarithmic growth phase were harvested and counted using a blood cell counter. Cell viability was detected by trypan blue exclusion method to ensure that the cell viability was above 90%.

[0687] c) The cell density was adjusted using complete medium, and then inoculated in a 96-well cell culture plate at 90uL per well, with a total of 10,000 cells.

[0688] d) The cells in the 96-well plate were incubated at 37℃, 5% CO2 overnight.

[0689] e) Prepare 10-fold drug solutions. The highest working concentration of the test compound is 100 nM. There are 10 concentrations, and each is diluted 3 times. Then, transfer 10 μL of each serially diluted compound to the corresponding experimental wells of a 96-well cell plate. Set up three replicates for each drug concentration.

[0690] f) The cells in the drug-treated 96-well plates were cultured at 37°C and 5% CO2 for 24 hours, and then the target protein degradation analysis was performed.

[0691] g) Melting The HiBiT Lytic Detection System reagent equilibrates the cell plate to room temperature for 30 minutes.

[0692] h) Take a new 50mL sterile tube and use an appropriate volume of room temperature water. HiBiT Lytic Buffer diluted LgBiT Protein (1:100) and Mix HiBiT Lytic Substrate (1:50) by inverting the container.

[0693] i) Add 100 μL of the prepared solution to each well. The HiBiT lysis reagent was used to lyse the cells by shaking at 300 rpm on a fixed-track shaker for 5 minutes in the dark.

[0694] j) Place the cell plate at room temperature for 20 minutes to stabilize the cold light signal.

[0695] k) Use a multi-functional microplate reader ( Plus, BMG) reads signal values ​​and collects data in Luminescence mode.

[0696] 2.3 Data Analysis and Processing:

[0697] Data was analyzed using GraphPad Prism 7.0 software. A nonlinear S-curve regression was used to fit the data to derive the dose-response curve, and the dose-response ratio (DC) was calculated from this curve. 50 value.

[0698] Hibit signal:%of Control=(Lum 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照 -Lum 培养液对照 )×100%.

[0699] Degradation efficiency: Degradation% = 1 - (Lum) 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照Lum 培养液对照 ) x 100%.

[0700] Table 2.1 Degradation activity of representative compounds on VAV1 target

[0701] Reference molecule structure: From the above results, it can be seen that the representative molecules have higher degradation activity compared with the reference molecule.

[0702] Test Example 3: Pharmacokinetic study of test substances on mice

[0703] The pharmacokinetic properties of the compounds of the present application were evaluated by mouse pharmacokinetic experiments: SPF male ICR mice were used, which were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. Single IV administration: the compound was dissolved in 5% DMSO-15% solutol-80% saline, the solution concentration was 0.2 mg / mL, and the administration volume was 5 mL / kg (single intravenous administration, the dose was 1 mg / kg). Single gavage administration (dose 10 mg / kg): the compound was dissolved in 5% DMSO-15% solutol-80% water, the solution concentration was 1 mg / mL, and the administration volume was 10 mL / kg. The animals were fasted overnight before the experiment and were not deprived of water, and food was restored 4 hours after administration. After IV administration: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h. Blood was collected; after gavage administration: 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h blood was collected. Blood was collected through the facial vein, 0.04 ml per blood collection point. The samples were centrifuged at 4200 rpm for 5 min at 4°C, the plasma was transferred to a centrifuge tube, and was stored at -80°C until analysis. The plasma sample analysis used acetonitrile protein precipitation method to extract the test compound and internal standard (Labetalol & tolbutamide & Verapamil & dexamethasone & glyburide & Celecoxib) in mouse plasma, and the extract was analyzed by LC / MS / MS. The measured plasma concentration-time data of individual animals were analyzed by non-compartment model using Phoenix WinNonlin 7.0 (Pharsight, USA) software, and the mouse pharmacokinetic parameters were as follows: maximum (peak) plasma drug concentration Cmax; peak time Tmax; half-life T1 / 2 and area under the plasma concentration-time curve AUC0-inf extrapolated to infinite time.

