CRBN ligand and preparation method and application thereof

Abstract

The invention provides a compound or enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope labeled compound or prodrug thereof, and application of the compound in treatment of CRBN-mediated diseases or symptoms.

Description

A CRBN ligand and its preparation method and application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 2023103926330 filed on April 4, 2023, and the entire text of the above-mentioned Chinese patent application is hereby cited as part of this application. Technical Field

[0003] The present invention relates to a CRBN ligand and a preparation method and application thereof. Background Art

[0004] The ubiquitin-proteasome system (UPS) is a major pathway for cells to regulate protein levels. It is involved in the degradation of over 80% of proteins within cells, specifically damaged, misfolded, or excessive proteins. Multiple ubiquitin molecules are covalently linked to terminal lysine residues by E3 ubiquitin ligases, forming ubiquitinated chains that allow the substrate proteins to be recognized and hydrolyzed by the proteasome.

[0005] PROTACs (Proteolysis targeting chimeras) are a drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins. Structurally, PROTACs consist of three components: a target protein ligand (POI), a linker, and an E3 ubiquitin ligase ligand. Currently, over 600 E3 ubiquitin ligases have been discovered in the human genome, primarily belonging to four families: the RING finger (Really Interesting New Gene), HECT (Homologous to E6-APCarboxyl Terminus), RBR (RING-Between-RING), and RCR (RINGCys-Relay). The RING family is the most widely expressed ubiquitin ligase in the human body. Currently, the number of E3 ligase ligands used in clinical PROTACs is limited, primarily to CRBN and VHL ligands. Furthermore, CRBN, an E3 ubiquitinase that is relatively easy to administer orally, has a relatively limited number of ligands for clinical use. Therefore, the development of novel CRBN ligands is crucial. This article focuses on the development of novel small molecule ligands targeting CRBN.

[0006] Cereblon (CRBN) is a 442-amino acid multifunctional protein highly conserved from plants to humans. It primarily interacts with DNA damage binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B), and the regulator of cullins 1 (RoC1) to form a functional E3 ubiquitin ligase complex (CRL4-CRBN-E3 ubiquitin ligase complex). CRBN acts as a substrate receptor for the E3 ubiquitin ligase complex, mediating protein ubiquitination and degradation. As an important target for anti-tumor and immunomodulatory drugs (IMiDs), CRBN has been shown to have clear therapeutic effects in various hematological malignancies, such as multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), as well as autoimmune diseases such as systemic lupus erythematosus (SLE). Currently, three compounds targeting CRBN are already on the market, including thalidomide, lenalidomide, and pomalidomide. Compounds entering clinical development include CC-122, CC-220, CC-90009, and CC-92480, all of which are derivatives of thalidomide compounds. However, thalidomide compounds can cause side effects such as neutropenia, thrombocytopenia, and peripheral neuropathy. Therefore, there is an urgent need to develop novel CRBN ligands. In addition, CRBN is a commonly used ubiquitin enzyme for PROTAC. The development of novel CRBN ligands can further enhance the clinical therapeutic ability of PROTAC molecules and has excellent application prospects.

[0007] Summary of the Invention

[0008] In order to solve the above-mentioned technical problems existing in the prior art, the present invention provides a CRBN ligand for forming a PROTAC molecule for treating CRBN-mediated diseases or conditions, which has a high activation rate and has good drug development prospects.

[0009] In one aspect, the present invention provides a compound having a structure as shown in Formula I or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0010] in,

[0011] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 Each is independently a bond, carbon, nitrogen, oxygen or sulfur; Ring W is a 5-, 6- or 7-membered ring;

[0012] With X 1 、X 2 、X 3 、X 4 、X 5 and X 6 Connected Each independently represents a single bond or a double bond; two Different double bonds; when X 1 、X 2 、X 3 、X 4 、X 5 or X 6 When it is oxygen or sulfur, the is a single bond;

[0013] Each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclylamino; optionally, two R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino or two R a The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0014] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0015] R b For hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; optionally, R b With R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or R b With R aThe 3-7 membered monocarbocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0016] Y is a bond, NH, CH2, CH2CH2, NHCH2 or CH2NH; optionally, Y is substituted by 1, 2, 3 or 4 R Y Replacement; each R Y are independently hydrogen, deuterium, halogen, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0017] Z is NH, O, S or CH2; optionally, Z is replaced by 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, halogen, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl; optionally, R Z With R a , or R Z With R b connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, or R Z With R b The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0018] R c For hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0019] U is CH2, NH, O, S;

[0020] E and A are each independently a bond, CH2, NH, O, or S; wherein E and A are not simultaneously a bond, NH, or O;

[0021] Optionally, U, E or A are independently replaced by 1 or 2 R e Replacement; each R e are independently hydrogen, deuterium, halogen, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, two R e Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0022] Q 1 , Q 2 , Q 3 , Q 4 are each independently CH or N;

[0023] R d are independently hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; optionally, two adjacent R d connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH-, C 6-10 Aryl S(=O)2NH- or two adjacent R d The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 R d1 Replace, each R d1 are independently selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl OC(=O)-; optionally, two R d1 connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein two R d1 connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0024] m is 0, 1, 2, 3 or 4.

[0025] In another aspect, the present invention provides a PROTAC molecule comprising a ligand capable of binding to CRBN, wherein the ligand comprises or is based on the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug.

[0026] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or PROTAC molecule of the present invention and at least one pharmaceutically acceptable carrier.

[0027] On the other hand, the present invention provides a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or PROTAC molecule of the present invention, or pharmaceutical composition of the present invention, for use in treating a CRBN-mediated disease or condition.

[0028] In another aspect, the present invention provides a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention for the preparation of a medicament for treating a CRBN-mediated disease or condition.

[0029] In another aspect, the present invention provides a method for treating a CRBN-mediated disease or condition, comprising administering to a human in need thereof a therapeutically effective amount of a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention.

[0030] Another aspect of the present invention relates to methods for preparing, separating and purifying the compounds represented by formula I, II-1, II-2 and III.

[0031] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0032] The foregoing description only summarizes certain aspects of the present invention, but is not intended to be limiting. These and other aspects will be described in more detail and fully below. All references in this specification are incorporated herein by reference in their entirety. DETAILED DESCRIPTION

[0033] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0034] definition

[0035] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0036] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0037] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0038] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0039] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0040] The term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to a primate (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0041] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0042] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0043] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0044] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0045] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0046] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0047] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0048] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0049] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0050] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0051] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0052] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0053] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0054] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0055] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0056] The term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0057] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0058] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or these salts can be obtained by other methods described in the literature, such as ion exchange methods. Further pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts formed between compounds and bases, including but not limited to inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed by compounds containing any N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins)), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.

[0059] Pharmaceutically acceptable acid addition salts can be formed by the action of the compounds of this invention with inorganic or organic acids, and pharmaceutically acceptable base addition salts can be formed by the action of the compounds of this invention with inorganic or organic bases. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0060] The term "solvate" refers to an association complex formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropyl alcohol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropyl alcohol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene or a mixture thereof, etc.

[0061] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0062] In addition, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

[0063] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, wherein R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

[0064] The term "isotopically labeled compound" means a compound of the present invention that is labeled with an isotope. It is identical to those compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0065] Compounds of the present invention containing the aforementioned isotopic labels and / or other isotopic labels of other atoms and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotope-labeled compounds, such as 3 H and 14 C is incorporated into the compounds of the present invention for drug and / or substrate tissue distribution analysis. Due to ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitutions may offer therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0066] In addition, the substitution of heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages, which are due to the higher metabolic stability. For example, an increase in in vivo half-life or a reduction in dosage requirements or an improvement in therapeutic index are achieved. It should be understood that deuterium in the present invention is considered a substituent of the compounds of formula I to VI. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0067] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound shown in Formula I in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylating the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0068] Unless otherwise expressly stated, the descriptions used in the present invention of "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0069] The terms "optional," "optionally," or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with" means that the substitution may or may not occur.

[0070] When the term "each independently" is used in combination with "optionally", for example, "each independently arbitrarily replaced by..." means that the specific options are either replaced by... or not replaced by... without affecting each other.

[0071] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0072] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0073] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0074] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, and tertiary amines and quaternary ammonium salts; or a form in which the hydrogen on the nitrogen atom in a heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl), or NRT (such as NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). Among the compounds involved in the present invention, when containing multiple heteroatoms, the compounds composed thereof conform to the covalent and compositional rules of organic compounds, that is, compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent and compositional rules of organic compounds.

[0075] The term "heterocyclyl" refers to a saturated (i.e., "heterocycloalkyl") or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, and NR', wherein R' represents a hydrogen atom or a C1-6 alkyl or a halo-C1-6 alkyl. The heterocyclyl group may be attached to the remainder of the molecule via any of the carbon atoms or the nitrogen atom, if present, in the ring. In particular, a 3-10 membered heterocyclyl group is a group having 3-10 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0076] The term "heterocyclyl" encompasses a ring structure, and the connection point of the ring structure to the other groups can be on any ring in the ring structure. Therefore, the heterocyclyl of the present invention also includes but is not limited to heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C4-6 (mono) cycloalkyl, examples of which include but are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0077] The term "heterocyclyl" encompasses bridged heterocyclyls and spiro heterocyclyls.

