Novel substituted heterocyclic compound serving as GRK2 degradation agent

Abstract

Disclosed in the present invention is a novel substituted heterocyclic compound having GRK2 target degradation activity. Specifically disclosed is a compound having the structure represented by formula (I) and serving as a GRK2 degradation agent or a pharmaceutically acceptable salt, solvate, hydrate, isotopic substituent or isomer of the compound.

Description

Novel substituted heterocyclic compounds as GRK2 degraders

[0001] The present application claims the priority of:

[0002] The priority of the prior application with the patent application number 202411385878.1, entitled "Novel substituted heterocyclic compounds as GRK2 degraders", filed on September 30, 2024, with the State Intellectual Property Office of China;

[0003] The priority of the prior application with the patent application number 202411905500.X, entitled "Novel substituted heterocyclic compounds as GRK2 degraders", filed on December 23, 2024, 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 GRK2 degradation activity, compositions containing such compounds, and methods of using such compounds for the preparation of drugs for the treatment or prevention of diseases related to the GRK2 signaling pathway. BACKGROUND

[0006] GRK2 (G Protein-Coupled Receptor Kinase 2), also known as β-AR protein kinase 1, is a kind of enzyme with serine / threonine protein kinase activity. It is widely expressed in various organs and tissues, and participates in various intercellular mediation and communication processes. At the same time, GRK2 also plays a key role in the intracellular regulation of G protein-coupled receptor (GPCR) signal transduction pathways.

[0007] Studies have shown that GRK2 is involved in the development of various diseases, and the imbalance of GRK2 can lead to the occurrence and rapid progression of cardiovascular-related diseases such as heart attack, heart ischemia, cerebral infarction, and inflammatory diseases such as arthritis, tumors, etc., which seriously threaten the lives of patients. Therefore, GRK2 has become a very promising and potential therapeutic target.

[0008] However, although the GRK2 target has great therapeutic potential, the development of therapeutic drugs targeting this target has always been very challenging, and so far there is no good inhibitor or degrader of drug properties, so it is urgent to develop new candidate molecules with good drug properties. SUMMARY

[0009] In one aspect of the present application, the compound or its pharmaceutically acceptable salt, isotopically substituted or isomer thereof has the structure of formula (I),

[0010] wherein,

[0011] A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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;

[0012] is a fragment structure capable of binding to a ubiquitinated protein or a chaperone protein, and is preferably selected from the following structures:

[0013] wherein, is optionally a single bond or a double bond, and when is a single bond, X, X1, and X2 are 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(=Y)-, -OS(=Y)-, -S(=O)2-; and when is a double bond, X, X1, and X2 are independently selected from C(R d1 ) or N;

[0014] L1and L2are independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(Rd1 )S-, d2 )S-, d3 )-, d4 )-, d5 )-, d6 )-, d7 )-, d3 )C(=O)-, d4 )C(R d1 )(R d2 )-, d1 )(R d2 )N(R d4 )-, d4 )-OC(=O)-, d1 )-C(=O)-, d2 )-C(=S)-, d1 )-S(=O)2-, d2 )-C(R d1 )(R d2 )C(=O)-, d1 )(R d2 ),

[0015] Y is independently selected from O, S, or =NR0;

[0016] each R0may be the same or different and is independently selected from hydrogen, deuterium, sulfurium pentafluoride, C 1-10 alkoxy, C 1-10 alkylthio, C 1-10 alkylamino, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, CN, NR d1 R d2 , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogens on R° are further optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, CN, NR 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, sulfuropentafluoride, halogen, haloalkyl, cyano, OCH3, and OH;

[0017] each R1may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, -CN, -OH, -SH, and -NH2, -COOH, or a -Q-M group 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, deuterium, sulfuropentafluoride, halogen, OCH3, carboxyl, OH, CN, and NR d8 R d9Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may 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 atoms on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group are optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 Substitution of cycloalkyl groups;

[0018] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 C1-6 alkyl and C 1-6 alkoxy is optionally further substituted with 1 to 3 groups selected from hydrogen, deuterium, a sulfur pentafluoride group, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and a saturated or partially saturated C 3-6 cycloalkyl group; wherein the hydrogen on R2is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, a sulfur pentafluoride group, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, and a saturated or partially saturated C 3-6 cycloalkyl group, and C 1-6 alkyl and C 1-6 alkoxy is optionally further substituted with 1 to 3 groups selected from hydrogen, deuterium, a sulfur pentafluoride group, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and a saturated or partially saturated C 3-6 cycloalkyl group;

[0019] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, halogen, 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 cycloalkyl, C 3-10 heterocycloalkyl, a C 3-10 cycloalkyl, or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and a C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl; any two adjacent R3together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, a sulfur pentafluoride group, 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 a saturated or partially saturated C 3-6 cycloalkyl group, and C 1-6 alkyl and C 1-6The alkoxy group is optionally surrounded by one or more groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen at R3 is optionally replaced by one to one plurality of groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0020] Q can be arbitrarily and independently selected as non-existent, single key, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-SC(R d1 (R) d2 )-、-C(R d1 (R) d2 )S-、-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)-、-N(R d4 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )N(R d4 )-, -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;

[0021] M is independently selected at random from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure can be selected at random from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure; and the hydrogen on M is optionally substituted optimally by 1 to a plurality of substituents, said substituents are preferably selected from hydrogen, deuterium, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, sulfur pentafluoride group, halogen, -CN, -OH, -SH and -NH2, -COOH or 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;

[0022] each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are selected at random and independently of each other from hydrogen, deuterium, sulfur pentafluoride group, 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 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, C3-10 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, pentafluorosulfanyl, halogen, oxo, CN, OH, and C 3-10 Saturated or partially substituted groups Saturated cycloalkyl or heterocyclyl are substituted with substituents selected from the group consisting of hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, OH, and C

[0023] The hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0024] The halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0025] m is any integer selected from 0, 1, 2, 3, and 4;

[0026] n is any integer selected from 0, 1, 2, 3, 4, and 5;

[0027] t is any integer selected from 0, 1, 2, 3, 4, and 5;

[0028] p is any integer selected from 0, 1, 2, 3, and 4;

[0029] q is any integer selected from 0, 1, 2, 3, and 4.

[0030] 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),

[0031] wherein,

[0032] A is any independently selected monocyclic or polycyclic structure of 3 to 18 carbon atoms, which 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 spirocyclic ring, or a bridged ring structure;

[0033] L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NRd5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -N(R d3 )C(=O)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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)-, (R d1 )(R d2 )C(=O)-, a double bond, a triple bond, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl;

[0034] Y is independently selected from O, S, or =NR0;

[0035] each R0may be the same or different, and is independently selected from hydrogen, deuterium, a sulfurium pentafluoride group, halogen, a C 1-10 alkoxy group, a C 1-10 alkylthio group, a C 1-10 alkylamino group, -CN, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, -NR d8 R d9 , a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl group, the C 2-10 alkenyl group, the C 2-10 alkynyl group, the C 1-10 alkoxy group, the 6-10 membered aryl, the 5-8 membered heteroaryl, the 3-8 membered saturated or partially saturated cycloalkyl, and the 3-8 membered saturated or partially saturated heterocyclyl is optionally substituted with 1 to multiple substituents, which are independently selected from hydrogen, deuterium, a sulfurium pentafluoride group, halogen, an alkyl group, a haloalkyl group, an alkoxy group, an alkylamino group, O=, CN, OH, -NR d1 R d2, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the hydrogens on R° are further optionally substituted with one to multiple substituents independently selected from the group consisting of hydrogen, deuterium, sulfuρentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl are optionally substituted with one to three substituents selected from the group consisting of H, deuterium, sulfuρentafluoride, halogen, haloalkyl, cyano, OCH3and OH;

[0036] each R1may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, sulfuρentafluoride, 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with one to multiple substituents selected from the group consisting of H, deuterium, sulfuρentafluoride, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; 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 heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with substituents selected from the group consisting of hydrogen, deuterium, sulfuρentafluoride, 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 C1-6 alkyl, C 3-6 alkyl, C

[0037] each R2may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, pentafluorosulfanyl, halogen, CN, OH, SH, and NH2, -COOH, C 1-10 alkyl, C 2-10 alkyl, C 2-10 alkyl, C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkyl, C 3-10 alkyl, C 3-10 alkyl, C 3-10 alkyl, C 3-10 alkyl, C 3-10 alkyl, C 3-10 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 3-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 3-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 3-6cycloalkyl, and C 1-6 alkyl, and C 1-6 alkoxy is optionally further substituted with 1 to 3 groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl, and C

[0038] each R3may be the same or different, and is independently of each other selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, CN, OH, SH, and NH2, -COOH, or from C 1-10 alkyl, and C 2-10 alkenyl, and C 2-10 alkynyl, and C 1-10 alkoxy, and C 2-10 heteroalkyl, and C 3-10 cycloalkyl, and C 3-10 heterocycloalkyl, and C 3-10 cycloalkyl, and C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and C 3-10 cycloalkyl, and C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl; 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 1-6 alkyl, and 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 is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl, and C 3-10 saturated or partially saturated cycloalkyl, or heterocycloalkyl;

[0039] Q is independently selected from absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1(R) d2 )O-、-SC(R d1 (R) d2 )-、-C(R d1 (R) d2 )S-、-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)-、-N(R d4 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )N(R d4 )-, -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;

[0040] M is arbitrarily and independently selected from a monocyclic or polycyclic structure of 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; and the hydrogen on M is optionally preferably substituted by one or more substituents, wherein the substituents are preferably selected from hydrogen, deuterium, haloalkyl, deuteralkyl, haloalkoxy, deuteralkoxy, pentafluoride sulfo, halogen, -CN, -OH, -SH and -NH2, -COOH or 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 groups;

[0041] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0042] The term "hybrid" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0043] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0044] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0045] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0046] t is an integer selected from 0, 1, 2, 3, 4, and 5.

[0047] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (IB),

[0048] wherein,

[0049] A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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; and is preferably selected from a benzene ring, a pyridine ring, a thiazole ring, an isothiazole ring, for example * is attached to L1and the other end is attached to Q;

[0050] L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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), alkenyl, alkynyl, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl;

[0051] Y is independently selected from O, S, or =NR0;

[0052] Each R0may be the same or different and is independently selected from hydrogen, deuterium, sulfuropentafluoride, halo, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-10 alkoxy, C 1-10 alkylthio, C 1-10 alkylamino, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl are optionally substituted with 1 to multiple substituents independently selected from hydrogen, deuterium, sulfuropentafluoride, halo, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogen on R0is further optionally substituted with 1 to multiple substituents independently selected from hydrogen, deuterium, sulfuropentafluoride, halo, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfuropentafluoride, halo, haloalkyl, cyano, OCH3, and OH;

[0053] Each R1may be the same or different and is independently selected from hydrogen, deuterium, sulfuropentafluoride, halo, -CN, -OH, -SH, and -NH2, -COOH, or from C 1-10 alkyl, C 2-10 alkenyl, C2-10 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 -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, sulfuropentafluoride group, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; 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 heterocyclyl, 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, sulfuropentafluoride group, 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, sulfuropentafluoride group, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0054] each R2may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride group, halogen, CN, 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 cycloalkyl acyl, C 3-10 cycloalkoxy acetyl, C 3-10 cycloalkyl sulfonyl and C 3-10 cycloalkyl sulfinyl; any two adjacent R2together 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 hydrogen, deuterium, sulfuryl pentafluoride, 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 further substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl pentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl pentafluoride, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)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, sulfuryl pentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl pentafluoride, halogen, -CN, -OH, CF3, C

[0055] each R3may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuryl pentafluoride, 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 3-10C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; any two adjacent R3s together with their attached atoms 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 alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen at R3 is optionally replaced by one to one plurality of groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0056] Each R4 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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; any two adjacent R4 atoms together with their attached atoms 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 alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 C1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1 to 5 groups selected from hydrogen, deuterium, a sulfur pentafluoride group, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, a saturated or partially saturated C 3-6 cycloalkyl or heterocyclyl group; wherein the hydrogen on R4is optionally substituted with 1 to 5 groups selected from hydrogen, deuterium, a sulfur pentafluoride group, halogen, oxo, CN, OH, and a saturated or partially saturated C 3-10 saturated or partially saturated cycloalkyl or heterocyclyl group;

[0057] Q is independently selected at each occurrence from nothing, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0058] M is independently selected at each occurrence from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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;

[0059] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0060] The term "hybrid" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0061] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0062] m is any integer selected from 1, 2, 3, and 4;

[0063] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0064] t is an integer optionally selected from 0, 1, 2, 3, 4, and 5.