[0704] Table 3.1 Pharmacokinetic parameters of representative compounds in mice

[0705] Reference molecule structure: From the above results, it can be seen that the representative molecules have higher degradation activity compared with the reference molecule.

[0706] From the results in the above table, it can be seen that the compounds of the present application are better absorbed orally, have lower clearance, higher exposure (7-fold increase in exposure) and longer half-life than the reference compound, and are thus more suitable for development as an oral drug.

[0707] The above describes embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. A compound represented by Formula (I), a pharmaceutically acceptable salt, solvate, enantiomer, or isotopically substituted material thereof, wherein, Z is independently selected from a carbonyl or oxiranyl, oxetanyl structure; A and D are independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole or structure; Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer independently selected from 0, 1, 2, 3, and 4; n is an integer independently selected from 0, 1, 2, 3, and 4; t is an integer independently selected from 0, 1, or 2; p is an integer independently selected from 0, 1, or 2.

2. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof of claim 1, wherein, having the structure of formula (IA-1) or (IA-2), wherein, X is independently selected from C(R d1 ) or N; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer independently selected from 0, 1, 2, 3, and 4; n is an integer independently selected from 0, 1, 2, 3, and 4; t is an integer independently selected from 0, 1, or 2; p is an integer independently selected from 0, 1, or 2. Preferably, it has the structure of formula (IB-1) or formula (IB-2), wherein, independently represents a single or double bond; Z is independently selected from a carbonyl or oxiranyl, oxetanyl structure; X is independently selected from C(R d1 ) or N; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring C is independently selected from a monocyclic or polycyclic structure of 3 to 8 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer independently selected from 0, 1, 2, 3, and 4; n is an integer independently selected from 0, 1, 2, 3, and 4; t is an integer independently selected from 0, 1, or 2; p is an integer independently selected from 0, 1, or 2. Preferably, it has the structure of formula (IC), wherein, Ring D is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; X1, X2are independently selected from C(R d1 ) or N; Y is independently selected from NR d1 , O or S; Z is independently selected from a carbonyl or oxiranyl, oxetanyl structure; Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer independently selected from 0, 1, 2, 3, and 4; n is an integer independently selected from 0, 1, 2, 3, and 4; t is an integer independently selected from 0, 1, or 2; p is an integer independently selected from 0, 1, or 2. Preferably, it has the structure of formula (ID-1) or formula (ID-2), wherein, X, X1, X2are independently selected from C(R d1 ) or N; Z is independently selected from a carbonyl or oxiranyl, oxetanyl structure; Ring B is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro, or bridged structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; The halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3 and 4; t is any integer selected from 0, 1 or 2; p is any integer selected from 0, 1 or 2; Preferably, it has the structure of formula (IE-1) or formula (IE-2), wherein, Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Z is any independently selected from carbonyl or oxiranyl, oxetanyl structure; X and X1are independently selected from C(R d1 ) or N; Ring B is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; The halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; t is any integer selected from 0, 1 or 2; p is any integer selected from 0, 1 or 2; Preferably, it has the structure of formula (IF-1)~(IF-3), wherein, Z is any independently selected from carbonyl or oxiranyl, oxetanyl structure; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; The halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2 or 3; t is any integer selected from 0, 1 or 2; p is any integer selected from 0, 1 or 2; Preferably, it has the structure of formula (IH-1), formula (IH-2) or formula (IH-3), wherein, Z is any independently selected from carbonyl or oxiranyl, oxetanyl structure; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; The halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2 or 3; t is any integer selected from 0, 1 or 2; p is any integer selected from 0, 1 or 2; Preferably, it has the structure of formula (IJ-1), formula (IJ-2) or formula (IJ-3), wherein, Z is any independently selected from carbonyl or oxiranyl, oxetanyl structure; X and X1 are any independently selected from CR2 or N; Ring B is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be any independently selected from aromatic, heteroaromatic, aliphatic, heterocyclic, fused, spiro or bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; The halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is an integer optionally selected from 0, 1, 2, or 3; t is an integer optionally selected from 0, 1, or 2; p