[0078] The term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

[0079] The term "monospiro heterocyclyl" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated or partially unsaturated rings sharing a ring atom. "Monospiro heteroalkyl ring group" is a monospiro heterocyclyl group in which each ring forming a spiro ring is a saturated ring. Monospiro heterocycloalkyl includes but is not limited to 5-11 membered monospiro heterocycloalkyl, 6-10 membered monospiro heterocycloalkyl, 7-10 membered monocyclic heterocycloalkyl, 6-10 membered nitrogen-containing spiro heterocycloalkyl, 6-10 membered oxygen-containing spiro heterocycloalkyl, 6-10 membered sulfur-containing spiro heterocycloalkyl, etc. Monospiro heterocycloalkyl can include, for example, 3-membered / 5-membered ring system, 4-membered / 4-membered ring system, 4-membered / 5-membered ring system, 4-membered / 6-membered ring system, 5-membered / 5-membered ring system, 5-membered / 6-membered ring system, and 6-membered / 6-membered ring system, wherein the count of each ring includes spiro atoms. Examples include, but are not limited to The "nitrogen-containing monospiro heterocycloalkyl", "oxygen-containing monospiro heterocycloalkyl" and "sulfur-containing monospiro heterocycloalkyl" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing monospiro heterocycloalkyl" refers to a spiro heterocyclic group containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

[0080] The term "heteromonocycle" refers to a monocyclic heterocyclic group containing carbon atoms and heteroatoms, which may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring.

[0081] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from the group consisting of: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. 4-7 Cycloalkyl refers to a cycloalkyl group having 4 to 7 ring atoms. 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring atoms.

[0082] The term "carbomonocyclic ring" refers to a monocyclic ring containing carbon atoms, which may be fully saturated or contain one or more degrees of unsaturation, but may not contain an aromatic ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0083] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic and tricyclic aromatic system containing heteroatoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroatoms have the definition described in the present invention. In some embodiments, the heteroaryl group is a heteroaryl group composed of 5 to 10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-10 membered heteroaryl group; the heteroaryl group is a heteroaryl group composed of 5 to 8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-8 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group composed of 5 to 7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-7 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6-membered heteroaryl group; In some embodiments, the heteroaryl group is a 5-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a 6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g. 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g. 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrazolyl (e.g. 2-pyrazolyl, 3-pyrazolyl), isothiazolyl, Oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiodiazolyl (e.g., 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl), pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic or tricyclic groups, but is in no way limited to the following groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3 [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and the like.

[0084] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring." A 6-10 membered aryl group refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0085] The term "hydrogen" means 1 H; "deuterium" refers to 2 H.

[0086] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0087] The term "amino" refers to -NH2.

[0088] The term "hydroxy" refers to -OH.

[0089] The term "mercapto" refers to -SH.

[0090] The term "cyano" refers to -CN.

[0091] The term "nitro" refers to -NO2.

[0092] The term "carboxyl" refers to HO(C=O)-.

[0093] The term "oxo" and "O=" are used interchangeably, that is, when the substituent is O=", O is connected to the substituted group through a double bond.

[0094] The term "thio" and "S=" are used interchangeably, that is, when the substituent is S=", S is connected to the substituted group through a double bond.

[0095] The term "alkyl" or "alkyl group" refers to a saturated, straight-chain or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 Alkyl; In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, ie, C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0096] When two groups are used together, it means that one of the groups is connected to the rest of the molecule through the other group, such as arylalkyl, which means that the aryl group is connected to the molecule through the alkyl group; 6-10 Aryl C 1-6 Alkyl means an aryl group having 6 to 10 carbon atoms and an alkyl group having 1 to 6 carbon atoms.

[0097] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing carbon atoms, wherein at least one site of unsaturation exists, i.e., one carbon-carbon sp2 double bond, including "cis" and "tans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., C2-C6 alkenyl; in another embodiment, the alkenyl group contains 2-4 carbon atoms, i.e., C2-C4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0098] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing carbon atoms, wherein at least one site of unsaturation, i.e., a carbon-carbon triple bond, sp, is present. In one embodiment, the alkynyl group contains 2-6 carbon atoms, i.e., a C2-C6 alkynyl; in another embodiment, the alkynyl group contains 2-4 carbon atoms, i.e., a C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.

[0099] The term "heteroalkyl" refers to a group formed by adding one or more heteroatoms to an alkyl group. The alkyl group and heteroatom are as defined herein. The heteroalkyl group may be attached to the rest of the molecule via a carbon atom or a heteroatom.

[0100] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkoxy group contains 1-4 carbon atoms, ie, C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, ie, C 1-3 Alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2 CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0101] The term "alkylamino" means an alkyl group attached to the rest of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkylamino group contains 1 to 6 carbon atoms, i.e., C 1-6 Alkylamino groups, including (C 1-6 alkyl)NH- and (C 1-6 In another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C 1-4 In another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C 1-3 Examples include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), N,N-dimethylamino, N,N-diethylamino, and the like.

[0102] When an aryl, heteroaryl, cycloalkyl, heterocyclyl or the like group is used in conjunction with an oxy or amino group, it means that the aryl, heteroaryl, cycloalkyl, heterocyclyl or the like group is attached to the rest of the molecule through an oxygen atom or a nitrogen atom; for example, aryloxy means that the aryl group is attached to the rest of the molecule through an oxygen atom.

[0103] The term "two substituents are linked to form a ring" means that the two substituents are linked by a bond or a long chain of one atom or multiple atoms, together with the atoms between the two substituents in the parent molecule to form a ring.

[0104] The term "two R's a Connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring" includes two R a Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring fused to Ring W (e.g., ), two R a Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring and form a spirocyclic ring with ring W (e.g., or ), or two R a Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring and form a bridged ring with Ring W (e.g., ).

[0105] The term "R b With R a connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring" refers to R b With R a Together with the atoms on the ring W, they form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring and form a bridged ring with the ring W (for example, ).

[0106] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0107] As described herein, the substituent R is connected to the central ring by a bond to form a ring system (as shown below) and represents the substituent R at any substitutable or any reasonable position on the ring A. For example, formula f represents any possible substitutable position on the ring A, as shown in formulas f1-f4:

[0108] As described herein, a substituent is connected to a central ring by a bond to form a ring system, such as (R x ) n , representing n substituents R x Substitution can be made at any substitutable position on the ring. For example, formula a represents a benzene ring which can be substituted with n R x replace.

[0109] As described herein, *(R,S) means that the labeled chiral center is in either the R or S configuration but does not specify whether it is the R or S configuration.

[0110] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of the others. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0111] In addition, in order to simplify the page, when it is mentioned that a certain group can be substituted, it means that the group that can be substituted in multiple options of the group can be substituted. For example, when R' is hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C1-6 Alkyl; R' is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from hydrogen, deuterium, oxo (O =), thio (S =), halogen, cyano, hydroxyl, refers to C in R' 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy.

[0112] Unless otherwise stated, substituents or group combinations contemplated herein for Markush structures are those that are stable or chemically feasible.

[0113] Description of the compounds of the present invention

[0114] The present invention provides a compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which plays an active role in treating CRBN-mediated diseases or conditions.

[0115] Specifically, the present invention provides a compound having the structure shown in Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs;

[0116] in,

[0117] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 Each is independently a bond, carbon, nitrogen, oxygen or sulfur; Ring W is a 5-, 6- or 7-membered ring;

[0118] With X 1 、X 2 、X 3 、X 4 、X 5 and X 6 Connected Each independently represents a single bond or a double bond; two Different double bonds; when X1 、X 2 、X 3 、X 4 、X 5 or X 6 When it is oxygen or sulfur, the is a single bond;

[0119] Each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclylamino; optionally, two R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino or two Ra The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0120] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0121] R b For hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; optionally, R b With R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or R b With R a The 3-7 membered monocarbocyclic ring or 3-7 membered heterocyclic ring formed by the connection are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0122] Y is a bond, NH, CH2, CH2CH2, NHCH2 or CH2NH; optionally, Y is substituted by 1, 2, 3 or 4 R Y Replacement; each R Y are independently hydrogen, deuterium, halogen, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0123] Z is NH, O, S or CH2; optionally, Z is replaced by 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, halogen, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, R Z With R a , or R Z With R b connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, or R Z With R bThe 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0124] R c For hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0125] U is CH2, NH, O, S;

[0126] E and A are each independently a bond, CH2, NH, O, or S; wherein E and A are not simultaneously a bond, NH, or O;

[0127] Optionally, U, E or A are independently replaced by 1 or 2 R e Replacement; each R e are independently hydrogen, deuterium, halogen, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, two R e Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0128] Q 1 , Q 2 , Q 3 , Q 4 are each independently CH or N;

[0129] R d are independently hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; optionally, two adjacent R d connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH-, C 6-10 Aryl S(=O)2NH- or two adjacent R d The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 R d1 Replace, each R d1 are independently selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl OC(=O)-; optionally, two R d1 connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein two R d1 connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0130] m is 0, 1, 2, 3 or 4.

[0131] In some embodiments, for X 1 、X 2 、X 3 、X 4 、X 6 、R b , W, R a , n has the definition described in the present invention.

[0132] In some embodiments, Selected from:

[0133] Wherein, X is O or S; n1 is 0, 1, 2, 3 or 4; X 1 、X 2 、X 3 、X 4 、X 6 、R b 、R a , having the definition described in the present invention.

[0134] In some embodiments, Selected from:

[0135] wherein X or X' are each independently O or S; n2 is 0, 1, 2, 3 or 4; R b 、R a Has the definition described in the present invention.

[0136] Preferably, Selected from: wherein X or X' are each independently O or S; n2 is 0, 1, 2, 3 or 4, R b 、R a It has the definition described in the present invention. Preferably, n2 is 0, 1, 2, or 3.

[0137] In some embodiments, Selected from R b Has the definition described in the present invention.

[0138] Preferably, Selected from R b Has the definition described in the present invention.

[0139] In some embodiments, Selected from R b Has the definition described in the present invention.