[0065] p is an integer optionally selected from 0, 1, 2, 3, 4, and 5.

[0066] In an aspect of the application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (IC),

[0067] wherein,

[0068] L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl;

[0069] Y is independently selected from O, S, or =NR0;

[0070] Each R0may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, an OH group, a C 1-10 alkoxy group, a C 1-10 alkylthio group, a C 1-10 alkylamino group, -CN, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, a -NR d8 R d9 , a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with 1 to multiple substituents, which are independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, an alkylamino group, O=, CN, OH, a -NR d1 R d2 , a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10 saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group; wherein the hydrogen on R0is further optionally substituted with 1 to multiple substituents, which are independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, OH, a C 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, wherein the C 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, a sulfurium pentafluoride group, a halogen, a haloalkyl group, a cyano group, OCH3, and OH;

[0071] Each R1may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, -CN, -OH, -SH, and -NH2, -COOH, or a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, or a C 1-10 alkoxy group, a C 2-10 heteroalkyl group, a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted with C 1-10 alkyl, C 3-10 cycloalkyl substituted with C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, sulfuropentafluoride, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; 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 heterocyclyl, 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, sulfuropentafluoride, 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, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0072] each R2may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, CN, 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 3-10cycloalkylsulfinyl; any two vicinal R2together 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 hydrogen, deuterium, pentafiuorosulfuryl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or C 1-6 alkoxy, C 3-6 heteroalkyl, C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 3-6 alkyl, and C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 1-6 alkyl, and C 1-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-6 alkyl, and C 1-6 cycloalkyl, C 3-6 heterocycloalkyl, C

[0073] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, pentafiuorosulfuryl, halogen, 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 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 alkyl, and C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, C 3-10 alkyl, and C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, Cheteroalkyl; 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfuropentafluoride, 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 is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R3is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl;

[0074] each R4may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, CN, OH, SH, and NH2, -COOH, or a group 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; any two adjacent 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfuropentafluoride, 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 C1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl or heterocyclyl; wherein the hydrogen on R4is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocyclyl;

[0075] Q is optionally and independently selected from absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0076] M is optionally and independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure is optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; preferably benzene ring, pyridine ring, pyrimidine ring, thiazole ring, thiophene ring;

[0077] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0078] The term "hybrid" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0079] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

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

[0081] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0082] t is an integer optionally selected from 0, 1, 2, 3, 4, and 5.

[0083] p is an integer optionally selected from 0, 1, 2, 3, 4, and 5.

[0084] In an aspect of the application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of Formula (ID-1) or Formula (ID-2),

[0085] wherein,

[0086] L1and L2are 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-, d1 d2 d1 d2 d3 d4 d5 d6 d7 d3 d4 d1 d2 d1 d2 d4 d4 d1 d2 d1 d2 d1 d2 d1 d2 an alkene, an alkyne, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl;

[0087] Y is independently selected from O, S, or =NR0;​​​​​​​​​​​​​​​​​​​​​​​​

[0088] Each R0may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, an OH group, a C 1-10 alkoxy group, a C 1-10 alkylthio group, a C 1-10 alkylamino group, -CN, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, -NR d8 R d9 , a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with 1 to multiple substituents, which are independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, an alkylamino group, O=, CN, OH, -NR d1 R d2 , a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10 saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group; wherein the hydrogen on R0is further optionally substituted with 1 to multiple substituents, which are independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, OH, a C 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, wherein the C 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, a sulfurium pentafluoride group, a halogen, a haloalkyl group, a cyano group, OCH3, and OH;

[0089] Each R1may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, -CN, -OH, -SH, and -NH2, -COOH, or a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, or a C 1-10 alkoxy group, a C 2-10 heteroalkyl group, a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10saturated 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, sulfuropentafluoride, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; 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 heterocyclyl, 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, sulfuropentafluoride, 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, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0090] each R2may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, CN, 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 3-10cycloalkylsulfinyl; any two vicinal R2together 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 hydrogen, deuterium, pentafiuorosulfuryl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or C 1-6 alkoxy, C 3-6 heteroalkyl, C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 3-6 alkyl, and C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or C 1-6 alkoxy, C 3-6 heteroalkyl, C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 3-6 alkyl, and 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 alkyl, and C 3-10 alkyl, C 1-10 alkenyl, C 3-10 alkynyl, or C 3-10 alkoxy, C 1-10 heteroalkyl, C

[0091] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, pentafiuorosulfuryl, halogen, 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 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 alkyl, and C 3-10 alkyl, C 1-10 alkenyl, C 3-10 alkynyl, or C 3-10 alkoxy, C 1-10 heteroalkyl, C

[0091] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, pentafiuorosulfuryl, halogen, CN, OH, SH, and NH2, -COOH, or a Cheteroalkyl; 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfurium pentafluoride, 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 is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfurium pentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R3is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfurium pentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl;

[0092] Each R4may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, sulfurium pentafluoride, halogen, CN, OH, SH, and NH2, -COOH or a group 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; any two adjacent 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfurium pentafluoride, 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 C1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl or heterocyclyl; wherein the hydrogen on R4is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocyclyl;

[0093] Q is optionally and independently selected from absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0094] M is optionally and independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure is optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; preferably benzene ring, pyridine ring, pyrimidine ring, thiazole ring, thiophene ring;

[0095] each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 several substituents selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a halogen, an oxo group, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0096] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0097] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0098] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0099] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0100] p is an integer selected from 0, 1, 2, 3, 4, and 5.

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

[0102] wherein,

[0103] A and B independently represent a single or double bond;

[0104] A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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;

[0105] L1and L2are independently selected from the absence, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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 ), alkenyl, alkynyl, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl;

[0106] Y is independently selected from O, S, or =NR0;

[0107] Each R0may be the same or different and is independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, halo, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-10 alkoxy, C 1-10 alkylthio, C 1-10 alkylamino, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl are optionally substituted with 1 to multiple substituents independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, halo, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C d1 R d2 , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogen on R0is further optionally substituted with 1 to multiple substituents independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, halo, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfuriyl pentafluoride, halo, haloalkyl, cyano, OCH3, and OH;

[0108] X1, X2, and X3are independently selected from -O-, -S-, =N-, =CH-, -N(R d7 )-, -C(R d1 )(R d2)-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )O-;

[0109] each R1may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride group, 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with up to a plurality of substituents selected from the group consisting of H, deuterium, sulfuropentafluoride group, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together 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, heterocycloalkyl are optionally substituted with up to a plurality of groups selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride group, 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 up to a plurality of groups selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride group, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl;

[0110] each R2may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride group, halogen, CN, OH, SH and NH2, -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C1-10 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; any two adjacent R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfuryl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkyloxy, -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 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R2is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl, 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, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0111] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, sulfuryl, halogen, CN, OH, SH, and NH2, -COOH, or a group 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 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; any two adjacent R3s together with their attached atoms 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 alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen at R3 is optionally replaced by one to one plurality of groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0112] Q can be arbitrarily and independently selected as non-existent, single key, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-SC(R d1 (R) d2 )-、-C(R d1 (R) d2 )S-、-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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0113] M is optionally independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; and the hydrogens on M are optionally substituted, optimally by 1 to multiple substituents, said substituents are preferably selected from hydrogen, deuterium, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, sulfur pentafluoride, halogen, -CN, -OH, -SH and -NH2, -COOH or 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;

[0114] each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, and are each independently selected from hydrogen, deuterium, sulfur pentafluoride, halogen, CN, OH, SH and NH2, -COOH, 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; 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, pentafluorosulfanyl, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted group saturated cycloalkyl or heterocyclyl is substituted by;

[0115] the hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0116] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0117] m is any integer selected from 0, 1, 2, 3 and 4;

[0118] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0119] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0120] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted or isomer thereof, has a structure of formula (IF-1) to (IF-4),

[0121] wherein,

[0122] any independently represents a single or double bond;

[0123] L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl;

[0124] Y is independently selected from O, S, or =NR0;

[0125] each R0may be the same or different and is independently selected from hydrogen, deuterium, a sulfur pentafluoride group, a C 1-10 alkoxy group, a C 1-10 alkylthio group, a C 1-10 alkylamino group, -CN, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, -NR d8R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from H, deuterium, sulfuriyl pentafluoride, halogen, alkyl, haloalkyl, cyano, OCH3, and OH; d1 R d2 , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogen on R0is further optionally substituted with 1 to 3 substituents independently selected from H, deuterium, sulfuriyl pentafluoride, halogen, alkyl, haloalkyl, cyano, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from H, deuterium, sulfuriyl pentafluoride, halogen, haloalkyl, cyano, OCH3, and OH;

[0126] X1, X2, and X3are independently selected from -O-, -S-, =N-, =CH-, -N(R d7 )-, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, or -C(R d1 )(R d2 )O-;

[0127] X4and X5are independently selected from N or CR1;

[0128] each R1may be the same or different, and is independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, 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 3-10saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 2-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C d8 saturated or partially saturated heterocycloalkyl, C d9 saturated or partially saturated heterocycloalkyl, C 1-6 saturated or partially saturated heterocycloalkyl, C 1-6 saturated or partially saturated heterocycloalkyl, C 1-6 saturated or partially saturated heterocycloalkyl, C 1-6 saturated or partially saturated heterocycloalkyl, C 3-6 saturated or partially saturated heterocycloalkyl, C 1-6 saturated or partially saturated heterocycloalkyl, C 1-6 saturated or partially saturated heterocycloalkyl, C 3-6 saturated or partially saturated heterocycloalkyl, C

[0129] saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 2-10 saturated or partially saturated heterocycloalkyl, C 2-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 1-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C3-10 cycloalkylsulfinyl; any two vicinal R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or C 1-6 alkoxy, C 3-6 heteroalkyl, C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 3-6 substituted with 1 to 2 groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or C 1-6 alkoxy, C 3-6 heteroalkyl, C 1-6 cycloalkyl, C 1-6 heterocycloalkyl, C 3-6 substituted with 1 to 2 groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C

[0130] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, pentafluorosulfanyl, halogen, 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 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 substituted with 1 to 2 groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 3-10 alkyl, and C 1-10 substituted with 1 to 2 groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 3-10 alkyl, C 3-10 alkenyl, C 1-10heteroalkyl; 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfuρentafluoride, 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 is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuρentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R3is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuρentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl;

[0131] Each R4may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, sulfuρentafluoride, halogen, CN, OH, SH, and NH2, -COOH or a group 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; any two adjacent 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfuρentafluoride, 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 C1-6 alkoxy is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl or heterocyclyl; wherein the hydrogen on R4is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocyclyl;

[0132] Q is optionally and independently selected from absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0133] M is optionally and independently selected from monocyclic or polycyclic structure of 3 to 18 carbon atoms, said monocyclic or polycyclic structure is optionally selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, fused ring, spiro ring or bridged ring structure; preferably benzene ring, pyridine ring, pyrimidine ring, thiazole ring, thiophene ring;

[0134] each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo group, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl;

[0135] said hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0136] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0137] m is any integer selected from 1, 2, 3 and 4;

[0138] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0139] t is an integer optionally selected from 0, 1, 2, 3, 4, and 5;

[0140] p is an integer optionally selected from 0, 1, 2, 3, 4, and 5.