is an integer optionally selected from 0, 1, or 2; Preferably, it has the structure of formula (IK-1) or formula (IK-2), wherein, Z is optionally independently selected from a carbonyl or oxiranyl, oxetanyl structure; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is optionally independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, selected from the group consisting of C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl-substituted C 3-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl-substituted C 3-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents a heteroatom optionally independently selected from O, N, S, P and isotopes thereof; said halogen is optionally independently selected from F, Cl, Br, I and isotopes thereof; m is an integer optionally selected from 0, 1, 2, 3, and 4; n is an integer optionally selected from 0, 1, 2, or 3; t is an integer optionally selected from 0, 1, or 2; p is an integer optionally selected from 0, 1, or 2; Preferably, it has the structure of formula (IL-1), formula (IL-2) or formula (IL-3), wherein, Z is optionally independently selected from a carbonyl or oxiranyl, oxetanyl structure; X, X1, X3, are optionally independently selected from CR2or N; Ring B is optionally independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents a heteroatom optionally independently selected from O, N, S, P and isotopes thereof; said halogen is optionally independently selected from F, Cl, Br, I and isotopes thereof; m is an integer optionally selected from 0, 1, 2, 3, and 4; n is an integer optionally selected from 0, 1, 2, or 3; t is an integer optionally selected from 0, 1, or 2; p is an integer optionally selected from 0, 1, or 2; Preferably, it has the structure of formula (IM-1) or formula (IM-2), wherein, Z is optionally independently selected from a carbonyl or oxiranyl, oxetanyl structure; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is optionally independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 cycloalkyl substituted with C 3-10 alkyl or C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents a heteroatom optionally independently selected from O, N, S, P and isotopes thereof; said halogen is optionally independently selected from F, Cl, Br, I and isotopes thereof; m is an integer optionally selected from 0, 1, 2, 3, and 4; n is an integer optionally selected from 0, 1, 2, or 3; t is an integer optionally selected from 0, 1, or 2; p is an integer optionally selected from 0, 1, or 2; Preferably, it has the structure of formula (IN-1) to (IN-4), wherein, Z is optionally independently selected from a carbonyl or oxiranyl, oxetanyl structure; Ring A is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is optionally independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents a heteroatom optionally independently selected from O, N, S, P and isotopes thereof; said halogen is optionally independently selected from F, Cl, Br, I and isotopes thereof; m is an integer optionally selected from 0, 1, 2, 3, and 4; n is an integer optionally selected from 0, 1, 2, or 3; t is an integer optionally selected from 0, 1, or 2; p is an integer optionally selected from 0, 1, or 2; Preferably, it has the structure of formula (IO-1)~(IO-2), wherein, Z is optionally independently selected from a carbonyl or oxiranyl, oxetanyl structure; structure; Ring B is optionally independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which monocyclic or polycyclic structure is optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; said hetero represents a heteroatom optionally independently selected from O, N, S, P and isotopes thereof; said halogen is optionally independently selected from F, Cl, Br, I and isotopes thereof; m is an integer optionally selected from 0, 1, 2, 3, and 4; n is an integer optionally selected from 0, 1, 2, or 3; t is an integer optionally selected from 0, 1, or 2; p is an integer optionally selected from 0, 1, or 2; wherein, Z is independently selected from carbonyl or oxiranyl, oxetanyl structure; Ring D is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, Cl, Br, I and isotopes thereof; m is independently selected from an integer of 0, 1, 2, 3 and 4; n is independently selected from an integer of 0, 1, 2 or 3; t is independently selected from an integer of 0, 1 or 2; p is independently selected from an integer of 0, 1 or 2; Preferably, it has the structure of formula (IP-1)~(IP-2), wherein, Z is independently selected from carbonyl or oxiranyl, oxetanyl structure; Ring D is independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring, or a bridged ring structure; preferably a benzene ring, a benzofuran, a benzopyrrole, a benzodihydrofuran, a benzodihydropyrrole, a thiazole ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, an isothiazole, or structure; Ring B is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Y represents independently for each occurrence =0 or =NR d7 ; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, Cl, Br, I and isotopes thereof; m is independently selected from an integer of 0, 1, 2, 3 and 4; n is independently selected from an integer of 0, 1, 2 or 3; t is independently selected from an integer of 0, 1 or 2; p is independently selected from an integer of 0, 1 or 2.

3. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof of claim 1 or 2, wherein, having the structure of formula (1-I), wherein, A is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or -L1-Q; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; further R1hydrogens are optionally substituted with 1 to multiple groups selected from the group consisting of H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, and saturated or partially saturated C 3-6 cycloalkyl substitution, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; R3, R4, R5may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3, R4or R5together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; each R7may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted with C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2- 10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted with C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted with C 3-10 heterocyclyl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; L1is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L2is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, Cl, Br, I and isotopes thereof; m is independently selected from an integer of 0, 1, 2, 3 and 4; n is independently selected from an integer of 0, 1, 2, 3, 4 and 5; Preferably, it has the structure of formula (1-IA-1 or formula 1-IA-2), wherein, independently represents single bond or double bond; A is independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, which can be optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=X)–, -OS(=X)-, -S(=O)2, C(R d1 ) or N; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or -L1-Q; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; further R1hydrogens are optionally substituted with 1 to multiple groups selected from the group consisting of H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2 is arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogen on R2 is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; each R3may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or is selected from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl, or C 3- 10 heterocycloalkyl-substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl, and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1 is independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C Each R7 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2- 10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, Cl, Br, I and isotopes thereof; m is independently selected from an integer of 0, 1, 2, 3 and 4; n is independently selected from an integer of 0, 1, 2, 3, 4 and 5; p is independently selected from an integer of 0, 1, 2, 3, 4 and 5; Preferably, it has the structure of formula (1-IB-1 or 1-IB-2), wherein, independently represents single bond or double bond; X is independently selected from N or CR1; X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=X)–, -OS(=X)-, -S(=O)2, C(R d1 ) or N; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or -L1-Q; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; further, the hydrogens on R1are optionally substituted with 1 to multiple groups selected from the group consisting of H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2 is arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogen on R2 is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; each R3may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or is selected from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1 is independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R7may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2- 10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents a heteroatom independently selected from O, N, S, P and isotopes thereof; the halogen is independently selected from F, Cl, Br, I and isotopes thereof; m is independently selected from an integer of 0, 1, 2, 3 and 4; n is independently selected from an integer of 0, 1, 2, 3, 4 and 5; p is independently selected from an integer of 0, 1, 2, 3, 4 and 5; Preferably, it has the structure of formula (1-IC), wherein, X is independently selected from N or CR1; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate substituted with C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to multiple groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, and saturated or partially saturated C 3-6 cycloalkyl substitution, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; each R3may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or is selected from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1 is independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituted by substituents; each R7may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2- 10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 substituted with C 1-10 alkyl, or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 Or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3, 4 and 5; p is any integer selected from 0, 1, 2, 3, 4 and 5. provided that when and only when R2is hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl or Br, at least one of R1and R3is present and is selected from the group consisting of sulfenyl, dialkylphosphinyl and cycloalkylphosphinyl; Preferably, it has the structure of formula (1-ID-1 or 1-ID-2), wherein, represents independently a single or double bond; X1and X2are independently selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), -C(=S)-, -S(=O)-, -(R d4 )P(=X)-, -OS(=X)-, -S(=O)2, C(R d1 ) or N; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate substituted with alkyl, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to multiple substituents selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, and saturated or partially saturated C 3-6 cycloalkyl substitution, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; each R3may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or is selected from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituted by substituents; Each R7 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2- 10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3, 4 and 5; p is any integer selected from 0, 1, 2, 3, 4 and 5. Preferably, it has the structure of formula (1-IE), wherein, each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or -L1-Q; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; further, the hydrogens on R1are optionally substituted with 1 to multiple groups selected from the group consisting of H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2is any independently selected from CN, sulfenyl, dialkylphosphinyl, cycloalkylphosphinyl; each R3may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or is selected from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R7may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2- 10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3, 4 and 5; p is any integer selected from 0, 1, 2, 3, 4 and 5. Preferably, it has the structure of formula (1-IF), wherein, each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 carboxyl or carboxyl surrogate substituted with C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; still further, a hydrogen on R1is optionally substituted with 1 to multiple groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, and saturated or partially saturated C 3-6 cycloalkyl substitution, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; each R3may be the same or different and is independently of one another selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or from the group consisting of C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, from C 3-10 cycloalkyl or C 3- 10 heterocycloalkyl substituted C 1-10 alkyl, and from C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3- 10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3, R4or R5together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1is independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R7may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, or C 1-10 alkynyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2- 10 alkenyl, or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 substituted with C 1-10 alkyl, or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; R a and R b may be the same or different and are each independently selected from the group consisting of hydrogen, deuterium, OH, SH and NH2, -COOH or from the group consisting of C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl; or R a and R b are linked together with the atom to which they are attached to form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3, 4 and 5; p is any integer selected from 0, 1, 2, 3, 4 and 5.

4. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof according to any one of claims 1-3, wherein, having the structure of formula (2-I), wherein, X is independently selected from C(R d1 ) or N; A is any independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, the monocyclic or polycyclic structure is any independently selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituted by substituents; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3 and 4; t is any integer selected from 0, 1 or 2; Preferably, it has the structure of formula (2-IA), wherein, R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1 and L3 are each independently selected from non-existent, single bond, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, and alkyne bonds; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is any integer selected from 0, 1, 2, 3 and 4; n is any integer selected from 0, 1, 2, 3 and 4; t is any integer selected from 0, 1 or 2; Preferably, it has the structure of formula (2-IB), wherein, represents independently a single or double bond; X1, X2, and X3 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=X)–, -OS(=X)-, -S(=O)2, C(R d1 ) or N; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituted by substituents; each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylacyl, C 2-10 alkylsulfonyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof; the halogen is any independently selected from F, Cl, Br, I and isotopes thereof; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; t is an integer selected from 0, 1 or 2; Preferably, it has the structure of formula (2-IC), wherein, X1and X2are independently selected from C(R d1 ) or N; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R4is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, selected from C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)-, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl, C 3-10 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents any independently selected from O, N, S, P and isotopes thereof; said halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; Preferably, it has the structure of formula (2-ID), wherein, R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3, R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atom to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents any independently selected from O, N, S, P and isotopes thereof; said halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; t is an integer selected from 0, 1 or 2; Preferably, it has the structure of formula (2-IE), wherein, R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an alkene bond, an alkyne bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents each R d1 , R d2 , R d3 , R d4 , R d5 , R d7 , R d8 or R d9 may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; wherein said C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkynyl, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl-substituted C 1-10 alkyl or C 3-10 cycloalkyl-substituted C 3-10 heterocycloalkyl, C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents any independently selected from O, N, S, P and isotopes thereof; said halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; t is an integer selected from 0, 1 or 2; Preferably, it has the structure of formula (2-IF-1 or 2-IF-2), wherein, represents independently a single or double bond; X1, X3are independently selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), -C(=S)-, -S(=O)-, -(R d4 )P(=X)-, -OS(=X)-, -S(=O)2, C(R d1 ) or N; X1, X3are independently selected from -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), -C(=S)-, -S(=O)-, -(R d4 )P(=X)-, -OS(=X)-, -S(=O)2, C(R d1 ) or N; R1is independently selected from hydrogen, deuterium, halogen, pentafluorosulfanyl, -CN, -OH, -SH and -NH2, -COOH or from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl surrogate, dialkylphosphoryl, cycloalkylphosphoryl or Q group; R2is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, SF5, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; R3and R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, dialkylphosphoryl, cycloalkylphosphoryl; or any two adjacent R3or R4together with the atoms to which they are attached form a 5-6 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocyclyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, =0, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; L1, L2, L3are each independently selected from the group consisting of absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 )(R d2 ), an olefinic bond, an acetylenic bond; Q is independently selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-18 membered saturated or partially saturated cycloalkyl, or 3-18 membered saturated or partially saturated heterocyclyl, which cycloalkyl or heterocyclyl can be fused, spiro, or bridged; and hydrogen on Q is optionally substituted with 1 to multiple substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl substituents Each R d1 R d2 R d3 R d4 R d5 R d7 R d8 or R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; said hetero represents any independently selected from O, N, S, P and isotopes thereof; said halogen is independently selected from F, CI, Br, I and isotopes thereof; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; t is an integer selected from 0, 1 or 2.

5. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof according to any one of claims 1-4, wherein: Z is preferably a carbonyl, oxetanyl structure; most preferably C=0; R2is preferably hydrogen, deuterium, halogen, CN, pentafluorosulfanyl, OH, or C 1-10 alkyl; most preferably CI; Rings A and D are preferably phenyl, benzofuran, benzopyrrole, pyridine, thiazole, isothiazole or thiophene ring or structure; Ring B is preferably a benzene ring, a pyridine ring, a thiazole ring, an isothiazole ring or a thiophene ring, a pyrimidine, a pyridazine, a piperidine, a piperazine, a pyrazole, an imidazole, an oxazole, a morpholine, a pyrrole, a tetrahydropyrrole, a furan, a tetrahydrofuran, a piperidone, and the following structures: Most preferred is 6. The compound, pharmaceutically acceptable salt, solvate, enantiomer, or isotopically substituted material of any one of claims 1-5, wherein, having the structure of formula (II), Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl; B is selected from a single bond or C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl; T is selected from a single bond or -L1-L2-L3-, L1 is attached to ring A; L1 is selected from CH2, O, NH; L2 is selected from C(=0), C(=S), S(=0)2; L3 is selected from CH2, O, NH; each R1, R2, R3is the same or different, independently of one another H, CN, oxo (=0), halogen, C 1-10 alkyl, C 1-10 alkoxy, -P(=0)(C 1-10 alkyl)(C 1-10 alkyl); p is selected from 0, 1 or 2; t is selected from 0, 1 or 2; preferably, ring A is selected from C6 aryl, 9-10 membered heteroaryl, 3-6 membered heterocyclyl preferably, ring A is selected from phenyl, benzofuranyl, thienyl, thiazolyl, indolyl, azetidinyl; Preferably, ring A is selected from * end to connection; Preferably, selected from the group consisting of * end to connection; Preferably, selected from the group consisting of * end to connection; Preferably, B is selected from a single bond, phenyl; Preferably, B is selected from a single bond, Preferably, selected from -P(=O)(C 1-6 alkyl)(C 1-6 alkyl), Preferably, selected from the group consisting of Preferably, each R1, R2, R3 is identical or different, independently from each other H, CN, oxo (=0), halogen, C 1-6 alkyl, C 1-6 alkoxy, -P(=0)(C 1-6 alkyl)(C 1-6 alkyl); Preferably, each R1is the same or different, independently of one another, selected from H, oxo (=0), halogen; for example from H, oxo (=0), F, Cl, preferably, R2 is selected from H, CN, halogen; for example from H, CN, CI; preferably, each R3 is the same or different, independently selected from H, halogen; for example from H, F.

7. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof according to any one of claims 1-6, wherein, The compound is preferably a compound of the following structure: (For example )、 (For example )、 (For example )、 (For example )、 (For example )。 8. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof according to any one of claims 1-7, wherein, said compound is selected from the novel compounds of the structures disclosed in the specification.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds, pharmaceutically acceptable salts, solvates, enantiomers or isotopically substituted thereof according to any one of claims 1-8.

10. Use of the compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically-substituted compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament for preventing and / or treating a disease associated with VAV1 target and signaling pathway.

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