[0140] In some embodiments, Selected from

[0141] #with X 6 Connected, @ and X 1 connected to the double bond,

[0142] Each R b1 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Substitution of cycloalkyl groups;

[0143] Each R Z1 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of the alkylamino group;

[0144] In some embodiments, preferably, each R b1 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of the alkylamino group;

[0145] In some embodiments, each R b1 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl; wherein the methyl, ethyl, propyl, isopropyl are each independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, and dimethylamino;

[0146] In some embodiments, each R b1 are independently hydrogen, deuterium, F, Cl, Br, cyano, methyl;

[0147] In some embodiments, each R b1 is hydrogen;

[0148] In some embodiments, each R Z1 are independently hydrogen, deuterium, C 1-4 Alkyl; wherein the C 1-4The alkyl group is optionally substituted by 1, 2 or 3 groups selected from deuterium, F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of the alkylamino group;

[0149] In some embodiments, each R Z1 are independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0150] In some embodiments, Selected from R Z1 、R b1 Has the definition described in the present invention.

[0151] In some embodiments, R c For hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of the alkylamino group;

[0152] In some embodiments, R c For halogen, cyano, C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of the alkylamino group;

[0153] In some embodiments, R c For halogen, cyano, C 1-6 Alkyl or C 6-10 Aryl, the C 1-6 Alkyl or C 6-10Aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-4 alkyl;

[0154] In some embodiments, R c For halogen, cyano, C 1-4 Alkyl or phenyl, the C 1-6 The alkyl or phenyl groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, halogen, cyano, hydroxy, amino, C 1-4 Substitution of alkyl groups;

[0155] In some embodiments, R c It is F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or phenyl.

[0156] In some embodiments, Selected from A, E, U, R d , m has the definition described in the present invention.

[0157] In some embodiments, Selected from

[0158] Among them, T 1 、T 2 、T 3 、T 4 、T 5 Each is independently a bond, carbon, nitrogen, oxygen or sulfur; Ring M is a 3-, 4-, 5-, 6- or 7-membered ring;

[0159] With T 1 、T 2 、T 3 、T 4 and T 5 Connected Each independently represents a single bond or a double bond; two Different double bonds; when T 1 、T 2 、T 3 、T 4 and T 5 When it is oxygen or sulfur, the is a single bond;

[0160] Each R d2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0161] m1 is 0, 1, or 2;

[0162] m2 is 0, 1, 2, 3, 4 or 5;

[0163] m3 is 0, 1, 2, 3 or 4; preferably m3 is 0, 1 or 2;

[0164] A,E,U,Q1,Q2,Q3,Q4,R d1 Has the definition described in the present invention.

[0165] In some embodiments, each R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0166] In some embodiments, each R d2and 1,2,3,6-tetrahydropyridinyl, benzyl, 8-azabicyclo[3.2.1]octanyl, cyclopropylmethyl, piperidinylmethyl, methoxy, ethoxy, methylamino, dimethylamino, phenoxy, pyridinyloxy, cyclopropyloxy, phenylamino, cyclopropylamino, piperidinylamino, NH2C(=O)-, methylNHC(=O)-, ethyl NHC(=O)-, methyl C(=O)NH-, ethyl C(=O)NH-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, ethyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, ethyl S(=O)2-, ethyl OC(=O)-, methyl S(=O)NH-, ethyl S(=O)NH-, methyl S(=O)2NH-, ethyl S(=O)2NH-, phenyl C(=O)-, phenyl S(=O)-, phenyl S(=O)2-, phenyl OC(=O)-, phenyl S(=O)NH- or phenyl S(=O)2NH-; wherein the methyl, ethyl, propyl, isopropyl, tert-butyl, ethylene yl, ethynyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, benzyl, 8-azabicyclo[3.2.1]octanyl, cyclopropylmethyl, piperidinylmethyl, methoxy, ethoxy, methylamino, dimethylamino, phenoxy, pyridyloxy, cyclopropyloxy, phenylamino, cyclopropylamino, piperidinylamino, NH2C(=O)-, methyl NHC(=O)-, ethyl NHC(=O)-, methyl C(=O)NH-, ethyl C(=O)NH-, methyl C(=O)-, ethyl C(=O)-, methyl S 2-, phenyl OC(=O)-, phenyl S(=O)NH-, phenyl S(=O)-, phenyl S(=O)2-, phenyl OC(=O)-, phenyl S(=O)NH- or phenyl S(=O)2NH- is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, oxo (O=), thioxo (S=), F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino;

[0167] In some embodiments, Selected from

[0168] in,

[0169] Each R 1 are independently hydrogen, deuterium, C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0170] R 2 and R 3 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R 2 and R 3Connected to form oxo (O=), thio (S=), or R 2 and R 3 Together with the C atom to which it is connected, it forms a 3-6-membered carbon monocycle or a 3-6-membered heteromonocycle; wherein the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0171] R d3 Each is independently hydrogen, deuterium, halogen, oxo (O=), thio (S=), cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-;

[0172] R d4 Each independently represents hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 Alkyl NHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 1-6 Alkyl NHC(=O)-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-;

[0173] m4 is 0, 1, or 2;

[0174] m1 and m3 have the definitions described in the present invention.

[0175] In some embodiments, each R 1 are independently hydrogen, deuterium, C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0176] In some embodiments, each R 1are independently hydrogen, deuterium, methyl, ethyl, isopropyl, tert-butyl, NH2C(=O)-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl; wherein the methyl, ethyl, isopropyl, tert-butyl, NH2C(=O)-, methyl C(=O)- , ethyl C(═O)-, methyl S(═O)-, methyl S(═O)2-, ethyl S(═O)-, ethyl S(═O)2-, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, oxo (O═), thioxo (S═), F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino;

[0177] In some embodiments, each R 1 are independently hydrogen, deuterium, methyl, ethyl, isopropyl, NH2C(=O)-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl; wherein the methyl, ethyl, isopropyl, NH2C(=O)-, methyl C(= O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino;

[0178] In some embodiments, R 2 and R 3 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R 2 and R 3Connected to form oxo (O=), thio (S=), or R 2 and R 3 Together with the C atom to which it is connected, it forms a 3-6-membered carbon monocycle or a 3-6-membered heteromonocycle; wherein the C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The substituents of the cycloalkyl group and the 3-6 membered heterocyclic group are substituted by substituents;

[0179] In some embodiments, R d3 Each is independently hydrogen, deuterium, F, Cl, Br, oxo (O=), thio (S=), cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-;

[0180] In some embodiments, R d3 Each is independently hydrogen, deuterium, F, Cl, Br, oxo (O=), thio (S=), cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-;

[0181] In some embodiments, R d3 Each is independently hydrogen, deuterium, F, Cl, Br, oxo (O=), thio (S=), cyano, hydroxyl, mercapto, nitro, amino, carboxyl, methyl, ethyl, vinyl, ethynyl, NH2C(=O)-, methyl NHC(=O)-, methyl C(=O)NH-, methyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, methyl S(=O)NH-, methyl S(=O)2NH-, ethyl NHC(=O)-, ethyl C(=O)NH-, ethyl C(=O)-, ethyl S(=O)-, ethyl S(=O)2-, ethyl OC (=O)-, ethyl S(=O)NH-, ethyl S(=O)2NH-, isopropyl NHC(=O)-, isopropyl C(=O)NH-, isopropyl C(=O)-, isopropyl S(=O)-, isopropyl S(=O)2-, isopropyl OC(=O)-, isopropyl S(=O)NH-, isopropyl S(=O)2NH-, tert-butyl NHC(=O)-, tert-butyl C(=O)NH-, tert-butyl C(=O)-, tert-butyl S(=O)-, tert-butyl S(=O)2-, tert-butyl OC(=O)-, tert-butyl S(=O)NH-, tert-butyl S(=O)2NH-;

[0182] In some embodiments, R d4 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-;

[0183] In some embodiments, R d4 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-;

[0184] In some embodiments, R d4 Each is independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, mercapto, nitro, amino, carboxyl, methyl, ethyl, vinyl, ethynyl, NH2C(=O)-, methyl NHC(=O)-, methyl C(=O)NH-, methyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, methyl S(=O)NH-, methyl S(=O)2NH-, ethyl NHC(=O)-, ethyl C(=O)NH-, ethyl C(=O)-, ethyl S(=O)-, ethyl S(=O)2-, ethyl OC(=O)-, ethyl alkyl S(=O)NH-, ethyl S(=O)2NH-, isopropyl NHC(=O)-, isopropyl C(=O)NH-, isopropyl C(=O)-, isopropyl S(=O)-, isopropyl S(=O)2-, isopropyl OC(=O)-, isopropyl S(=O)NH-, isopropyl S(=O)2NH-, tert-butyl NHC(=O)-, tert-butyl C(=O)NH-, tert-butyl C(=O)-, tert-butyl S(=O)-, tert-butyl S(=O)2-, tert-butyl OC(=O)-, tert-butyl S(=O)NH-, tert-butyl S(=O)2NH-;

[0185] In some embodiments, Selected from m3 is 0, 1, 2, 3 or 4, R d2 、R 1 Has the definition described in the present invention.

[0186] In some embodiments, Selected from m3 is 0, 1, 2, 3 or 4, R d2 、R 1 Has the definition described in the present invention.

[0187] 1. In some embodiments, a compound having a structure of Formula I-1 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0188] Among them, X 1 、X 2 、X 3 、X 4 、X 5 , Q 1 , Q 2 , Q 3 , Q 4 、R a 、R b 、R c 、R d2 ,X,Y,n,m3,R 1 Has the definition described in the present invention.

[0189] In some embodiments, a structure having formula II-1 or II-2 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0190] Among them, X 1 、X 2 、X 3 、X 4 、X 5 , Q 1 , Q 2 , Q 3 , Q 4 、R a 、R b 、R c 、R d2 、n、m3、R 1 Has the definition described in the present invention; wherein 0-2 means 0, 1, or 2;

[0191] In some embodiments, a structure having formula II-1-1, II-1-2, II-1-3, II-1-4, II-1-5, II-2-1, II-2-2, II-2-3, II-2-4 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

[0192] Among them, Q 1 , Q 2 , Q 3 , Q 4 、R c 、R Z ,X,X ’ 、n2R d2 、m3、R 1 Having the definitions described in the present invention;

[0193] In the general formulas II-1-1, II-1-2, II-2-1, II-2-2, II-2-3, and II-2-4, each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclylamino are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0194] In the general formula II-1-3, II-1-4, and II-1-5, there are at least two R a connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, or at least one R b and an R on the adjacent carbon atom a Forming a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring;

[0195] When there are two R a When connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle, the remaining R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino and 3-6 membered heterocyclylamino are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0196] R b For hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0197] When there is R b and an R on the adjacent carbon atom aWhen forming a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, the remaining R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino and 3-6 membered heterocyclylamino are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thioxo (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group is substituted by a substituent.