[0141] In one aspect of the present disclosure, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has a structure of Formula (IG-1) to (IG-5),

[0142] wherein,

[0143] represents, independently, a single bond or a double bond;

[0144] L1and L2are 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-, d1 d2 d1 d2 d3 d4 d5 d6 d7 d3 d4 d1 d2 d1 d2 d4 d4 d1 d2 d1 d2 d1 d2 d1 d2 ​​​​​​​​​​​​​​​​​​​​​​​​), alkenyl, alkynyl, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl;

[0145] X is independently selected from CR1or N;

[0146] Y is independently selected from O, S, or =NR0;

[0147] Each R0may be the same or different and is independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, halo, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-10 alkoxy, C 1-10 alkylthio, C 1-10 alkylamino, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, halo, alkyl, haloalkyl, cyano, OCH3, and OH; d1 R d2 , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogen on R0is further optionally substituted with 1 to 3 substituents independently selected from hydrogen, deuterium, sulfuriyl pentafluoride, halo, alkyl, haloalkyl, cyano, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfuriyl pentafluoride, halo, haloalkyl, cyano, OCH3, and OH;

[0148] X1and X2are independently selected from -O-, -S-, =N-, NR d7 , =CH-, -C(R d1(R) d2 )-、-OC(R d1 (R) d2 - or -C(R) d1 (R) d2 )O-;

[0149] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, pentafluoride sulfide, 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 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 or -QM group; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, sulfonium pentafluoride, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may 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 atoms on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group are optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 Cycloalkyl group substitution;

[0150] Each R2 may be the same or different, and is independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C2-10 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; any two adjacent R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, sulfuryl, 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, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R2is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl, 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, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuryl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0151] each R3may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuryl, halogen, CN, OH, SH, and NH2, -COOH or is selected from the group consisting of 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, 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; 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from hydrogen, deuterium, sulfuropentafluoride, 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, sulfuropentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, sulfuropentafluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl;

[0152] each R4may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, CN, OH, SH, and NH2, -COOH or a group 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 1-10heteroaryl, 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 1 to 3 groups selected from hydrogen, deuterium, thiofluoride, 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 are optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, thiofluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, thiofluoride, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl;

[0153] Q is optionally and independently selected from absent, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0154] M can be arbitrarily and independently selected from monocyclic or polycyclic structures with 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; preferably benzene rings, pyridine rings, pyrimidine rings, thiazole rings or thiophene rings;

[0155] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, oxo, CN, OH and C. 3-10saturated or partially substituted group saturated cycloalkyl or heterocyclyl is substituted by substituents;

[0156] said hetero represents any independently selected from O, N, S, P and isotopes thereof;

[0157] said halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0158] m is any integer selected from 0, 1, 2, 3, 4 and 5;

[0159] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0160] s is any integer selected from 0, 1, 2, 3, 4 and 5;

[0161] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0162] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0163] In one aspect of the present application, the compound or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, has the structure of formula (IH-1) to (IH-6),

[0164] wherein,

[0165] any independently represents a single or double bond;

[0166] L1and L2are independently selected from absent, a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2)-、-C(R d1 (R) d2 )N(R d4 )-, -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, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0167] Y is independently selected from O, S, or =NR0;

[0168] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl, wherein said C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl, optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, SF5, halogen, haloalkyl, cyano, OCH3and OH;

[0169] X is independently selected from CR1or N;

[0170] X2is independently selected from -O-, -S-, NR d7 or -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )O-;

[0171] each R1may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, SF5, 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, SF5, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; 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 heterocyclyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with 1 to 3 substituents selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -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 one to more groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl substituted;

[0172] each R2may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, pentafluorosulfanyl, halogen, CN, 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; any two adjacent R2together 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, heterocycloalkyl is optionally substituted with one to more groups selected from hydrogen, deuterium, pentafluorosulfanyl, 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 one to more groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl substituted; wherein the hydrogen on R2is optionally substituted with one to more groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl, -N(C 3-6 alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl, -N(C 3-6 alkyl, -N(C 1-10 alkyl, -N(C 2-10 alkyl, -N(C 2-10 alkyl, -N(C 1-10 alkyl, -N(C 2-10 alkyl, -N(C 3-10 alkyl, -N(C 3-10 alkyl, -N(C 3-10 alkyl, -N(C 3-10 alkyl, -N(C 1-10 alkyl, -N(C 3-10 alkyl, -N(C 3-10 alkyl, -N(C 1-10 alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl, -N(C 3-6 alkyl, -N(C 1-6 alkyl, -N(C 1-6 alkyl, -N(C 3-6 alkyl, -N(C 3-10 alkyl, -N(C alkyl, -N(C

[0173] alkyl, -N(C alkyl, -N(C

[0174] alkyl, -N(CEach R4may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a group selected from hydrogen, deuterium, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl;

[0175] Q is 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NRd5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-、-N(R d4 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )N(R d4 )-, -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;

[0176] M can be any independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; preferably benzene rings, pyridine rings, pyrimidine rings, thiazole rings or thiophene rings;

[0177] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 3-10heteroalkyl, 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 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, sulfuryl, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted by substituents;

[0178] the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0179] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0180] m is any integer selected from 0, 1, 2, 3, 4 and 5;

[0181] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0182] s is any integer selected from 0, 1, 2, 3, 4 and 5;

[0183] t is any integer selected from 0, 1, 2, 3, 4 and 5;

[0184] p is any integer selected from 0, 1, 2, 3 or 4.

[0185] In one aspect of the present application, the compound or its pharmaceutically acceptable salt, isotope substitute or isomer thereof, has a structure of formula (II-1)~(II-10),

[0186] wherein,

[0187] any independently represents a single bond or a double bond;

[0188] L1and L2are 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-、-SC(R d1 (R) d2 )-、-C(R d1 (R) d2 )S-、-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)-、-N(R d4 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )N(R d4 )-, -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, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0189] X is independently selected from CR1 or N;

[0190] Y is independently selected from O, S, or =NR0;

[0191] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, -NR d1 R d2 , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclyl, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogens on R° are further optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, -NR 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl are optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, sulfuropentafluoride, halogen, haloalkyl, cyano, OCH3, and OH;

[0192] X2is independently selected from the group consisting of -O-, -S-, NR d7 or -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, or -C(R d1 )(R d2 )O-;

[0193] each R1may be the same or different, and is independently selected from the group consisting of hydrogen, deuterium, sulfuropentafluoride, 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 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, C1-10 Alkyl-substituted carboxyl or -QM group; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, sulfonium pentafluoride, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may 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 atoms on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group are optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 Substitution of cycloalkyl groups;

[0194] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 further substituted with 1 to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R2are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)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, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl;

[0195] each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, pentafluorosulfanyl, 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, saturated or partially saturated C 3-10 cycloalkyl, or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, and saturated or partially saturated C 3-10 cycloalkyl, C 3-10 heterocycloalkyl substituted C 1-10 heteroalkyl; any two adjacent R3together 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, heterocycloalkyl are optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6alkyl, C 3-6 cycloalkyl, and C 1-6 alkyl, and C 1-6 alkoxy is optionally substituted with one to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with one to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocyclyl;

[0196] Each R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, pentafluorosulfanyl, halogen, CN, OH, SH, and NH2, -COOH, or a group 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, a group selected from C 3-10 cycloalkyl, or C 3-10 heterocycloalkyl, C 1-10 alkyl, and a group selected from C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 heteroalkyl; any two adjacent 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, heterocycloalkyl are optionally substituted with one to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, 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 is optionally substituted with one to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with one to multiple groups selected from hydrogen, deuterium, pentafluorosulfanyl, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocyclyl;

[0197] Q is 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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;

[0198] M 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; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring;

[0199] each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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 optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl are substituted with;

[0200] the hetero represents any independently selected heteroatom from O, N, S, P and isotopes thereof;

[0201] the halogen is any independently selected from F, Cl, Br, I and isotopes thereof;

[0202] m is any integer selected from 0, 1, 2 and 3;

[0203] n is any integer selected from 0, 1, 2, 3, 4 and 5;

[0204] s is any integer selected from 0, 1, 2, 3, 4 and 5;

[0205] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0206] p is any integer selected from 0, 1, 2, 3 or 4.

[0207] In an aspect of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a corresponding isomer, isotopically substituted compound thereof, wherein L1and L2are preferably selected from a single bond, -C(R d1 )(R d2 )-, -N(R d7 )-, -O-, -S-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-;

[0208] In an aspect of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a corresponding isomer, isotopically substituted compound thereof, wherein X2is preferably selected from O, S or NR d7 ;

[0209] In an aspect of the present application, is preferably selected from

[0210] In an aspect of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a corresponding isomer, isotopically substituted compound thereof, has a structure represented by Formula (III),

[0211] wherein ring A is selected from a 5-10 membered heteroaryl;

[0212] R1is selected from C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 6-10 aryl, C 3-10 cycloalkyl-C 1- 10 alkyl, 5-10 membered heteroaryl-C 1-10 alkyl, 3-10 membered heterocyclyl-C 1-10 alkyl, C 6-10 aryl-C 1-10 alkyl;

[0213] ring B is selected from a 5-10 membered heterocyclyl, 5-10 membered heteroaryl;

[0214] R2is selected from H, halogen, C 1-10 alkyl, C 1-10 alkoxy;

[0215] L2is selected from NH, O, CH2;

[0216] m is selected from 0, 1, 2, 3, 4 or 5.

[0217] n is selected from 0, 1, 2, 3, 4, or 5.

[0218] According to embodiments of the present application, ring A is selected from 5-6 membered heteroaryl;

[0219] According to embodiments of the present application, ring A is selected from pyridyl, thiazolyl;

[0220] According to embodiments of the present application, ring A is selected from

[0221] According to embodiments of the present application, R1is selected from C 6-10 aryl-C 1-6 alkyl;

[0222] According to embodiments of the present application, R1is selected from benzyl.

[0223] According to embodiments of the present application, is selected from

[0224] According to embodiments of the present application, is selected from

[0225] According to embodiments of the present application, ring B is selected from 9-10 membered heterocyclyl, 9-10 membered heteroaryl;

[0226] According to embodiments of the present application, ring B is selected from phenyl;

[0227] According to embodiments of the present application, ring B is selected from is connected to .