[0198] In some embodiments, the compound has a structure of Formula III or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0199] Among them, Q 1 , Q 2 , Q 3 , Q 4 、R a 、R b 、R c , Z, X, X', n2, R d2 、m3、R 1 Has the definition described in the present invention.

[0200] In some embodiments, a compound having a structure of Formula III-1 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0201] Among them, X', X, Q 1 , Q 2 , Q 3 , Q 4 、R a 、R b 、R c 、R d2 、n2、m3、R 1 Has the definition described in the present invention.

[0202] In some embodiments, a compound having a structure of Formula III-2 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0203] Among them, X', X, Q 1 , Q 2 , Q 3 , Q 4 、R a 、R b 、R c 、R d2 、n2、m3、R 1 Has the definition described in the present invention.

[0204] In some embodiments, the compound has a structure represented by Formula IV-1, IV-2, IV-3, IV-4, IV-5, or IV-6, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0205] Among them, R a 、R b 、R c 、R Z ,X,X',n2,R d2 、m3、R 1 Has the definition described in the present invention.

[0206] In some embodiments, each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclylamino; optionally, two R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino or two R a The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0207] In some embodiments, each R a are independently hydrogen, deuterium, F, Cl, Br, -NH2, -NH(C 1-6 )alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), or two R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle, wherein the 3-7 membered carbon monocycle or the 3-7 membered heteromonocycle is optionally substituted by 1-3 atoms selected from deuterium, F, Cl, Br, C 1-4 Alkyl substituted;

[0208] In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, n is 0, 1, 2, or 3;

[0209] In some embodiments, n2 is 0, 1, 2, 3 or 4;

[0210] In some embodiments, n2 is 0, 1, or 2;

[0211] In some embodiments, X or X' are each independently O or S;

[0212] In some embodiments, X or X' are each independently O;

[0213] In some embodiments, R b For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; optionally, R b With R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or R b With R a The 3-7 membered monocarbocyclic ring or 3-7 membered heterocyclic ring formed by the connection are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0214] In some embodiments, R b H, deuterium, F, Cl, Br, C 1-4 alkyl; optionally, R b With R a connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle, wherein the 3-7 membered carbon monocycle or the 3-7 membered heteromonocycle is optionally substituted by 1, 2 or 3 selected from D, C 1-4 Substitution of alkyl groups;

[0215] In some embodiments, Y is a bond, NH, CH2, CH2CH2, NHCH2, or CH2NH; optionally, Y is substituted by 1, 2, 3, or 4 R Y Replacement; each R Y are independently deuterium, F, Cl, Br, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0216] In some embodiments, Y is a bond;

[0217] In some embodiments, Z is NH, O, S or CH2; optionally, Z is replaced by 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, R Z With R a , or R Z With R b connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl or R Z With R a or R Z With R b The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10Aryl, 5-10 membered heteroaryl, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group; preferably, Z is NH, O, S or CH2; optionally, Z is substituted by 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl;

[0218] In some embodiments, R Z are independently hydrogen, C 1-4 alkyl;

[0219] In some embodiments, R c For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 substituted by cycloalkyl, 3-6 membered heterocyclic group; preferably, R c For hydrogen, deuterium, F, Cl, Br, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0220] In some embodiments, each R e are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-4Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, two R e Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring; preferably, each R e are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxy, amino, oxo (O=), thio (S=), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; optionally, two R attached to the same carbon atom e Together with the atoms to which they are attached, they form a 3-7 membered carbon monocyclic ring;

[0221] In some embodiments, R d are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; optionally, two adjacent R d connected to form a 3-7 membered carbon monocycle or a 3-7 membered heteromonocycle; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- or two R d The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 R d1 Replace, each R d1 independently selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-4 alkylOC(=O)-substituted; optionally, two R d1 connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein two R d1 connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0222] In some embodiments, R d are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkynyl, 5-10 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)2NH-, wherein R d Each independently optionally substituted by 1, 2, or 3 R d1 Replace, each R d1independently selected from hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0223] In some embodiments, R d are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 alkyl;

[0224] In some embodiments, each R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 Alkyl NHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution of cycloalkyl or 3-6 membered heterocyclic group;

[0225] In some embodiments, R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of the alkylamino group;

[0226] In some embodiments, R d2 are independently hydrogen, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, F, Cl, Br, cyano, hydroxy, amino, C 1-4 Substitution of alkyl groups;

[0227] In some embodiments, m3 is 0, 1, 2, 3 or 4;

[0228] In some embodiments, m3 is 0, 1 or 2.

[0229] In some embodiments, a compound having a structure of Formula IV or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0230] wherein X' and X are independently selected from O or S;

[0231] Q 1 , Q 2 , Q 3 , Q 4 CR q or N, each R q independently selected from H, deuterium, halogen, hydroxyl, cyano, carboxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -COR q1 、-C(O)OR q1 、-C(O)NHR q2 、-C(O)NR q2 R q3 、C 6-10 aryl, 5-7 membered heterocyclic group or 5-7 membered heteroaryl, wherein each R q1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, each R q2 and R q3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl;

[0232] R 1 Selected from H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -COR q1 Among them, R q1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl;

[0233] R c Selected from H, deuterium, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl;

[0234] Rn is selected from H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl-C 1-6 alkyl;

[0235] R a Selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or two R attached to the same carbon atom a Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0236] R b Selected from H, deuterium, halogen, C 1-6 Alkyl, or an R a With R b Connected to form C 1-4 alkylene;

[0237] n4 is 0, 1, 2, 3 or 4.

[0238] In some embodiments, a compound having a structure of Formula IV or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, N-oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0239] Wherein, X' and X are independently O or S;

[0240] Q 1 , Q 2 , Q 3 , Q 4 At most one of them is N, and the rest are CR q , each R q independently selected from H, deuterium, halogen, hydroxyl, cyano, carboxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0241] R 1Selected from H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -COR q1 Among them, R q1 Selected from H, C 1-6 alkyl;

[0242] R c Selected from H, deuterium, C 1-6 Alkyl, C 1-6 alkyl halide;

[0243] Rn is selected from H, deuterium, C 1-6 Alkyl, C 1-6 alkyl halide;

[0244] R a Selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0245] R b selected from H or deuterium;

[0246] n4 is 0, 1, 2, 3 or 4.

[0247] In some embodiments, the compound has the structure shown below or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, or prodrugs;

[0248] In another aspect, the present invention provides a PROTAC molecule comprising a ligand capable of binding to CRBN, wherein the ligand comprises or is based on any compound of any one of the present invention or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof.

[0249] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or a PROTAC molecule of the present invention and at least one pharmaceutically acceptable carrier.

[0250] On the other hand, the present invention provides a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention, for use in treating a CRBN-mediated disease or condition.

[0251] In another aspect, the present invention provides a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention for the preparation of a medicament for treating a CRBN-mediated disease or condition.

[0252] In another aspect, the present invention provides a method for treating a CRBN-mediated disease or condition, comprising administering to a human in need thereof a therapeutically effective amount of a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention.

[0253] In some embodiments, the CRBN-mediated diseases or disorders include proliferative disorders, neurological disorders, and transplantation-related disorders.

[0254] In some embodiments, the CRBN-mediated condition or disease is a proliferative disease.

[0255] In some embodiments, the proliferative disease is a leukemia; the leukemia is selected from acute leukemia, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute myeloid leukemia (AML), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryocytic leukemia, adult acute leukemia, differentiated myeloid leukemia, adult acute monocytic leukemia, adult acute monocytic leukemia, adult acute leukemia, mature acute myeloid leukemia, immature adult acute myeloid leukemia, abnormal adult acute myeloid leukemia, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroblastic leukemia, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute myeloid leukemia in remission, adult acute promyelocytic leukemia with PML-RARA, alkylating agent-associated acute myeloid leukemia, prolymphocytic leukemia, or chronic myelomonocytic leukemia;

[0256] In some embodiments, the proliferative disease is a lymphoma; the lymphoma is selected from adult grade III lymphomatoid granuloma, adult nasal type extranodal NK / T cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T cell lymphoma, cutaneous B cell non-Hodgkin lymphoma, mucosal associated extranodal marginal zone lymphoma lymphoid tissue, hepatosplenic T cell lymphoma, intraocular lymphoma, non-cutaneous extranodal site lymphoma involvement, mature T cell and NK cell non-Hodgkin lymphoma, lymph node marginal zone lymphoma lymphoma, post-transplant lymphoproliferative disorder, relapsed adult Burkitt lymphoma, relapsed adult diffuse large cell lymphoma, relapsed adult diffuse mixed cell lymphoma, relapsed adult diffuse small cleaved cell lymphoma, relapsed adult grade III lymphomatoid granuloma, relapsed adult immunoblastic lymphoma, relapsed adult lymphoblastic lymphoma, relapsed adult T-cell leukemia / lymphoma, relapsed cutaneous T-cell non-Hodgkin lymphoma, relapsed grade 1 follicular lymphoma, relapsed Recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoides and Sézary syndrome, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, refractory hairy cell leukemia, Richter syndrome, small intestinal lymphoma, splenic marginal zone lymphoma, T-cell large granular lymphocytic leukemia, testicular lymphoma, Waldenstrom's macroglobulinemia, adult T-cell leukemia-lymphoma, peripheral T-cell lymphoma Myeloma, B-cell lymphoma, Hodgkin's disease, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma, central nervous system lymphoma, refractory primary cutaneous large B-cell lymphoma (leg type), relapsed or refractory chronic lymphocytic leukemia, refractory anemia, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, or secondary myelodysplastic syndrome.

[0257] In some embodiments, the CRBN-mediated condition or disease is a neurological disease.

[0258] In some embodiments, the neurological disease is Alzheimer's disease.

[0259] In some embodiments, the CRBN-mediated disorder or disease is a transplantation-related disease or graft-versus-host disease.

[0260] Pharmaceutical compositions and methods of administration

[0261] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier.

[0262] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents. Other components may also include excipients such as excipients, binders, and fillers, as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0263] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0264] The present invention also relates to pharmaceutical compositions comprising as active ingredients a compound of formula I, II-1, II-2, III or a pharmaceutically acceptable salt thereof, which can be used in particular for the treatment of neoplastic diseases, in particular cancer, as described herein. The compositions can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or in particular for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (coated where applicable), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, in particular humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions can contain the active ingredient alone, or preferably, together with a pharmaceutically acceptable carrier.

[0265] The compound of formula I, II-1, II-2, III or its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic excipients to produce oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, flow agents such as fumed silica can be used as such excipients for the preparation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are such as vegetable oils, waxes, fats, semisolid and liquid polyols etc.

[0266] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0267] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0268] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0269] The dosage can vary within wide limits and, of course, will be adapted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula I per person should be appropriate, although the above lower or upper limits may also be exceeded if necessary.

[0270] The compounds of formula I, II-1, II-2, III can also be used in combination with one or more other pharmacologically active compounds that are also effective against the same disease, preferably using a different mode of action, or that reduce or prevent possible undesirable side effects of the compounds of formula I, II-1, II-2, III. The combination partners can be administered simultaneously in such treatment, for example by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms (each containing one or more combination partners).

[0271] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, alleviation of a condition, slowing or delaying disease progression, or prevention of a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent, and / or ameliorate a CRBN-mediated disease or condition, disorder, or condition.

[0272] The term "treatment" or "treating" as used herein in the context of treating a disease or disorder generally relates to treatment and therapy for humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., suppressing the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder. Also included are treatments (i.e., preventions) as preventive measures. For example, a patient who has not yet developed the disease or disorder but is at risk of developing the disease or disorder is covered by the term "treatment." For example, treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.

[0273] In some embodiments, the present invention provides the use of I, II-1, II-2, III compound or pharmaceutical composition or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CRBN-mediated disorders or diseases.

[0274] In some embodiments, the present invention provides a method for treating CRBN-mediated disorders or diseases, comprising administering a therapeutically effective amount of compound I, II-1, II-2, or III, or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the present invention provides compounds I, II-1, II-2, or III or pharmaceutical compositions for use in treating CRBN-mediated disorders or diseases.

[0276] Synthesis method

[0277] Compounds of formula I, II-1, II-2, III can be synthesized by the methods given below, by the methods given in the experimental section below, or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds of formula I, II-1, II-2, III; rather, other techniques known to skilled chemists can also be used for compound synthesis.

[0278] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The units of ppm are given. NMR measurements were performed on a Bruker Advance III-400M NMR spectrometer using deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or deuterated dimethyl sulfoxide (DMSO-d6) as the internal standard, with tetramethylsilane (TMS). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), brs (broadened singlet). The coupling constant, J, is expressed in Hertz (Hz).

[0279] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent mass spectrometer (Agilent 1260, Agilent 6125B). High-performance liquid chromatography (HPLC) was performed using a Gilson high-pressure liquid chromatograph (Gilson GX-281) with a C18 column (10 μM, 19 mm x 250 mm). UV detection was performed at 220 and 254 nm, and the elution conditions were a 15-minute gradient of 5–95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate).

[0280] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0281] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0282] The thin layer chromatography silica gel plates used were Qingdao GF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) were 0.15-0.20 mm in size, and those used for preparative thin layer chromatography were 0.4-0.5 mm in size. Silica gel column chromatography generally used Qingdao 200-300 mesh silica gel as the carrier.

[0283] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0284] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperature is room temperature, 20°C to 30°C.

[0285] It will be appreciated by those skilled in the art of organic synthesis that optimal reaction conditions may vary with the specific reactant or solvent used, but these conditions may be determined by conventional optimization procedures. In some cases, the order of the following reaction scheme and / or reaction steps may be changed to promote reaction or to avoid forming unwanted by-products. In addition, the functional group present in each position of the molecule must be compatible with the proposed reagent and reaction. This limitation of the substituent compatible with the reaction conditions is apparent to those skilled in the art, and then an alternative method must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, and it is assumed that such a blocking group (PG) is in the appropriate position if necessary. Conventional blocking groups can be used according to standard practices well known in the art (about explanation, referring to Greene TW, Wuts PGM, Protective Groups in Organic Synthesis [blocking group in organic synthesis], 5th edition, publisher: John Wiley & Sons (John Wiley & Sons), 2014). Blocking groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or blocking groups can be removed in subsequent reaction steps or aftertreatment.

[0286] The following abbreviations are used throughout this invention:

[0287] LCMS: liquid chromatography-mass spectrometry;

[0288] M, mol / L: moles per liter;

[0289] ml, mL: milliliter;

[0290] g: grams;

[0291] mmol: millimole;

[0292] ℃: degrees Celsius;

[0293] HNO3: nitric acid;

[0294] H2SO4: sulfuric acid;

[0295] Ac2O: acetic anhydride;

[0296] SnCl2: stannous chloride;

[0297] H2O: water;

[0298] DMSO: dimethyl sulfoxide.

[0299] The following examples are provided to facilitate understanding of the present invention. However, it should be understood that these examples and accompanying drawings are intended to illustrate the present invention only and are not intended to limit the present invention in any way. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present invention.

[0300] Example 1

[0301] Step 1: Preparation of compound 1-2

[0302] To a solution of compound 1-1 (1.00 g, 4.72 mmol) in acetic anhydride (10 mL) was added 1,1,1-trimethoxyethane (1.21 mL, 9.43 mmol), and the mixture was stirred at 90 ° C under a nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. The mixture was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 1 to 1 / 100) to obtain compound 1-2. LC-MS: m / z: 310.1 [M+H] + .

[0303] Step 2: Preparation of compound 1-3

[0304] Potassium carbonate (103 mg, 0.75 mmol) was added to a solution of compound 1-2 (230 mg, 0.74 mmol) in methanol (5 mL), and the mixture was stirred at 25°C for 18 hours. The mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1 to 20 / 1) to give compound 1-3. LC-MS: m / z: 268.1 [M+H] + .

[0305] Step 3: Preparation of compound 1

[0306] To a solution of compound 1-3 (80 mg, 0.30 mmol) in 1,4-dioxane (2 mL) were added 3-aminohexahydropyridine-2,6-dione hydrochloride (50 mg, 0.30 mmol) and triethylamine (61 mg, 0.60 mmol), and the mixture was stirred at 100 ° C for 4 hours. The mixture was poured into water (20 mL) to form a suspension. Filter and wash the filter cake with water (20 mL). The filter cake was then dried in vacuo to obtain compound 1. LC-MS: m / z: 366.0 [M + H] + .

[0307] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.69(d,J=8.4Hz,1H),10.53(s,1H),7.44(d,J=2.0Hz,1H),7.08(dd,J=8.0,2.0 Hz,1H),6.79(d,J=8.0Hz,1H),4.97-4.85(m,1H),2.85-2.73(m,1H),2.62-2.54(m,1H),2.45(s,3H),2.23-2.11(m,2H).

[0308] Example 2

[0309] Step: Preparation of compound 2

[0310] To a solution of compound 2-1 (300 mg, 0.97 mmol) in 1,4-dioxane (5 ml) were added 3-aminohexahydropyridine-2,6-dione hydrochloride (167 mg, 1.01 mmol) and triethylamine (196 mg, 1.94 mmol), and the mixture was stirred at 100°C under a nitrogen atmosphere for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (Gilson_306_1741, column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 41%-95%, flow rate: 25 mL / min) to obtain compound 2. LC-MS: m / z: 406.0 [M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.73(d,J=8.0Hz,1H),8.12(d,J=8.4Hz,1H),7.59(d,J=1.6Hz,1H),7.24 (dd,J=8.4,1.6Hz,1H),5.11-4.95(m,1H),2.87-2.75(m,1H),2.69-2.57(m,4H),2.55(s,3H),2.34-2.14(m,2H).

[0312] Example 3

[0313] Step 1: Preparation of compound 3-2

[0314] Compound 3-1 (500 mg, 2.21 mmol) and acetic anhydride (5 mL) were added to a single-necked flask at room temperature, and trimethyl orthoacetate (565 μL, 4.42 mmol) was added with stirring. The reaction atmosphere was purged with nitrogen three times, and the reaction was allowed to proceed at 90°C for 18 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0%-5%) and concentrated in vacuo to obtain compound 3-2. LC-MS: m / z: 282.0 [M+H] + .

[0315] Step 2: Preparation of compound 3

[0316] Compound 3-2 (55 mg, 0.19 mmol) and 3-amino-2,6-piperidinedione hydrochloride (35.29 mg, 0.21 mmol) were added to a single-necked flask at room temperature, followed by dioxane (1.5 mL). Triethylamine (81.07 μL, 0.58 mmol) was added with stirring, and the mixture was reacted at 100°C for 3 hours. The reaction solution was filtered, and the filter cake was washed with dioxane (20 mL) to obtain a crude product. The crude product was slurried with acetonitrile (10 mL) to obtain compound 3. LC-MS: m / z: 378.0 [M+H] + .

[0317] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.65(d,J=8.3Hz,1H),7.50(d,J=1.5Hz,1H),7.18(dd,J=8.2,1.6Hz,1H),6.97(d,J=8. 3Hz,1H),4.92(dd,J=17.8,8.2Hz,1H),3.24(s,3H),2.87–2.72(m,1H),2.60(d,J=17.5Hz,1H),2.47(s,3H),2.24–2.08(m,2H).