[0228] According to embodiments of the present application, R2is selected from H, halo, C 1-6 alkyl;

[0229] According to embodiments of the present application, R2is selected from H, F.

[0230] According to embodiments of the present application, is selected from is connected to .

[0231] In one aspect of the present application, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a corresponding isomer, isotopically substituted thereof, is a novel compound selected from the structures disclosed in the examples.

[0232] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds represented by Formula (I), pharmaceutically acceptable salts, solvates, enantiomers and isotopically-substituted materials thereof.

[0233] 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.

[0234] According to an embodiment of the present application, the pharmaceutical composition is preferably administered orally.

[0235] 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.

[0236] 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, fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, humectants, pH adjusting agents, solubilizers or co-solubilizers, and osmotic pressure adjusting agents. Those skilled in the art can easily determine how to select the corresponding excipients and their amounts according to the needs of the specific dosage form.

[0237] According to an embodiment of the present application, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0238] Another object of the present application is to provide the use of the above-mentioned compounds in the preparation of a medicament for preventing and / or treating a disease related to the GRK2 signaling pathway. The disease related to the GRK2 signaling pathway includes, but is not limited to, cancer, metabolic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, nervous system diseases, and the like.

[0239] The present application also provides the use of the compounds represented by Formula (I), pharmaceutically acceptable salts, solvates, enantiomers and isotopically-substituted materials thereof, and the pharmaceutical composition in preventing and / or treating a disease related to the GRK2 signaling pathway. The disease related to the GRK2 signaling pathway has the definition described above.

[0240] The present application also provides a method for preventing and / or treating a disease related to the GRK2 signaling 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 materials thereof, or administering to a patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition. The disease related to the GRK2 signaling pathway has the definition described above.

[0241] In some embodiments, the patient mammal is preferably a human.

[0242] Technical effects

[0243] The present inventors have surprisingly found that the heterocyclic compounds with novel structure have high GRK2 target degradation ability. Further, the novel heterocyclic compounds with partial structure of formula (I) of the present application not only have significant GRK2 degradation activity, but also have good anti-mast cell proliferation effect, pharmacokinetic characteristics, bioavailability and safety characteristics, and are more suitable as candidate drugs for preventing or treating diseases related to the GRK2 target or signaling pathway.

[0244] Definitions and explanations:

[0245] 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 ;

[0246] 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 referred to 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 a straight-chain and branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Said alkyl group is, 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.

[0247] The term "monocyclic or polycyclic structure of 3 to 18 carbon atoms" 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 structures can be selected from 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 structures can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annelated ring, spirocyclic ring or bridged ring structures; wherein aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, annelated ring, spirocyclic ring or bridged ring are defined below.

[0248] The term "alkenyl" is to be understood as meaning a straight-chain or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C 2-10 alkenyl". "C 2-10 The term "alkenyl" is to be understood as preferably meaning a straight-chain or branched hydrocarbon group containing one or more double bonds and having 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 preferably meaning a straight-chain or branched hydrocarbon group containing one or more double bonds and having 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.

[0249] 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.

[0250] 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 remainder of the molecule, e.g., as an alkoxy, alkylthio, alkylamino, ether group. Examples of heteroalkyl groups 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.

[0251] The term "1 to multiple" as used herein means 1 or more, e.g., 1, 2, 3, 4, 5 or more.

[0252] 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. 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 decalinyl or isobornyl.

[0253] 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" (or 6-14 membered aryl)". The term "C 6-14"Aryl (or 6-14 membered aryl)" is understood to mean preferably an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl (or 6 membered aryl)", for example phenyl; or a biphenyl group, or a ring having 9 carbon atoms ("C9 aryl (or 9 membered aryl)", for example indanyl or indenyl, or a ring having 10 carbon atoms ("C10 aryl (or 10 membered aryl)", for example tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C13 aryl (or 13 membered aryl)", for example fluorenyl, or a ring having 14 carbon atoms ("C14 aryl (or 14 membered aryl)", for example anthryl. When the aryl group is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, for example ortho, para or meta substitution. 10 13 14 The term "spiro ring" means a ring system in which two rings share 1 ring-forming atom, which can contain an aliphatic, heterocyclic, aromatic or heteroaromatic ring as described previously.

[0254] The term "fused ring" means a ring system in which two rings share 2 ring-forming atoms, which can contain an aliphatic, heterocyclic, aromatic or heteroaromatic ring as described previously.

[0255] The term "bridged ring" means a ring system in which two rings share 3 or more ring-forming atoms, which can contain an aliphatic, heterocyclic, aromatic or heteroaromatic ring as described previously.

[0256] The term "bridged ring" means a ring system in which two rings share 3 or more ring-forming atoms, which can contain an aliphatic, heterocyclic, aromatic or heteroaromatic ring as described previously.

[0257] ​​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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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 either a wedge or a dashed wedge. 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.

[0272] 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

[0273] 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 typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] The term "halo" or "halogen" means fluorine, chlorine, bromine, and iodine.

[0279] The present application is now further described by the examples. The examples given below are for illustrative purposes only and are not intended 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, or by modifications thereof. Preferred methods include, but are not limited to, the methods described below.

[0280] Unless otherwise indicated, 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 using 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.

[0281] 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-methyl pyrrolidinone; 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.

[0282] The compounds can be named manually or using ChemDraw® If commercially purchased, the catalog name of the supplier can be used. TLC or LC-MS is generally used to determine whether the reaction is completed. DETAILED DESCRIPTION

[0283] 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.

[0284] Example 1, Synthesis of (5-benzylpyridin-2-yl)carbamic acid 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl ester (Compound 1):

[0285] 1. Synthesis of 5-fluoro-7-nitro-2,3-dihydrobenzofuran

[0286] Dissolve 5-fluoro-2,3-dihydrobenzofuran (9 g, 65.15 mmol) in nitric acid (80 mL) solution, stir at -10 °C for 0.5 h. Then quench with water (125 mL) dropwise at -10 °C, and extract with ethyl acetate (3 x 100 mL). Dry the combined organic phase over anhydrous Na2S04, filter, and concentrate under reduced pressure to give 5-fluoro-7-nitro-2,3-dihydrobenzofuran (11.9 g, 65.03 mmol, yield: 99.8%).

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 7.71-7.68 (m, 1H), 7.63-7.61 (m, 1H), 4.81 (t, J = 8.0 Hz, 2H), 3.32-3.30 (m, 2H).

[0288] 2. Synthesis of 5-fluoro-2,3-dihydrobenzofuran-7-amine

[0289] To a solution of 5-fluoro-2,3-dihydrobenzofuran (11.9 g, 65.03 mmol) in ethyl acetate (100 mL), add Pd, C (15.3 g, 10% content), stir at 25 °C under hydrogen atmosphere for 12 h. Filter the mixture reaction solution, collect the filtrate and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent PE:EA = 0%~50%, Rf=0.5) to give 5-fluoro-2,3-dihydrobenzofuran-7-amine (7.5 g, 49.02 mmol, yield: 75.4%). f

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 6.24-6.20 (m, 2H), 4.90 (s, 2H), 4.47 (t, J = 8.0 Hz, 2H), 3.09 (t, J = 8.0 Hz, 2H).

[0291] 3. Synthesis of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine

[0292] ​To a solution of 5-fluoro-2,3-dihydrobenzofuran-7-amine (0.3 g, 1.959 mmol) in DMF (30 mL) was added NBS (0.27 g, 1.567 mmol) at 0 °C under nitrogen protection. The mixture was stirred at 0 °C for 1 h under nitrogen protection. The reaction was quenched by water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE:EA = 0%~50%) to give 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (347 mg, 1.496 mmol, yield: 76.3%).

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 6.40 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H), 4.55 (t, J = 8.0 Hz, 2H), 3.13 (t, J = 8.0 Hz, 2H).

[0294] 4. Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7- amine

[0295] To a solution of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (2.5 g, 10.78 mmol) in a mixture of 1,4-dioxane (102 mL) and water (17 mL) was added 2,6-bisbenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.4 g, 12.93 mmol), Pd(dppf)Cl2(0.78 g, 1.078 mmol) and Na2CO3(3.43 g, 32.33 mmol) under nitrogen protection. The mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature, quenched by water (130 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried, filtered and concentrated to dryness. The crude compound was purified by normal phase column chromatography (eluent: PE:EA = 0%~50%) to give 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol, yield: 84.8%) as a yellow solid, LCMS m / z: 443 [M+H] + .

[0296] 5. Synthesis of 2,6-bis(benzyloxy)-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine

[0297] To a mixture solution of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3- dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol) in MeCN (10 mL), HCl (12 M, 2 M) and water (10 mL) was added a solution of NaNO2(820 mg, 11.88 mmol) in water (2 mL) at 0 °C under nitrogen protection. The mixture was stirred at 0 °C for 1 h. Then a solution of KI (3.03 g, 18.28 mmol) in water (5 mL) was added dropwise to the above mixture solution. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent PE:EA = 0%~30%) to give 2,6-bis(benzyloxy)-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (3.4 g, 6.15 mmol, yield: 67.3%), LCMS m / z: 554 [M+H] + .

[0298] 6. Synthesis of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7- yl)azetidin-3-ol

[0299] To a solution of 2,6-bis(benzyloxy)-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (400 mg, 0.723 mmol) in tert-butanol (30 mL) was added azetidin-3-ol (264 mg, 3.614 mmol), K3PO4(1.074 g, 5.061 mmol), Brettphos Pd G3 (66 mg, 0.0723 mmol) under nitrogen protection. The mixture was stirred at 110 °C for 16 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 2:1, 254 nm) to give 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-ol (215 mg, 0.431 mmol, yield: 59.6%), LCMS m / z: 499 [M+H] + .

[0300] 7. Synthesis of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine- 2,6-dione

[0301] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3- dihydrobenzofuran-7-yl)azetidin-3-ol (230 mg, 0.461 mmol) in ethyl acetate (60 mL) was added Pd / C (491 mg) and Pd(OH)2(647 mg, 0.461 mmol) and stirred under hydrogen atmosphere at 25 °C for 1.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3- dihydrobenzofuran-4-yl)piperidine-2,6-dione (103 mg, 0.322 mmol, yield: 69.8%) LCMS m / z: 321 [M+H] + .

[0302] 8. Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-benzylpyridin-2-yl)carbamate

[0303] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4- yl)piperidine-2,6-dione (104 mg, 0.325 mmol) in 1,4-dioxane (20 mL) was added phenyl (5-benzylpyridin-2-yl)carbamate (98.8 mg, 0.325 mmol) and DMAP (48 mg, 0.39 mmol) and stirred at 90 °C for 2 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 5:1, 254 nm) to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-benzylpyridin-2-yl)carbamate (86.6 mg, 0.163 mmol, yield: 50.0%) LCMS m / z: 531 [M+H] + .

[0304] Example 2, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (5-benzylthiazol-2-yl)carbamate (Compound 2):

[0305] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)benzofuran-4-yl)piperidine-2,6-dione (100 mg, 0.31 mmol, 1.0 eq) in 1,4-dioxane (4 mL) was added phenyl (5-benzylthiazol-2-yl)carbamate (192 mg, 0.62 mmol, 2.0 eq) and DMAP (45 mg, 0.37 mmol, 1.2 eq) at room temperature, and the mixture was stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM:MeOH = 10:1 (30 mL) and filtered. The filter cake was collected and dried under vacuum to give the crude product. The crude product was purified by preparative high performance liquid chromatography (Waters 3767 / QDA, column: XBridge C18, 19*250mm, 10um; mobile phase A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 70%~75%; retention time: 15.2 min, total 19 min) to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (5-benzylthiazol-2-yl)carbamate (5.27 mg, 0.0098 mmol, yield: 3.16%), LCMS m / z: 535.5 [M+H] + .