[0318] Example 4

[0319] Step 1: Preparation of compound 4-2

[0320] To a solution of compound 4-1 (2.00 g, 13.6 mmol) in concentrated sulfuric acid (8 mL) was slowly added 70% nitric acid (1 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C under a nitrogen atmosphere for 1 hour. The mixture was poured into water (200 mL), filtered, and the filter cake was collected and dried under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 1 / 1 to 1 / 500) to obtain compound 4-2. LC-MS: m / z: 193.1 [M+H]+ .

[0321] Step 2: Preparation of compound 4-3

[0322] To a solution of compound 4-2 (1.00 g, 5.20 mmol) in acetic anhydride (8 mL) was added 1,1,1-trimethoxyethane (1.40 mL, 10.9 mmol), and the mixture was stirred at 90°C under a nitrogen atmosphere for 18 hours. The mixture was distilled under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 500 / 1 to 100 / 1) to obtain compound 4-3. LC-MS: m / z: 249.1 [M+H] + .

[0323] Step 3: Preparation of compound 4-4

[0324] To a solution of compound 4-3 (300 mg, 1.21 mmol) in 1,4-dioxane (8 mL) were added 3-aminohexahydropyridine-2,6-dione hydrochloride (219 mg, 1.33 mmol) and triethylamine (245 mg, 2.42 mmol), and the mixture was stirred at 100° C. for 4 hours. The mixture was poured into water (30 mL), filtered, and the filter cake was washed with water (20 mL). The filter cake was collected and dried in vacuo to obtain compound 4-4. LC-MS: m / z: 345.1 [M+H] + .

[0325] Step 4: Preparation of compound 4

[0326] To a solution of compound 4-4 (100 mg, 0.29 mmol) in dimethyl sulfoxide (3 mL) were added stannous chloride (276 mg, 1.46 mmol) and water (0.1 mL), and the mixture was stirred at 65°C for 6 hours. After the reaction, the mixture was filtered through celite and the filtrate was concentrated. The concentrated crude product was purified by high-performance liquid chromatography (Gilson_306_1741, column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 5%-95%, flow rate: 25 mL / min) to obtain compound 4. LC-MS: m / z: 315.1 [M+H] + .

[0327] 1 H NMR (400 MHz, DMSO-d 6)δ10.97(s,1H),10.48(d,J=8.4Hz,1H),6.77(d,J=1.6Hz,1H),6.66(d,J=8.0Hz,1H),6.32(d,J=8.0Hz,1H),4.8 8-4.76(m,1H),4.65(s,2H),3.14(s,3H),2.86-2.70(m,1H),2.66-2.54(m,1H),2.39(s,3H),2.24-2.04(m,2H).

[0328] Example 5

[0329] Step 1: Preparation of compound 5-2

[0330] Compound 5-1 (2.00 g, 13.6 mmol) and acetic anhydride (20 mL) were added to a single-necked flask at room temperature, and trimethyl orthoacetate (3.47 mL, 27.2 mmol) was added with stirring. The reaction atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at 90°C for 18 hours. The reaction solution was concentrated, and the resulting mixture was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0%-10%) and concentrated in vacuo to yield compound 5-2. LC-MS: m / z: 204.2 [M+H] + .

[0331] Step 2: Preparation of compound 5

[0332] Compound 5-2 (100 mg, 0.493 mmol) and 3-amino-2,6-piperidinedione hydrochloride (89.08 mg, 0.539 mmol) were added to a single-necked flask at room temperature, followed by dioxane (1.5 mL). Triethylamine (205 μL, 1.48 mmol) was added under stirring, and the reaction was replaced with nitrogen three times. The reaction was allowed to proceed at 90 ° C for 18 hours. The reaction solution was cooled, filtered, and the filter cake was washed with dioxane (3 mL). The filter cake was collected, mixed with acetonitrile (10 mL), stirred for three hours, filtered, and washed with acetonitrile (5 mL). The filter cake was dried under vacuum to obtain compound 5. LC-MS: m / z: 300.2 [M+H] + .

[0333] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.53(d,J=8.4Hz,1H),7.42(d,J=7.6Hz,1H),7.07–6.94(m,3H) ,4.94–4.83(m,1H),3.25(s,3H),2.86–2.73(m,1H),2.65–2.55(m,1H),2.47(s,3H),2.24–2.09(m,2H).

[0334] Example 6

[0335] Step 1: Preparation of compound 6-2

[0336] Compound 6-1 (690 mg, 3.59 mmol) and acetic anhydride (7 mL) were added to a single-necked flask at room temperature, and trimethyl orthopropionate (1.03 mL, 7.18 mmol) was added with stirring. The reaction atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at 90°C for 18 hours. Water (10 mL) was added to the reaction solution, the mixture was filtered, and the filter cake was washed with water (20 mL). The collected filter cake was dried under vacuum to obtain compound 6-2. LC-MS: m / z: 263.0 [M+H] + .

[0337] Step 2: Preparation of compound 6-3

[0338] Compound 6-2 (300 mg, 1.14 mmol) and 3-amino-2,6-piperidinedione hydrochloride (207 mg, 1.26 mmol) were added to a single-necked flask at room temperature, followed by dioxane (4.5 mL). Triethylamine (476 μL, 3.43 mmol) was added with stirring, and the reaction atmosphere was replaced with nitrogen three times. The reaction was allowed to proceed at 90°C for 18 hours. The reaction solution was filtered, and the filter cake was washed with dioxane (3 mL). The filter cake was collected and mixed with water (20 mL), stirred for 3 hours, filtered, and the filter cake was washed with water (5 mL). The collected filter cake was dried under vacuum to obtain compound 6-3. LC-MS: m / z: 359.2 [M+H] + .

[0339] Step 3: Preparation of compound 6

[0340] Compound 6-3 (150 mg, 0.42 mmol) and stannous chloride (397 mg, 2.09 mmol) were added to a single-necked flask at room temperature. DMSO (3 mL) and water (0.1 mL) were then added. The reaction atmosphere was purged with nitrogen three times and allowed to react at 60°C for 18 hours. Saturated ammonium bicarbonate (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The dichloromethane layer was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-Xbridge-C18-10μm-19*250 mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: 6% acetonitrile, flow rate: 25 mL / min) to obtain compound 6. LC-MS: m / z: 329.1 [M+H] + .

[0341] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.46(d,J=9.0Hz,1H),6.70(d,J=1.6Hz,1H),6.67(d,J=8.2Hz,1H),6.33(dd,J=8.0,1.6Hz,1H),4.8 6–4.73(m,1H),4.56(s,2H),3.14(s,3H),2.91–2.65(m,3H),2.58–2.5 3(m,1H),2.20–2.08(m,2H),2.14–2.07(m,1H),1.22(t,J=7.6Hz,3H).

[0342] Compound 6 was separated to obtain compound 6-A (enantiomer 1) and 6-B (enantiomer 2).

[0343] Compound 6-A (enantiomer 1), retention time: 2.985 min (Instrument: WATERS 150 preparative SFC (SFC-26); Column: ChiralCel OJ, 250×30 mm ID, 10 μm; Mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O); Gradient: B 45%; Flow rate: 150 mL / min; Back pressure: 100 bar).

[0344] Compound 6-B (enantiomer 2), retention time: 3.925 min (Instrument: WATERS 150 preparative SFC (SFC-26); Column: ChiralCel OJ, 250×30 mm ID, 10 μm; Mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O); Gradient: B 45%; Flow rate: 150 mL / min; Back pressure: 100 bar).

[0345] Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications, if necessary).

[0346] Biological part:

[0347] Biological evaluation of CRBN binding assay (HTRF method)

[0348] 1. Test Purpose

[0349] This experiment detects the binding of compounds to CRBN. 50 The size of the compound was used to evaluate its affinity for the CRBN target.

[0350] 2. Experimental Methods

[0351] The affinity of the compounds for CRBN was detected using CEREBLON BINDING KITS (CISBIO, 64 BDCRBNPEG) containing diluent #9, Human Cereblon WT GST-tagged protein, GST Eu Cryptate Antibody and Thalidomide-Red.

[0352] Transfer 20 nL of the compound into a 384-well plate (PerkinElmer, 6007299) using an Ehco650 device (Beckman, 650). Add 5 μL of 1X diluent #9 (CISBIO, 64BDCRBNPEG) to the 384-well plate, and then add 5 μL of 1X Human Cereblon WT GST-tagged protein (CISBIO, 64BDCRBNPEG). Seal the plate with a plate sealer, shake it on a shaker (Kylin-Bell, MH-2) for 10 s, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 5 min. Add 5 μL of 1X GST Eu Cryptate Antibody (CISBIO, 64BDCRBNPEG) and 5 μL of 1X Thalidomide-Red (CISBIO, 64BDCRBNPEG) to the 384-well plate, seal the plate with a plate sealer, shake it for 30 s, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 1 h. Read the signals at 665 nm and 620 nm using an Envision (PerkinElmer, 2105-0020).

[0353] III. Data analysis

[0354] Use Graphpad Prism9 software to calculate the IC50 value of the compound activity based on the ratio of the compound concentration and the signals at 665 nm and 620 nm. The calculation formula is %Inhibition = (Signal compound[Ratio(665 nm / 620 nm)*10000] - SignalAve_PC) / (SignalAve_NC - SignalAve_PC)*100

[0355] After testing, the compounds of the present invention have good affinity for the CRBN target. The activity test results of some compounds of the present invention measured by the above method are shown in Table 1 below.

[0356] Table 1

[0357] In Table 1, A represents IC50 ≤ 2 μM, B represents 2 μM < IC50 ≤ 5 μM, C represents 5 μM < IC50 ≤ 10 μM, and D represents IC50 > 10 μM.

[0358] The technical solution of the present invention is not limited to the limitations of the above specific embodiments. Any technical deformation made according to the technical solution of the present invention falls within the protection scope of the present invention.

Claims

1. A compound having a structure as shown in Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs; in, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Each is independently a bond, carbon, nitrogen, oxygen or sulfur; Ring W is a 5-, 6- or 7-membered ring; With X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Connected Each independently represents a single bond or a double bond; two When X 1 , X 2 , X 3 , X 4 , X 5 or X 6 When it is oxygen or sulfur, the is a single bond; Each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclylamino; optionally, two R a connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino or two R a The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R b is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; optionally, R b With R a connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or R b With R a The 3-7 membered monocarbocyclic ring or 3-7 membered heterocyclic ring formed by the connection are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Y is a bond, NH, CH2, CH2CH2, NHCH2 or CH2NH; optionally, Y is substituted by 1, 2, 3 or 4 R Y Replacement; each R Y are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl groups are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Z is NH, O, S or CH2; optionally, Z is replaced by 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; optionally, R Z With R a , or R Z With R b connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, or R Z With R b The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; R c is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; U is CH2, NH, O, S; E and A are each independently a bond, CH2, NH, O, S; wherein E and A are not simultaneously a bond, NH, O; Optionally, U, E or A are independently replaced by 1 or 2 R e Replacement; each R e are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, two R e Together with the atoms to which it is attached, it forms a 3-7-membered carbon monocyclic ring or a 3-7-membered heteromonocyclic ring; the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Q 1 , Q 2 , Q 3 , Q 4 are each independently CH or N; R d are independently hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 AlkylNHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; optionally, two adjacent R d connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 AlkylNHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH-, C 6-10 Aryl S(=O)2NH- or two adjacent R d The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other independently and optionally 1, 2, 3, 4 or 5 R d1 Replace, each R d1 are independently selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl OC(=O)-; optionally, two R d1 are connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein two R d1 The rings are connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, and are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; m is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein for Preferably, Selected from: Wherein, X is O or S; n1 is 0, 1, 2, 3, 4, 5 or 6; Preferably, Selected from: wherein X or X' is independently O or S; n2 is 0, 1, 2, 3 or 4; Preferably, Selected from: wherein X or X' is independently O or S; n2 is 0, 1, 2, 3 or 4; Preferably, Selected from Preferably, Selected from Preferably, Selected from 3. The compound according to any one of claims 1 to 2, wherein Selected from #withX 6 Connected, @ and X 1 connected to, & connected to a double bond, Each R b1 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 radicals selected from deuterium, oxo (O=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Substitution of cycloalkyl groups; Preferably, each R b1 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 radicals selected from deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of alkylamino groups; Preferably, each R b1 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl; wherein the methyl, ethyl, propyl, isopropyl are each independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, dimethylamino; More preferably, each R b1 are independently hydrogen, deuterium, F, Cl, Br, cyano, methyl; Most preferably, each R b1 is hydrogen; Each R Z1 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 radicals selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of alkylamino groups; Preferably, each R Z1 are independently hydrogen, deuterium, C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted by 1, 2 or 3 groups selected from deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of alkylamino groups; Preferably, each R Z1 are independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; Preferably, Selected from 4. The compound according to any one of claims 1 to 3, wherein R c is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 radicals selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of alkylamino groups; Preferably, R c For halogen, cyano, C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 6-10 The aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 radicals selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution of alkylamino groups; Preferably, R c For halogen, cyano, C 1-6 Alkyl or C 6-10 Aryl, the C 1-6 Alkyl or C 6-10 Aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, hydroxyl, amino, C1-4 alkyl; Preferably, R c For halogen, cyano, C 1-4 Alkyl or phenyl, the C 1-6 The alkyl or phenyl radicals are optionally substituted by 1, 2, 3, 4 or 5 radicals selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Substitution of alkyl groups; Preferably, R c It is F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, and phenyl.

5. The compound according to any one of claims 1 to 4, wherein Selected from Preferably, Selected from Among them, T 1 , T 2 , T 3 , T 4 , T 5 Each is independently a bond, carbon, nitrogen, oxygen or sulfur; Ring M is a 3, 4, 5, 6 or 7 membered ring; With T 1 , T 2 , T 3 , T 4 and T 5 Connected Each independently represents a single bond or a double bond; two When T 1 、T 2 、T 3 、T 4 and T 5 When it is oxygen or sulfur, the is a single bond; Each R d2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 AlkylNHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 AlkylNHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- is optionally substituted by 1, 2, 3, 4 or 5 radicals selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, each R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; Among them, the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- is optionally substituted by 1, 2, 3, 4 or 5 radicals selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, each R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, mercapto, nitro, amino, carboxyl, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, benzyl, 8-azabicyclo[3.2.1]octanyl, cyclopropylmethyl, piperidinylmethyl, methoxy, ethoxy, methylamino, dimethylamino, phenoxy, pyridyloxy, cyclopropyloxy, phenylamino, cyclopropylamino, piperidinylamino, NH2C(=O)-, methylNHC(=O)-, Ethyl NHC(=O)-, methyl C(=O)NH-, ethyl C(=O)NH-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, ethyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, ethyl S(=O)2-, ethyl OC(=O)-, methyl S(=O)NH-, ethyl S(=O)NH-, methyl S(=O)2NH-, ethyl S(=O)2NH-, phenyl C(=O)-, phenyl S(=O)-, phenyl S(=O)2-, phenyl OC(=O)-, phenyl S(=O)NH- or phenyl S(=O)2NH-; wherein the methyl, ethyl, propyl, isopropyl, tert-butyl, ethylene yl, ethynyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, benzyl, 8-azabicyclo[3.2.1]octanyl, cyclopropylmethyl, piperidinylmethyl, methoxy, ethoxy, methylamino, dimethylamino, phenoxy, pyridyloxy, cyclopropyloxy, phenylamino, cyclopropylamino, piperidinylamino, NH2C(=O)-, methyl NHC(=O)-, ethyl NHC(=O)-, methyl C(=O)NH-, ethyl C(=O)NH-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, ethyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, ethyl S(=O)2-, ethyl OC(=O)-, methyl S(=O)NH-, ethyl S(=O)NH-, methyl S(=O)2NH-, ethyl S(=O)2NH-, phenyl C(=O)-, phenyl S(=O)-, phenyl S(=O)2-, phenyl OC(=O)-, phenyl S(=O)NH- or phenyl S(=O)2NH- are optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino; m1 is 0, 1 or 2; m2 is 0, 1, 2, 3, 4 or 5; m3 is 0, 1, 2, 3 or 4; preferably m3 is 0, 1 or 2; Preferably, Selected from in, Each R 1 are independently hydrogen, deuterium, C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, each R 1 are independently hydrogen, deuterium, C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, each R 1 are independently hydrogen, deuterium, methyl, ethyl, isopropyl, tert-butyl, NH2C(=O)-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl; wherein the methyl, ethyl, isopropyl, tert-butyl, NH2C(=O)-, methyl C(=O)- , ethyl C(═O)-, methyl S(═O)-, methyl S(═O)2-, ethyl S(═O)-, ethyl S(═O)2-, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, oxo (O═), thioxo (S═), F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino; Preferably, each R 1 are independently hydrogen, deuterium, methyl, ethyl, isopropyl, NH2C(=O)-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl; wherein the methyl, ethyl, isopropyl, NH2C(=O)-, methyl C(= O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino; R 2 and R 3 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R 2 and R 3 connected to form oxo (O=), thio (S=), or R 2 and R 3 Together with the C atom to which it is connected, it forms a 3-6-membered carbon monocyclic ring or a 3-6-membered heteromonocyclic ring; wherein the C 1-6 Alkyl, NH2C(=O)-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, R 2 and R 3 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R 2 and R 3 connected to form oxo (O=), thio (S=), or R 2 and R 3 Together with the C atom to which it is connected, it forms a 3-6-membered carbon monocyclic ring or a 3-6-membered heteromonocyclic ring; wherein the C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The substituents of the cycloalkyl group and the 3-6 membered heterocyclic group are substituted by substituents; Preferably, R 2 and R 3 each independently represents hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, tert-butyl, NH2C(=O)-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolyl or imidazolyl, or R 2 and R 3 connected to form oxo (O=), or R 2 and R 3 Together with the C atom to which it is connected, it forms a cyclopropyl group; wherein the methyl, ethyl, isopropyl, tert-butyl, NH2C(=O)-, methyl C(=O)-, ethyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, ethyl S(=O)-, ethyl S(=O)2-, vinyl, ethynyl, cyclopropyl, cyclobutyl, Oxetanyl, azetidinyl, pyrrolyl or imidazolyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, oxo (O=), thioxo (S=), F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino; R d3 are independently hydrogen, deuterium, halogen, oxo (O=), thio (S=), cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 AlkylNHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; Optionally, R d3 are independently hydrogen, deuterium, F, Cl, Br, oxo (O=), thio (S=), cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 14 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; Optionally, R d3 each independently represents hydrogen, deuterium, F, Cl, Br, oxo (O=), thio (S=), cyano, hydroxyl, mercapto, nitro, amino, carboxyl, methyl, ethyl, vinyl, ethynyl, NH2C(=O)-, methyl NHC(=O)-, methyl C(=O)NH-, methyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, methyl S(=O)NH-, methyl S(=O)2NH-, ethyl NHC(=O)-, ethyl C(=O)NH-, ethyl C(=O)-, ethyl S(=O)-, ethyl S(=O)2-, ethyl OC (=O)-, ethyl S(=O)NH-, ethyl S(=O)2NH-, isopropyl NHC(=O)-, isopropyl C(=O)NH-, isopropyl C(=O)-, isopropyl S(=O)-, isopropyl S(=O)2-, isopropyl OC(=O)-, isopropyl S(=O)NH-, isopropyl S(=O)2NH-, tert-butyl NHC(=O)-, tert-butyl C(=O)NH-, tert-butyl C(=O)-, tert-butyl S(=O)-, tert-butyl S(=O)2-, tert-butyl OC(=O)-, tert-butyl S(=O)NH-, tert-butyl S(=O)2NH-; R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-6 AlkylNHC(=O)-, C 1-6 Alkyl C(=O)NH-, C 1-6 Alkyl C(=O)-, C 1-6 Alkyl S(=O)-, C 1-6 Alkyl S(=O)2-, C 1-6 Alkyl OC(=O)-, C 1-6 Alkyl S(=O)NH-, C 1-6 Alkyl S(=O)2NH-, C 1-6 AlkylNHC(=O)-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; Optionally, R d4 are each independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-、C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; Optionally, R d4 each independently represents hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, mercapto, nitro, amino, carboxyl, methyl, ethyl, vinyl, ethynyl, NH2C(=O)-, methyl NHC(=O)-, methyl C(=O)NH-, methyl C(=O)-, methyl S(=O)-, methyl S(=O)2-, methyl OC(=O)-, methyl S(=O)NH-, methyl S(=O)2NH-, ethyl NHC(=O)-, ethyl C(=O)NH-, ethyl C(=O)-, ethyl S(=O)-, ethyl S(=O)2-, ethyl OC(=O)-, ethyl alkyl S(=O)NH-, ethyl S(=O)2NH-, isopropyl NHC(=O)-, isopropyl C(=O)NH-, isopropyl C(=O)-, isopropyl S(=O)-, isopropyl S(=O)2-, isopropyl OC(=O)-, isopropyl S(=O)NH-, isopropyl S(=O)2NH-, tert-butyl NHC(=O)-, tert-butyl C(=O)NH-, tert-butyl C(=O)-, tert-butyl S(=O)-, tert-butyl S(=O)2-, tert-butyl OC(=O)-, tert-butyl S(=O)NH-, tert-butyl S(=O)2NH-; m4 is 0, 1, or 2; Preferably, Selected from Preferably, Selected from 6. A compound according to any one of claims 1 to 5, having a structure of formula I-1 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; 7. The compound of claim 6, having a structure of formula II-1 or II-2 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; 8. The compound of claim 7, having a structure of formula II-1-1, II-1-2, II-1-3, II-1-4, II-1-5, II-2-1, II-2-2, II-2-3, II-2-4 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; in, Q 1 , Q 2 , Q 3 , Q 4 , R c , R Z As defined in claim 1; X, X ’ , n2 as defined in claim 2; R d2 、m3、R 1 As defined in claim 5; In the general formulas II-1-1, II-1-2, II-2-1, II-2-2, II-2-3 and II-2-4, each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 The cycloalkylamino or 3-6 membered heterocyclylamino groups are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 Heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; In the general formula II-1-3, II-1-4, and II-1-5, there are at least two R a are connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, or at least R b With an R on the adjacent carbon atom a Form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; When there are two R a When connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, the remaining R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino and 3-6 membered heterocyclylamino are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; R b is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; When there is R b With an R on the adjacent carbon atom a When forming a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, the remaining R a are independently hydrogen, deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, 3-6 membered heterocyclic group C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino and 3-6 membered heterocyclylamino are each independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group are substituted by substituents.