[0306] 1 H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 10.86 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.35-7.19 (m, 5H), 7.14 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 12.4 Hz, 1H), 5.35-5.26 (m, 1H), 4.45-4.36 (m, 2H), 4.20 (dd, J = 12.8, 4.8 Hz, 1H), 4.05 (s, 2H), 4.03-3.97 (m, 2H), 2.83-2.72 (m, 1H), 2.56-2.54 (m, 1H), 2.28-2.15 (m, 1H), 2.01-1.91 (m, 1H).

[0307] 19 F NMR (377 MHz, DMSO-d6): δ -122.92.

[0308] Synthesis of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5-benzylthiazol-2-yl)carbamate or its enantiomer (Compound 3-1 and Compound 3-2):

[0309] 1) Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5- benzylthiazol-2-yl)carbamate

[0310] To a solution of 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (200 mg, 0.68 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) was added phenyl (5-benzylthiazol-2-yl)carbamate (254 mg, 0.82 mmol, 1.2 eq.) and 4-dimethylaminopyridine (100 mg, 0.82 mmol, 1.2 eq.) at room temperature and stirred at 90 °C for 2 h. The reaction mixture was directly purified by reverse phase column (conditions: Column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-85% B in 12 min; detector: 254 nm) at 80% B, fractions containing the product were collected and concentrated under reduced pressure to give 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5-benzylthiazol-2-yl)carbamate (70 mg, 0.14 mmol, yield: 20.58%) LCMS m / z: 513.2 [M+H] + .

[0311] 2) Resolution of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5- benzylthiazol-2-yl)carbamate or its enantiomer (Compound 3-1 and Compound 3-2):

[0312] The above compound 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5- benzylthiazol-2-yl)carbamate (70 mg, 0.14 mmol) was purified by SFC (conditions: system: Waters SFC 150 Waters SFC 150; column name: REGIS (S,S) WHELK-O1; column size: 250 x 30 mm 10 pm; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0 mol / L ammonia in IPA), A:B = 45:55; wavelength: 214 nm; flow rate: 80 mL / min; column temperature: room temperature; column pressure: 100 bar; injection volume: 4.5 mL; cycle time: 6.16 min) to give two single isomers: Compound 3-1 and Compound 3-2:

[0313] Compound 3-1: Peak 1, Chiral HPLC: 1.628 min; (10.70 mg, 0.021 mmol, yield: 15.28 %), LCMS m / z: 513.2 [M+H] + .

[0314] 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.86 (s, 1H), 7.34-7.21 (m, 5H), 7.18 (s, 1H), 6.21 (d, J = 10.8 Hz, 2H), 5.30-5.25 (m, 1H), 4.22-4.18 (m, 2H), 4.06-4.02 (m, 3H), 3.83-3.80 (m, 2H), 2.82-2.73 (m, 1H), 2.48-2.45 (m, 1H), 2.12-2.02 (m, 1H), 1.96-1.92 (m, 1H).

[0315] 19 F NMR (377 MHz, DMSO-d6) δ -114.218.

[0316] Compound 3-2: Peak 2, Chiral HPLC: 2.316 min; (5.24 mg, 0.010 mmol, yield: 7.48 %), LCMS m / z: 513.2 [M+H] + .

[0317] 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.86 (s, 1H), 7.34-7.21 (m, 5H), 7.18 (s, 1H), 6.21 (d, J = 10.8 Hz, 2H), 5.30-5.25 (m, 1H), 4.22-4.18 (m, 2H), 4.06-4.02 (m, 3H), 3.83-3.80 (m, 2H), 2.82-2.73 (m, 1H), 2.48-2.45 (m, 1H), 2.12-2.02 (m, 1H), 1.96-1.92 (m, 1H).

[0318] 19 F NMR (377 MHz, DMSO-d6) δ -114.157.

[0319] Example 4, Synthesis of (R)-1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl)urea or its enantiomer (Compound 4-1 and Compound 4-2):

[0320] 1) Synthesis of phenyl (5-benzylthiazol-2-yl)carbamate

[0321] To a solution of 5-benzylthiazol-2-amine (900 mg, 4.73 mmol, 1.0 eq) in THF (20 mL) and ACN (5 mL) was added phenyl chloroformate (816 mg, 5.20 mmol, 1.1 eq) and pyridine (747 mg, 9.46 mmol, 2.0 eq) at room temperature, and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1, Rf = 0.6, 254 nm) to give phenyl (5-benzylthiazol-2-yl)carbamate (1.34 g, 4.32 mmol, yield: 91.33%), LCMS m / z: 311.1 [M+H] f . + .

[0322] 2) Synthesis of 1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl)urea

[0323] To a solution of (3-(7-(3-aminoazetidin-1-yl)-5-fluorobenzofuran-4-yl)piperidine-2,6-dione (100 mg, 0.31 mmol, 1.0 eq) in 1,4-dioxane (4 mL) was added phenyl (5-benzylthiazol-2-yl)carbamate (192 mg, 0.62 mmol, 2.0 eq) and DMAP (45 mg, 0.37 mmol, 1.2 eq) at room temperature, and stirred at 100 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved with DCM:MeOH = 10:1 (30 mL), and filtered. The filter cake was collected and dried to give 1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl)urea (150 mg, 0.28 mmol, yield: 90.32%), LCMS m / z: 534.3 [M+H] + .

[0324] 3) Synthesis of (R)-1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5- fluorobenzofuran-7-yl)azetidin-3-yl)urea or its enantiomer

[0325] The compound 1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5- fluorobenzofuran-7-yl)azetidin-3-yl)urea (150 mg, 0.28 mmol) was purified by SFC (conditions: Waters SFC 80; Column name: REGIS (S, S) WHELK-O1 Column size 250*30 mm 10 pm; Mobile phase A: Supercritical CO2; Mobile phase B: IPA:ACN = 50:50 (+0.1% 7.0 mol / l ammonia in methanol), A:B = 45:55; Wavelength: 214 nm; Flow rate: 80 mL / min Column temperature: room temperature; Column pressure: 100 bar, Injection volume: 4.5 mL; Cycle time: 7.0 min) to give two isomers: Compound 4-1 and Compound 4-2:

[0326] Compound 4-1: Chiral HPLC: 1.820 min; (38.25 mg, 0.071 mmol, yield: 25.5%), LCMS m / z: 534.4 [M+H] + .

[0327] 1 H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 10.39 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.26-7.17 (m, 4H), 7.08 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.21 (d, J = 12.8 Hz, 1H), 4.66-4.54 (m, 1H), 4.34 (t, J = 7.6 Hz, 2H), 4.20 (dd, J = 12.8, 4.8 Hz, 1H), 4.01 (s, 2H), 3.92-3.85 (m, 2H), 2.83-2.72 (m, 1H), 2.58-2.54 (m, 1H), 2.29-2.15 (m, 1H), 2.01-1.91 (m, 1H).

[0328] 19 F NMR (377 MHz, DMSO-d6): δ -123.07.

[0329] Compound 4-2: Chiral HPLC: 3.911 min; (49.08 mg, 0.092 mmol, yield: 32.72%), LCMS m / z: 534.3 [M+H] + .

[0330] 1 H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 10.39 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.26-7.17 (m, 4H), 7.08 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.21 (d, J = 12.8 Hz, 1H), 4.66-4.54 (m, 1H), 4.34 (t, J = 7.6 Hz, 2H), 4.20 (dd, J = 12.8, 4.8 Hz, 1H), 4.01 (s, 2H), 3.92-3.85 (m, 2H), 2.83-2.72 (m, 1H), 2.58-2.54 (m, 1H), 2.29-2.15 (m, 1H), 2.01-1.91 (m, 1H).

[0331] 19 F NMR (377 MHz, DMSO-d6): δ -123.07.

[0332] Example 5, Synthesis of (R)-1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)urea or its enantiomer (Compound 5-1 and Compound 5-2):

[0333] 1), Synthesis of 1-(5-benzylthiazol-2-yl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)urea

[0334] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 0.34 mmol, 1.0 eq.) in 1,4-dioxane (5 mL) was added phenyl (5-benzylthiazol-2-yl)carbamate (127 mg, 0.41 mmol, 1.2 eq.) and 4-dimethylaminopyridine (50 mg, 0.41 mmol, 1.2 eq.) at room temperature, heated to 90 °C and stirred for 2 h. The reaction mixture was directly purified by reverse phase column (conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-85% B in 12 min; detector: 254 nm). Fractions containing the product were collected at 80% B and concentrated under reduced pressure to give l-(5-benzylthiazol-2-yl)-3-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)urea (70 mg, 0.14 mmol, yield: 40.46%), LCMS m / z: 512.4 [M+H] + .

[0335] 2), (R)-l-(5-benzylthiazol-2-yl)-3-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)urea or its enantiomer (Compound 5-1 and Compound 5-2) synthesis

[0336] Compound l-(5-benzylthiazol-2-yl)-3-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)urea (70 mg, 0.14 mmol) was purified by SFC (conditions: system: Waters SFC 150 Waters SFC 150; column name: REGIS (S,S) WHELK-Ol; column size: 250 x 30 mm 10 pm: mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0 mol / L ammonia in IPA), A:B = 45:55; wavelength: 214 nm; flow rate: 80 mL / min; column temperature: room temperature; column pressure: 100 bar; injection volume: 4.5 mL; cycle time: 4.1 min) to give two single isomers: Compound 5-1 and Compound 5-2:

[0337] Compound 5-1: Peak 1: Chiral HPLC: 2.433 min; (20.79 mg, 0.04 mmol, yield: 29.70%), LCSM m / z: 512.2 [M+H] + .

[0338] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.39 (s, 1H), 7.33-7.29 (m, 2H), 7.25-7.19 (m, 4H), 7.09 (s, 1H), 6.16 (d, J = 10.8 Hz, 2H), 4.58-4.50 (m, 1H), 4.13-4.09 (m, 2H), 4.06-4.04 (m, 1H), 4.01 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.81-2.73 (m, 1H), 2.51-2.48 (m, 1H), 2.12-2.05 (m, 1H), 1.96-1.92 (m, 1H).

[0339] 19 F NMR (377 MHz, DMSO-d6) δ -114.273, -114.284, -114.335, -114.464.

[0340] Compound 5-2: Peak 2: Chiral HPLC: 3.478 min; (22.07 mg, 0.04 mmol, yield: 31.53%), LCMS m / z: 512.2 [M+H] + .

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.36 (s, 1H), 7.33-7.29 (m, 2H), 7.25-7.20 (m, 3H), 7.17-7.15 (m, 1H), 7.09 (s, 1H), 6.16 (d, J = 11.2 Hz, 2H), 4.56-4.52 (m, 1H), 4.11 (t, J = 7.6 Hz, 2H), 4.06-4.05 (m, 1H), 4.01 (s, 2H), 3.68-3.64 (m, 2H), 2.82-2.73 (m, 1H), 2.50-2.48 (m, 1H), 2.10-2.02 (m, 1H), 1.96-1.92 (m, 1H).

[0342] 19 F NMR (377 MHz, DMSO-d6) δ -114.100, -114.284, -114.324, -114.494.