9. The compound according to any one of claims 1 to 7, having a structure of Formula III or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; in, Q 1 , Q 2 , Q 3 , Q 4 , R a , R b , R c , Z as defined in claim 1; X, X', n2 as defined in claim 2; R d2 、m3、R 1 As defined in claim 5.

10. The compound of claim 9, having a structure of formula III-1 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; in, Q 1 , Q 2 , Q 3 , Q 4 , R a , R b , R c , R Z As defined in claim 1; X, X', n2 as defined in claim 2; R d2 、m3、R 1 As defined in claim 5.

11. The compound according to claim 1, having a structure shown in formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs; in, R a , R b , R c , R Z As defined in claim 1; X, X', n2 as defined in claim 2; R d2 、m3、R 1 As defined in claim 5.

12. The compound according to any one of claims 1 to 11, wherein Each R a are independently hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclylamino; optionally, two R a are connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein, The C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino or 3-6 membered heterocyclic amino or two R a The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, each R a are independently hydrogen, deuterium, F, Cl, Br, -NH2, -NH(C 1-6 )alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), or two R a connected to form a 3-7-membered carbon monocyclic ring or a 3-7-membered heteromonocyclic ring, wherein the 3-7-membered carbon monocyclic ring or the 3-7-membered heteromonocyclic ring is optionally substituted by 1-3 deuterium, F, Cl, Br, C 1-4 Alkyl substituted; n is 0, 1, 2, 3, 4, 5 or 6; n2 is 0, 1, 2, 3 or 4; Preferably, n is 0, 1, 2, 3; n2 is 0, 1, 2; X or X' are each independently O or S; Preferably, X or X' is each independently O; R b For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; optionally, R b With R a connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or R b With R a The 3-7 membered monocarbocyclic ring or 3-7 membered heterocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, R b H, deuterium, F, Cl, Br, C 1-4 alkyl; optionally, R b With R a connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring, wherein the 3-7 membered carbon monocyclic ring or the 3-7 membered heteromonocyclic ring is optionally substituted by 1, 2 or 3 selected from D, C 1-4 Substitution of alkyl groups; Y is a bond, NH, CH2, CH2CH2, NHCH2 or CH2NH; optionally, Y is substituted by 1, 2, 3 or 4 R Y Replacement; each R Y are independently deuterium, F, Cl, Br, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 substituted by a cycloalkyl or 3-6 membered heterocyclic group; preferably, Y is a bond; Z is NH, O, S or CH2; optionally, Z is replaced by 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; optionally, R Z With R a , or R Z With R b connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl or R Z With R a or R Z With R b The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other is independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group; preferably, Z is NH, O, S or CH2; optionally, Z is 1 or 2 R Z Replacement; each R Z are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl; preferably, R Z are independently hydrogen, C 1-4 alkyl; R c For hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 substituted by a cycloalkyl or 3-6 membered heterocyclic group; preferably, R c For hydrogen, deuterium, F, Cl, Br, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; Each R e are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-4 Alkyl, NH2C(=O)-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; optionally, two R e Together with the atoms to which they are attached, they form a 3-7-membered carbon monocyclic ring; preferably, each R e are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, oxo (O=), thio (S=), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; optionally, two R attached to the same carbon atom e Together with the atoms to which it is attached, it forms a 3-7 membered carbon monocyclic ring; R d are each independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Fang Base C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; optionally, two adjacent R d connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl C 1-4 Alkyl, 5-10 membered heteroaryl C 1-4 Alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 6-10 Arylamino, 5-10 membered heteroarylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- or two R d The 3-7 membered carbon monocyclic ring or 3-7 membered heteromonocyclic ring formed by connecting each other independently and optionally 1, 2, 3, 4 or 5 R d1 Replace, each R d1 independently selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-4 alkylOC(=O)-; optionally, two R d1 are connected to form a 3-7 membered carbon monocyclic ring or a 3-7 membered heteromonocyclic ring; wherein two R d1 The 3- to 7-membered carbon monocyclic ring or the 3- to 7-membered heteromonocyclic ring are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, R d are each independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkynyl, 5-10 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, C 3-6 Cycloalkylamino, 3-6 membered heterocyclylamino, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)2NH-, where R d Each independently optionally 1, 2, 3 R d1 Replace, each R d1 independently selected from hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; More preferably, R d are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 alkyl; Each R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH-; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, NH2C(=O)-, C 1-4 AlkylNHC(=O)-, C 1-4 Alkyl C(=O)NH-, C 1-4 Alkyl C(=O)-, C 1-4 Alkyl S(=O)-, C 1-4 Alkyl S(=O)2-, C 1-4 Alkyl OC(=O)-, C 1-4 Alkyl S(=O)NH-, C 1-4 Alkyl S(=O)2NH-, C 6-10 Aryl C(=O)-, C 6-10 Aryl S(=O)-, C 6-10 Aryl S(=O)2-, C 6-10 Aryl OC(=O)-, C 6-10 Aryl S(=O)NH- or C 6-10 Aryl S(=O)2NH- is optionally substituted by 1, 2, 3, 4 or 5 radicals selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Substitution by a substituent of a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, R d2 are independently hydrogen, deuterium, F, Cl, Br, cyano, hydroxyl, thiol, nitro, amino, carboxyl, C 1-4 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group are optionally substituted by 1, 2, 3, 4 or 5 groups selected from deuterium, oxo (O=), thio (S=), F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substituents of alkylamino groups replace; Preferably, R d2 are independently hydrogen, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 radicals selected from deuterium, F, Cl, Br, cyano, hydroxyl, amino, C 1-4 Substitution of alkyl groups; m3 is 0, 1, 2, 3 or 4; preferably m3 is 0, 1 or 2.

13. The compound according to any one of claims 1 to 12, having the structure shown below or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs; 14. A PROTAC molecule comprising a ligand capable of binding to CRBN, wherein the ligand comprises or is based on any compound of any one of claims 1 to 13 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or a PROTAC molecule according to claim 14 and at least one pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1 to 13 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a PROTAC molecule according to claim 14, or a pharmaceutical composition according to claim 15, for use in treating a CRBN-mediated disease or condition.

17. Use of a compound according to any one of claims 1 to 13 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or, or the PROTAC molecule according to claim 14, or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating a CRBN-mediated disease or condition.

18. A method for treating a CRBN-mediated disease or condition, comprising administering to a person in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 13 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug, or a PROTAC molecule as described in claim 14, or a pharmaceutical composition as described in claim 15.

19. A compound according to claim 16 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the use in the preparation of a medicament according to claim 17, or the method for treating a CRBN-mediated disease or condition according to claim 18, wherein the CRBN-mediated disease or condition includes a proliferative disorder, a neurological disorder and a transplant-related disorder.