[0343] Example 6, Synthesis of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7- yl)azetidin-3-yl(5-benzylpyridin-2-yl)carbamate or its enantiomer (Compound 6-1 and Compound 6-2):

[0344] 1) Synthesis of phenyl (5-benzylpyridin-2-yl)carbamate

[0345] To a solution of 5-benzylpyridin-2-amine (400 mg, 2.17 mmol, 1.0 eq) in THF (20 mL) and ACN (5 mL) was added phenyl chloroformate (374 mg, 2.38 mmol, 1.1 eq) and pyridine (342 mg, 4.34 mmol, 2.0 eq) at room temperature, and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (column: spherical C18, 20-40 um, 330 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 75% B-80% B in 25 min; detection wavelength: 254 nm) to give phenyl (5-benzylpyridin-2-yl)carbamate (250 mg, 0.82 mmol, yield: 37.89%), LCMS m / z: 305.2 [M+H] + .

[0346] 2) Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl(5- benzylpyridin-2-yl)carbamate

[0347] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)benzofuran-4-yl)piperidine-2,6- dione (200 mg, 0.62 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was added NaH (37 mg, 0.93 mmol, 1.5 eq) at 0 °C, and stirred at 0 °C for 0.5 hours. Then phenyl (5-benzylpyridin-2- yl)carbamate (377 mg, 1.24 mmol, 2.0 eq) was added, and stirred at room temperature for 3 hours. The reaction was quenched with H2O (50 mL), and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0% ~ 5%, DCM:MeOH = 10:1, Rf=0.3, 5% MeOH) to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl(5-benzylpyridin-2-yl)carbamate (100 mg, 0.19 mmol, yield: 30.65%), LCMS m / z: 573.2 [M+H] f= 0.6, 254 nm) to give 1 -(4-(2, 6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (5- benzylpyridin-2-yl)carbamate (170 mg, 0.32 mmol, yield: 51.83%), LCMS m / z: 529.2 [M+H] + .

[0348] 3), (R)-1 -(4-(2, 6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (5- benzylpyridin-2-yl)carbamate or its enantiomer (Compound 6-1 and Compound 6-2) synthesis

[0349] Compound 1 -(4-(2, 6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (5- benzylpyridin-2-yl)carbamate (170 mg, 0.32 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: REGIS (S, S) WHELK-O1 column size: 250*25 mm 10 pm; mobile phase A; supercritical CO2; mobile phase B: IPA (+0.1% 7.0 mol / l ammonia in methanol): ACN = 1 : 1; A: B = 45: 55; wavelength: 214 nm; flow rate: 80 mL / min; column temperature: room temperature; column pressure: 100 bar, injection: 4.5 mL; cycle time: 7.3 min) to give MRANK-023-G005-1 and MRANK-033-G005-2:

[0350] Compound 6-1 : Chiral HPLC: 1.304 min; (8.73 mg, 0.016 mmol, yield: 5.14%), LCMS m / z: 529.4 [M+H] + .

[0351] 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 10.32 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.25-7.16 (m, 3H), 6.92 (d, J = 3.2 Hz, 1H), 6.26 (d, J = 12.4 Hz, 1H), 5.35-5.28 (m, 1H), 4.49-4.42 (m, 2H), 4.21 (dd, J = 12.8, 6.0 Hz, 1H), 4.05-3.99 (m, 2H), 3.91 (s, 2H), 2.83-2.72 (m, 1H), 2.60-2.54 (m, 1H), 2.30-2.16 (m, 1H), 1.99-1.91 (m, 1H).

[0352] 19 F NMR (377 MHz, DMSO-d6): δ -123.01.

[0353] Compound 6-2: Chiral HPLC: 2.989 min; (11.51 mg, 0.022 mmol, yield: 6.77%), LCMS m / z: 529.4 [M+H] + .

[0354] 1 H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 10.32 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.25-7.16 (m, 3H), 6.92 (d, J = 3.2 Hz, 1H), 6.26 (d, J = 12.4 Hz, 1H), 5.35-5.28 (m, 1H), 4.49-4.42 (m, 2H), 4.21 (dd, J = 12.8, 6.0 Hz, 1H), 4.05-3.99 (m, 2H), 3.91 (s, 2H), 2.83-2.72 (m, 1H), 2.60-2.54 (m, 1H), 2.30-2.16 (m, 1H), 1.99-1.91 (m, 1H).

[0355] 19 F NMR (377 MHz, DMSO-d6): δ -123.01.

[0356] Example 7, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5-benzylpyridin-2-yl)carbamate (Compound 7)

[0357] To a solution of phenyl (5-benzylpyridin-2-yl)carbamate (180 mg, 0.59 mmol, 1.0 eq.) and 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (175 mg, 0.59 mmol, 1.0 eq.) in DMF (5 mL) was added NaH (60% dispersion in paraffin liquid, 35 mg, 0.88 mmol, 1.5 eq.) at 0 °C, stirred at room temperature for 2 hours, the mixture was quenched with saturated NH4Cl (10 mL), filtered, the filter cake was washed with EA (10 mL), and dried under vacuum to give the crude product (290 mg).

[0358] The crude product (70 mg, 0.13 mmol, 1.0 eq.) was heated to 50 °C in a mixture of dichloromethane (30 mL) and methanol (3 mL) for 2 hours. The mixture was filtered under reduced pressure. The filter cake was collected and dried under vacuum to give 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl (5-benzylpyridin-2-yl)carbamate (24.55 mg, 0.048 mmol, yield: 35.07%), LCMS m / z: 507.4 [M+H] + .

[0359] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.33 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 - 7.55 (m, 1H), 7.38 - 7.09 (m, 5H), 6.22 (d, J = 11.2 Hz, 2H), 5.32 - 5.21 (m, 1H), 4.25 - 4.15 (m, 2H), 4.10 - 4.00 (m, 1H), 3.91 (s, 2H), 3.85 - 3.76 (m, 2H), 2.84 - 2.71 (m, 1H), 2.49 - 2.37 (m, 1H), 2.17 - 1.89 (m, 2H).

[0360] 19 F NMR (377 MHz, DMSO-d6) δ -114.159

[0361] Example 8, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azetidin-3-yl (4-benzylthiazol-2-yl)carbamate (Compound 8):

[0362] 1) Preparation of 4-benzylthiazol-2-amine

[0363] To a solution of (3-chloroprop-2-yn-1-yl)benzene (2.5 g, 16.66 mmol, 1.0 eq.) in DMF (30 mL) was added thiourea (1.26 g, 16.6 mmol, 1.0 eq.), K2CO3(4.6 g, 33.32 mmol, 2.0 eq.). Then the mixture was stirred at 110 °C for 3 h. The mixture was quenched with aqueous ammonium chloride solution, extracted with EA (100 mL x 3). The organic phases were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EA = 3 / 1) to give the product 4-benzylthiazol-2-amine (1.4 g, 7.36 mmol, 44.30% yield) as a white solid. LCMS m / z = 191.1 [M+H] +

[0364] 2) Preparation of phenyl (4-benzylthiazol-2-yl)carbamate

[0365] To a solution of 4-benzylthiazol-2-amine (1.4 g, 7.36 mmol, 1.0 eq.) in THF / ACN (20 mL / 20 mL) was added chloroformate phenyl (1.37 g, 8.83 mmol, 1.2 eq.), pyridine (1.67 g, 22.08 mmol, 3.0 eq.). Then the mixture was stirred at room temperature for 3 h. The mixture was quenched with aqueous ammonium chloride solution, extracted with EA (100 mL x 3). The organic phases were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EA = 5 / 1) to give phenyl (4-benzylthiazol-2-yl)carbamate (2.1 g, 6.77 mmol, 92.10% yield). LCMS m / z = 311.1 [M+H] +

[0366] 3) Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azetidin-3-yl (4-benzylthiazol-2-yl)carbamate

[0367] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-1H-indol-4-yl)piperidine- 2,6-dione (200 mg, 0.63 mmol, 1.0 eq.) in dioxane (10 mL) was added phenyl (4- benzylthiazol-2-yl)carbamate (489 mg, 1.57 mmol, 2.5 eq.) DMAP (154 mg, 1.26 mmol, 2.0 eq.) at room temperature and the mixture was stirred at 100 °C for 3 h. Concentrated. The residue was purified by reverse phase column with the following conditions (column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-100% B, 15 min; detector: 254 nm). Fractions containing the desired product were collected at 70% B and concentrated under reduced pressure to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azetidin-3-yl (4- benzylthiazol-2-yl)carbamate (189.07 mg, 0.354 mmol, 56.27% yield). LCMS M / Z = 534.2 [M+H] +

[0368] 1 H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 10.78 (s, 1H), 7.33-7.20 (m, 6H), 6.87 (s, 1H), 6.34-6.24 (m, 2H), 5.93 (s, 1H), 5.09-4.98 (m, 1H), 4.33 (t, J = 9.6 Hz, 1H), 4.18-4.11 (m, 1H), 3.98-3.89 (m, 3H), 3.70-3.57 (m, 2H), 2.83-2.72 (m, 1H), 2.59-2.52 (m, 1H), 2.30-2.16 (m, 1H), 2.01-1.91 (m, 1H).

[0369] 19F NMR (377 MHz, DMSO-d6): δ -126.609

[0370] Example 9, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (4-benzylthiazol-2-yl)carbamate (Compound 9):

[0371] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)benzofuran-4-yl)piperidine- 2,6-dione (240 mg, 0.75 mmol, 1.0 eq.) in dioxane (10 mL) was added phenyl (4- benzylthiazol-2-yl)carbamate (581 mg, 1.87 mmol, 2.5 eq.) DMAP (183 mg, 1.50 mmol, 2.0 eq.) at room temperature and the mixture was stirred at 100 °C for 3 h. Concentrated, the residue was purified by reverse phase column with the following conditions (column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-100% B, 15 min; detector: 254 nm). Fractions containing the desired product were collected at 70% B and concentrated under reduced pressure to give white solid product 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl (4- benzylthiazol-2-yl)carbamate (156.61 mg, 0.293 mmol, yield 38.86%). LCMS M / Z = 535.2 [M+H] +

[0372] 1 H NMR (400 MHz, DMSO-d6): δ 11.93 (s, 1H), 10.87 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.34-7.17 (m, 5H), 6.92 (d, J = 2.0 Hz, 1H), 6.79 (s, 1H), 6.26 (d, J = 12.4 Hz, 1H), 5.35 (s, 1H), 4.50-4.39 (m, 2H), 4.26-4.18 (m, 1H), 4.02 (d, J = 5.2 Hz, 2H), 3.91 (s, 2H), 2.87-2.68 (m, 1H), 2.60-2.53 (m, 1H), 2.37-2.16 (m, 1H), 2.02-1.90 (m, 1H).

[0373] 19F NMR (377 MHz, DMSO-d6): δ -122.896

[0374] Example 10, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azetidin-3- yl (5-benzylpyridin-2-yl)carbamate (Compound 10):

[0375] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-1H-indol-4-yl)piperidine- 2,6-dione (150 mg, 0.47 mmol, 1.0 eq.) in dioxane (10 mL) was added phenyl (5- benzylpyridin-2-yl)carbamate (216 mg, 0.71 mmol, 1.5 eq.) and 4-dimethylaminopyridine (87 mg, 0.71 mmol, 1.5 eq.) at room temperature, then the mixture was stirred at 90 °C for 2 h. The reaction mixture was directly purified by reverse phase column with the following conditions (column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-75% B in 12 min; detector: 254 nm). Fractions containing the desired product were collected at 70% B and concentrated under reduced pressure to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azetidin-3-yl (5- benzylpyridin-2-yl)carbamate (227.80 mg, 0.43 mmol, yield: 91.49%). LCMS: m / z = 528.4 [M+H] + .

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.66 (s, 1H), 10.38 (s, 1H), 7.74-7.72 (m, 1H), 7.65-7.62 (m, 1H), 7.32-7.18 (m, 7H), 6.39 (s, 1H), 6.08 (d, J = 12.4 Hz, 1H), 5.29 (t, J = 4.4 Hz, 1H), 4.44 (t, J = 7.6 Hz, 2H), 4.21-4.17 (m, 1H), 4.00-3.98 (m, 2H), 3.91 (s, 2H), 2.82-2.74 (m, 1H), 2.53-2.52 (m, 1H), 2.24-2.20 (m, 1H), 1.98-1.94 (m, 1H).

[0377] 19 F NMR (377 MHz, DMSO-d6) δ -127.114.

[0378] Example 11, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azetidin- 3-yl (5-benzylthiazol-2-yl)carbamate (Compound 11):

[0379] At room temperature, (5-benzylthiazolyl)carbamate (490 mg, 1.58 mmol, 2.0 eq.) and 4-dimethylaminopyridine (145 mg, 1.19 mmol, 1.5 eq.) were added to a solution of dioxane (10 mL) containing 3-(5-fluoro-7-(3-hydroxyazyrazo-1-yl)-1H-indol-4-yl)piperidine-2,6-dione (250 mg, 0.79 mmol, 1.0 eq.). The mixture was then stirred at 90 °C for 2 hours. The reaction mixture was purified directly by reverse-phase column chromatography under the following conditions: column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-75% B, over 12 min; detector: 254 nm). The fraction containing the desired product was collected at 70% B and concentrated under reduced pressure to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indol-7-yl)azacyclobutane-3-yl(5-benzylthiazo-2-yl)carbamate (234.2 mg, mixture). LCMS: m / z = 534.4 [M+H] + .

[0380] Example 12, Synthesis of the following compound:

[0381] Following similar steps to the synthesis of compounds in Examples 1-11, the following compounds can be obtained:

[0382] Table A

[0383] Table B

[0384] Test Example 1, Detection of the Degradation Activity of the Test Substance Target Protein

[0385] In this test, a pulmonary arterial hypertension cell model was established in human pulmonary arterial smooth muscle cells (HPASMC) by hypoxia induction, and the expression level of GRK2 protein was detected by Western Blot method. The degradation activity of the inventive compound on GRK2 protein was evaluated on this cell model.

[0386] 1. Experimental materials

[0387] The reagent consumables used in this test example are shown in Table 1-1

[0388] Table 1-1 Reagent Consumable Information

[0389] 2. Experimental method

[0390] 2-1, Compound preparation

[0391] The appropriate mass of the test compound was weighed, and the volume of DMSO required was calculated according to the formula: DMSO volume = actual amount x purity / (molecular weight x theoretical concentration), and the compound stock solution was prepared.

[0392] 2-2, Cell culture and plating

[0393] HPASMC cells were resuscitated and cultured according to the corresponding culture conditions until they were in good growth condition. When the cell density reached about 90%, the old culture medium was discarded and washed with DPBS. 0.05% Trypsin / EDTA solution was added to digest the cells, and then resuspended in SMCM complete culture medium. HPASMC cells were counted and inoculated in 6-well cell culture plates and incubated in a 37°C, 5% CO2 incubator overnight.

[0394] 1.1. Hypoxia induction and compound incubation

[0395] 1) According to Table 1-3 experimental grouping, the test substance was diluted to the corresponding working concentration with culture medium, and the culture medium in the HPASMC cells was replaced.

[0396] 2) The cell culture plate was placed in a HERAcell VIOS160i CO2 incubator and injected with a gas mixture containing 5% CO2, 2% O2 and 93% N2 for 24 hours of hypoxic induction treatment.

[0397] Table 1-2 Experimental grouping table

[0398] 1.2. Western blot detection

[0399] 1) Protein extraction: The treated HPASMC cells were taken out, the culture medium was removed, an appropriate amount of lysis buffer was added, and the cells were collected with a cell scraper and placed on ice for lysis. Centrifuge at 13,000 rpm, 4°C for 15 minutes, collect the supernatant. Take an appropriate amount of supernatant dilution, measure the protein concentration by BCA method, and adjust the same concentration of all treatment groups and prepare samples.

[0400] 2) SDS-PAGE gel electrophoresis separation: adjust the sample amount (protein sample amount is set to 30 μg), use 1.5 mm, 15 hole specification precast gel, according to 120 V constant voltage, 150 min electrophoresis separation.

[0401] 3) Membrane transfer and immunoblotting: use fast wet transfer method to transfer protein to PVDF membrane, block with fast blocking solution at room temperature for 1 hour, then incubate with antibody. GRK2 and β-actin primary antibody was incubated at 4°C overnight, HRP-secondary antibody was incubated at room temperature for 1 hour, then membrane development was performed.

[0402] 3、Data analysis and results

[0403] Data analysis was performed using software ImageJ and GraphPad Prism 8.0: β-actin was used as an internal reference to analyze the expression of GRK2 protein in each treatment group, and GRK2 / β-actin was used for statistical analysis.

[0404] Test Example 2, Test of the degradation activity of the test substance on the target protein

[0405] According to the change of fluorescence signal intensity of target point abundance in 293T-GRK2-HiBiT-KI-LgBiT cells, the degradation activity of the test substance on the target point GRK2 protein was evaluated by HiBiT method.

[0406] 2、1、Instruments, equipment and consumables:

[0407] The reagent consumables used in this test example are shown in Table 2-1

[0408] Table 2-1 Reagent and consumable information

[0409] 2、2、Experimental methods and operations:

[0410] a) The cell strain was cultured at 37°C, 5% CO2, in complete culture medium (DMEM + 10% FBS + 1 μg / mL Puromycin).

[0411] b) Harvest cells in log phase and count cells using a hemocytometer. Cell viability is checked by trypan blue exclusion to ensure that cell viability is above 90%.

[0412] c) Adjust cell density using complete media and then seed 96-well cell culture plates with 90 μL per well, with a total of 10,000 cells.

[0413] d) Incubate cells in 96-well plates at 37°C, 5% CO2 overnight.

[0414] e) Prepare 10x drug solutions, with a maximum concentration of 1000 nM for the test compound, 10 concentrations, 4-fold dilutions; then transfer 10 μL of each serially diluted compound to the corresponding experimental wells of the 96-well cell plate, with three replicates for each drug concentration.

[0415] f) Incubate cells in the drug-treated 96-well plates at 37°C, 5% CO2 for an additional 24 hours, after which the target protein degradation assay is performed. g) Thaw the HiBiT Lytic Detection System reagents to room temperature for 30 minutes.

[0416] h) Take a new 50 mL sterile tube and dilute the LgBiT Protein (1 : 100) and HiBiT Lytic Substrate (1 : 50) with appropriate volumes of room temperature HiBiT Lytic Buffer, mix well by inverting the tube.

[0417] i) Add 100 μL of the prepared HiBiT Lytic Mix reagent per well, protected from light, and shake the cells at 300 rpm for 5 minutes on an orbital shaker to lyse the cells.

[0418] j) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal.

[0419] k) Read the signal values using a multi-function microplate reader (CLARIO Plus, BMG) in Luminescence mode, collecting the data.

[0420] 2, 3, Data analysis and results

[0421] Data were analyzed using GraphPad Prism 7.0 software, and the dose-effect curves were fitted using non-linear S-curve regression to calculate the absolute and relative DC 50 values.

[0422] 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 ) x 100%.

[0423] 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%.

[0424] The degradation activity of the test compounds on the target GRK2 protein is shown in Table 2-2:

[0425] Table 2-2, degradation activity of representative compounds on the target GRK2 protein

[0426] The structure of the reference compound is The synthetic route is described in patent WO2024165075 for compound 1.

[0427] As can be seen from the above results, the representative novel skeleton molecular gel compound of the present application has stronger GRK2 target degradation ability than the reference compound, and some compounds have several hundred or even several thousand times more activity than the reference compound.

[0428] The above describes embodiments of the present application. However, the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A compound represented by Formula (I), a pharmaceutically acceptable salt, solvate, enantiomer, or isotopically substituted material thereof, wherein, A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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; to bind to a fragment of a ubiquitinated protein or chaperone protein, and preferably selected from the group consisting of: wherein Any represents a single or double bond, and when when a single bond, X, X1and X2are each 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(=Y)-, -OS(=Y)-, -S(=O)2-; and when X, X1and X2are independently selected from C(R d1 ) or N; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 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, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -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; any two adjacent R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from the group consisting of hydrogen, deuterium, SF5, 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 is optionally further substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R2is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, 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 multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, Each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, halogen, CN, OH, SH, and NH2, -COOH, or C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkoxy, C1-C6heteroalkyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C3-C8cycloalkenyl, C6-C10aryl, and C4-C8heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, and heteroaryl is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10aryl, and C4-C8heteroaryl; wherein any two vicinal 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, SF5, halogen, -CN, -OH, CF3, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10aryl, and C4-C8heteroaryl; and wherein any two vicinal 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, SF5, halogen, -CN, -OH, CF3, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10aryl, and C4-C8heteroaryl. 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; any two vicinal 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 heterocycloalkyl, and the hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, SF5, 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 3 groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R3is optionally substituted with 1 to 3 groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; and the hydrogens on M are optionally substituted with 1 to multiple substituents, said substituents are preferably selected from hydrogen, deuterium, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, sulfur pentafluoride, halogen, -CN, -OH, -SH, and -NH2, -COOH, or 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; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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, 3, 4 and 5; t 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 and 4; q is independently selected from an integer of 0, 1, 2, 3 and 4.

2. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof of claim 1, wherein, having the structure of formula (IA), wherein, A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, OH, an alkoxy group, an alkylamino group, -CN, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a saturated or partially saturated cycloalkyl group, and a saturated or partially saturated heterocyclyl group, wherein the hydrogen on R0is further optionally substituted with one to three substituents selected from the group consisting of H, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, OCH3, and OH. 1-10 an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, wherein the C 1-10 alkyl group, the C 1-10 alkyl group, the C 1-10 alkyl group, the C 2-10 alkyl group, the C 2-10 alkyl group, the C 1-10 alkyl group, the C d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1-10 alkyl group, the C 2-10 alkyl group, the C 2-10 alkyl group, the C 1-10 alkyl group, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl are optionally substituted with one to multiple substituents, which are independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, an alkylamino group, O=, CN, OH, -NR d1 R d2 , a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10 saturated or partially saturated heterocyclyl group, 6-10 membered aryl, and 5-8 membered heteroaryl; wherein the hydrogen on R0is further optionally substituted with one to multiple substituents, which are independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, OH, a C 1-3 alkyl group, the C 1-3 alkyl group, the C 1-3 alkyl group, the C 1-3 alkyl group, the C each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 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, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C. 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent R3together 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a member selected from the group consisting of hydrogen, deuterium, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; and the hydrogens on M are optionally substituted with 1 to multiple substituents, said substituents are preferably selected from hydrogen, deuterium, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, sulfur pentafluoride, halogen, -CN, -OH, -SH, and -NH2, -COOH, or 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; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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 are optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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; t is independently selected from an integer of 0, 1, 2, 3, 4 and 5.

3. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof of claim 1 or 2, wherein, having the structure of formula (IB), wherein, A is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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; and is preferably selected from a benzene ring, a pyridine ring, a thiazole ring, an isothiazole ring, for example * one end is connected to L1, the other end is connected to Q; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached 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, heterocycloalkyl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -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; any two adjacent R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from the group consisting of hydrogen, deuterium, SF5, 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 is optionally further substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R2is optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, 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 multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, Each R3may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Each R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a member selected from the group consisting of hydrogen, deuterium, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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 heteroaryl; 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 heteroaryl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocycloalkyl; 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; t 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.

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 (IC), wherein, L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 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, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -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; any two adjacent R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, SF5, 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, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R2is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, SF5, 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, and C 1-6 alkyl and C 1-6 alkyloxy is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a member selected from the group consisting of hydrogen, deuterium, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; each R4may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with a member selected from the group consisting of hydrogen, deuterium, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, which monocyclic or polycyclic ring 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; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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, a sulfuri pentyl group, a 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; t 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.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, having the structure of Formula (ID-1) or Formula (ID-2), wherein, L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C. 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; each R4may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is optionally independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different and are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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, a sulfuri pentyl group, a halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents a heteroatom selected from O, N, S, P and isotopes thereof; said halogen is optionally independently selected from F, Cl, Br, I and isotopes thereof; n is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; t is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; p is optionally selected from an integer of 0, 1, 2, 3, 4 and 5.

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 (IE-1) or Formula (IE-2), wherein, are optionally independently a single bond or a double bond; A is optionally independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. X1, X2and X3are independently selected from -0-, -S-, =N-, =CH-, -N(R d7 )-, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )0-; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached 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, heterocycloalkyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, halogen, -CN, -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; any two adjacent R2together 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 hydrogen on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from hydrogen, deuterium, SF5, 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 is optionally further substituted with 1 to multiple groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogen on R2is optionally substituted with 1 to multiple groups selected from hydrogen, deuterium, SF5, halogen, -CN, -OH, CF3, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, oxo, 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 multiple groups selected from hydrogen, deuterium, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; and the hydrogens on M are optionally substituted with 1 to multiple substituents, said substituents are preferably selected from hydrogen, deuterium, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, sulfur pentafluoride, halogen, -CN, -OH, -SH, and -NH2, -COOH, or 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; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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 heteroaryl; 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 heteroaryl is optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocycloalkyl; said hetero represents a heteroatom 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 optionally selected from an integer of 0, 1, 2, 3 and 4; n is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; t is optionally selected from an integer of 0, 1, 2, 3, 4 and 5.

7. The compound, pharmaceutically acceptable salt, solvate, enantiomer, or isotopically substituted thereof of any one of claims 1-6, wherein, having the structure of formula (IF-1) to (IF-4), wherein, are optionally independently a single bond or a double bond; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S or =NR0; Each R0may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, OH, a C 1-10 alkoxy group, a C 1-10 alkylthio group, a C 1-10 alkylamino group, -CN, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, -NR d8 R d9 , a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, OCH3, and OH; and d1 R d2 , a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10 saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group; wherein the hydrogen on R0is further optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, OCH3, and OH; and 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, wherein the C 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, a sulfurium pentafluoride group, a halogen, a haloalkyl group, a cyano group, OCH3, and OH. X1, X2and X3are independently selected from -0-, -S-, =N-, =CH-, -N(R d7 )-, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )0-; X4and X5are optionally 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, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached 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, heterocycloalkyl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C. 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Each R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is optionally independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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 heteroaryl; 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 heteroaryl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocycloalkyl; said hetero represents a heteroatom 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 optionally selected from an integer of 1, 2, 3 and 4; n is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; t is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; p is optionally selected from an integer of 0, 1, 2, 3, 4 and 5.

8. The compound, pharmaceutically acceptable salt, solvate, enantiomer or isotopically substituted thereof according to any one of claims 1-7, wherein, which have the structure of formula (IG-1) to (IG-5), wherein, are optionally independently a single bond or a double bond; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; X is independently selected from CR1or N; Y is independently selected from O, S or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. X1and X2are independently selected from -0-, -S-, =N-, NR d7 , =CH-, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )0-; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocycloalkyl, and the hydrogens on said aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl are optionally substituted with 1 to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C. 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Each R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M is optionally independently selected from a monocyclic or polycyclic ring structure of 3 to 18 carbon atoms, said monocyclic or polycyclic ring 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; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different, are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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 heterocycloalkyl-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 heterocycloalkyl-substituted C 3-10 heterocyclyl is optionally substituted with one to multiple substituents selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a halogen, oxo, CN, OH and C 3-10 saturated or partially substituted groups saturated cycloalkyl or heterocyclyl; said hetero represents a heteroatom 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 optionally selected from an integer of 0, 1, 2, 3, 4 and 5; n is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; s is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; t is optionally selected from an integer of 0, 1, 2, 3, 4 and 5; p is an integer selected from 0, 1, 2, 3, 4, and 5.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, having the structure of Formula (IH-1) - (IH-6), wherein, independently represent a single or double bond; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; Y is independently selected from O, S, or =NR0; Each R0may be the same or different and is independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, a cyanoethyl group, O=, OH, a C 1-10 alkoxy group, a C 1-10 alkylthio group, a C 1-10 alkylamino group, -CN, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, a -NR d8 R d9 , a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, OCH3, and OH; and d1 R d2 , a C 3-10 saturated or partially saturated cycloalkyl group, a C 3-10 saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group; wherein the hydrogen on R0is further optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, deuterium, a sulfurium pentafluoride group, a halogen, an alkyl group, a haloalkyl group, a cyano group, OCH3, and OH; and 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, wherein the C 1-3 alkyl group, a C 1-3 alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from the group consisting of H, deuterium, a sulfurium pentafluoride group, a halogen, a haloalkyl group, a cyano group, OCH3, and OH. X is independently selected from CR1or N; X2is independently selected from -0-, -S-, NR d7 or -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )0-; each R1may be the same or different, independently of one another, selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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 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 a -Q-M group; wherein the hydrogens on R1are optionally substituted with 1 to multiple substituents selected from the group consisting of H, deuterium, a sulfur pentafluoride group, a halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 ; or any two adjacent R1together with the atoms to which they are attached 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, heterocycloalkyl are optionally substituted with a group selected from the group consisting of hydrogen, deuterium, a sulfur pentafluoride group, a 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, a sulfur pentafluoride group, a halogen, an oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C. 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Each R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M 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 spiro ring, or a bridged ring structure; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, 2, 3, 4, and 5; s is an integer selected from 0, 1, 2, 3, 4, and 5; t is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, 2, 3, or 4.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, having the structure of Formula (II-1) to (II-10), wherein, independently represent a single or double bond; L1and L2are 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-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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, a 6-10 membered aryl, a 5-8 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, and a 3-8 membered saturated or partially saturated heterocyclyl; X is independently selected from CR1or N; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, sulfonium pentafluoride, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, said substituents being arbitrarily selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, sulfopentafluoride, halogen, haloalkyl, cyano, OCH3, and OH. X2is independently selected from -0-, -S-, NR d7 or -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )- or -C(R d1 )(R d2 )0-; Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, pentafluoride sulfide, 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 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 or -QM group; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, sulfonium pentafluoride, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may 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 atoms on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group are optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, sulfonium pentafluoride, halogen, CN, 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 Cycloalkyl sulfinyl group; any two adjacent R2 groups together with their attached atoms 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 atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, sulfopentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo group, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C. 3-6 The cycloalkyl group is substituted; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, sulfonium pentafluoride, 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 groups selected from hydrogen, deuterium, sulfopentafluoride, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C. 3-6 substituted with a group selected from the group consisting of: a C1-C6alkyl group, each R3may be the same or different, each being independently selected from the group consisting of hydrogen, deuterium, SF5, 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; 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R3are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Each R4may be the same or different, each independently selected from the group consisting of hydrogen, deuterium, SF5, 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; any two adjacent 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 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, SF5, 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, SF5, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 cycloalkyl; wherein the hydrogens on R4are optionally substituted with 1 to multiple groups selected from the group consisting of hydrogen, deuterium, SF5, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl or heterocycloalkyl; Q is independently selected from the group consisting of null, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )S-, -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)-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-, -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; M 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 spiro ring, or a bridged ring structure; preferably a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring; each R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 may be the same or different and are each independently selected from the group consisting of hydrogen, deuterium, a sulfuri pentyl group, a 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, a sulfuri pentyl group, a 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 an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, 3, 4, and 5; s is an integer selected from 0, 1, 2, 3, 4, and 5; t is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, 2, 3, or 4.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, isotopically substituted, or isomer thereof, having Formula (III), wherein Ring A is selected from 5-10 membered heteroaryl; R1is selected from C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 6-10 aryl, C 3-10 cycloalkyl-C 1- 10 alkyl, 5-10 membered heteroaryl-C 1-10 alkyl, 3-10 membered heterocyclyl-C 1-10 alkyl, C 6-10 aryl-C 1-10 alkyl; Ring B is selected from 5-10 membered heterocyclyl, 5-10 membered heteroaryl; R2is selected from H, halogen, C 1-10 alkyl, C 1-10 alkoxy; L2is selected from NH, O, CH2; m is selected from 0, 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5; Preferably, Ring A is selected from 5-6 membered heteroaryl; Preferably, Ring A is selected from pyridyl, thiazolyl; Preferably, ring A is selected from Preferably, R1is selected from C 6-10 aryl-C 1-6 alkyl; Preferably, R1is selected from benzyl; Preferably, selected from the group consisting of Preferably, selected from the group consisting of Preferably, Ring B is selected from 9-10 membered heterocyclyl, 9-10 membered heteroaryl; Preferably, ring B is selected from phenyl; Preferably, ring B is selected from * end to is connected to; Preferably, R2is selected from H, halogen, C 1-6 alkyl; Preferably, R2is selected from H, F; Preferably, selected from the group consisting of * end to is connected to.

12. The compound, pharmaceutically acceptable salt, solvate, enantiomer, or isotopically substituted material of any one of claims 1-10, wherein, L1and L2are preferably selected from the group consisting of a single bond, -C(R d1 )(R d2 )-, -N(R d7 )-, -O-, -S-, -N(R d4 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )N(R d4 )-; most preferably -C(R d1 )(R d2 )-, -N(R d7 )- or -O-; Preferably, X2is selected from O, S or NR d7 .

13. The compound, pharmaceutically acceptable salt, solvate, enantiomer, or isotopically substituted thereof of any one of claims 1-12, wherein, The compound is selected from the novel compounds of the structures disclosed in the specification.

14. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds, pharmaceutically acceptable salts, solvates, enantiomers, or isotopically-substituted versions thereof of any one of claims 1-13.

15. Use of the compounds, pharmaceutically acceptable salts, solvates, enantiomers, or isotopically-substituted versions thereof of any one of claims 1-13, or the pharmaceutical composition of claim 14, in the manufacture of a medicament for preventing and / or treating a disease associated with the GRK2 signaling pathway. Preferably, the disease related to the GRK2 signaling pathway includes, but is not limited to, cancer, metabolic disease, autoimmune disease, inflammatory disease, cardiovascular disease, nervous system disease, etc.

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