Aromatic compound, pharmaceutical composition containing the same and application thereof

Abstract

An aromatic compound containing an E3 ligand fragment, a pharmaceutical composition containing the same, and uses thereof. An aromatic compound, enantiomer, diastereomer, racemate, and mixture thereof as shown in Formula E, or a pharmaceutically acceptable salt thereof. Such compounds containing E3 ligand fragments can be used to prepare PROTAC compounds, which can recruit target proteins to CRBN E3 ubiquitin ligases and degrade them or inhibit the activity of target proteins in other ways. A degrader of the enzyme IRAK4 containing the same can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways. It has very good application prospects in IRAK4-mediated diseases including immune diseases, tumors, Alzheimer's disease, and fibrotic diseases, and provides a new option for clinical screening and / or preparation of drugs for diseases related to IRAK4 activity.

Description

[0001] This application claims priority to Chinese Patent Application No. 202110100562.3, filed on January 26, 2021; Chinese Patent Application No. 202110427240.x, filed on April 21, 2021; Chinese Patent Application No. 2021115401175, filed on December 15, 2021; and Chinese Patent Application No. 2021115401160, filed on December 15, 2021. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to an aromatic compound, a pharmaceutical composition containing the aromatic compound and application thereof. Background Art

[0003] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The ubiquitin-proteasome pathway (UPP) functions in vivo to selectively identify and remove excess proteins and degrade misfolded or abnormal proteins. Ubiquitin molecules are covalently linked to terminal lysine residues by E3 ubiquitin ligases, thereby tagging proteins for degradation by the proteasome into small peptides that are ultimately digested into their component amino acids, which are then used as building blocks for new proteins. The UPP plays a central role in multiple cellular processes and, if defective or unbalanced, contributes to the pathogenesis of numerous diseases. The UPP is central to regulating nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular mediators, ribosome biogenesis, and viral infection. Defective proteasomal degradation has been linked to a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer, among others.

[0004] Protein degradation targeting chimeras (PROTACs) are an effective means of degrading pathogenic proteins. They link small molecules that can bind to target proteins with small molecules that can bind to E3 ligases, including CRBN, VHL, MDM2, and DRAF, to form heterobifunctional molecules. By simulating the ubiquitin-proteasome pathway (UPP), the target protein is ubiquitinated, thereby achieving proteasome degradation of the target protein. Compared with small molecule inhibitors, a potential advantage of protein degradation targeting chimeras is that they can remove all functions of pathogenic proteins.

[0005] Currently, over 600 E3 ubiquitin ligases have been identified that promote the in vivo ubiquitination of diverse proteins. These ligases can be divided into four families: the HECT domain E3 family, the U-box E3 family, the monomeric RING E3 family, and the multi-subunit E3 family. Cereblon (CRBN) ligase is the most widely used E3 ligase in PROTAC technology. Cereblon, a 442-amino acid protein belonging to the Cullin RING E3 ubiquitin ligase family, forms the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex and interacts with the adaptor protein damaged DNA binding protein 1 (DDB1). Within the CRL4 complex, CRBN acts as a substrate-specific receptor. Known CRBN ligands include thalidomide and other derived immunomodulatory imide drugs. Upon ligand binding, CRBN's E3 ubiquitin ligase activity is reregulated, leading to increased recruitment of the transcription factors Ikaros and Aiolos, triggering subsequent ubiquitination and proteasomal degradation. Currently, CRBN, as an E3 ligase in PROTACs, has been successfully used to target more than 30 different proteins, including proteins associated with various cancers (Sun X. et al., 2019), proteins related to immune dysfunction (Bassi et al., 2018), proteins associated with neurodegenerative diseases (Silva et al., 2019), and hepatitis C virus proteins (de Wispelaere et al., 2019). Most PROTACs targeting CRBN use pomalidomide, 4-hydroxythalidomide, alkyl-linked thalidomide derivatives, or lenalidomide derivatives. However, it is possible to develop better CRBN ligands. These new CRBN ligands will provide more options for the development of PROTAC technology.

[0006] IRAK4, a serine / threonine kinase, is a key protein mediating signaling for the interleukin-1 (IL-1) receptor family (IL-1, IL-18, and IL-33 receptors) and pathogen-recognizing Toll-like receptors (TLRs). Studies have shown that upon recognition of foreign pathogens and inflammatory stress, the interleukin-1 receptor or TLR receptor, under the action of extracellular ligands, recruits the adaptor protein myeloid differentiation primary response protein (Myd88), which then forms a complex with IRAK4, activating the NF-κB light-chain enhancer and activator protein 1 (AP-1). This leads to the production of various inflammatory factors, such as tumor necrosis factor α (TNFα) and IL-6, which in turn trigger the development of various immune diseases, such as psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, and systemic lupus erythematosus. Furthermore, IRAK4 has been linked to lymphocytic leukemias and lymphomas, Alzheimer's disease, and fibrotic diseases. Therefore, IRAK4 is an attractive target for drug development.

[0007] Currently, major pharmaceutical companies, including Pfizer, Gilead, Bayer, and Curie, are advancing small molecule IRAK4 inhibitors into clinical trials for hematologic malignancies, psoriasis, rheumatoid arthritis, enteritis, and systemic lupus erythematosus. Among them, Pfizer's IRAK4 inhibitor PF-06650833 has entered Phase II clinical trials. Early clinical results demonstrate that PF-06650833 has a favorable safety profile and efficacy, demonstrating its ability to inhibit IRAK4-mediated inflammatory pathways. These clinical data strongly demonstrate that IRAK4 is a clinically validated druggable target with potential for treating a variety of diseases.

[0008] Recent studies have shown that in addition to the inflammatory signaling pathways mediated by IRAK4's kinase activity, the IRAK4 protein skeleton can also activate certain inflammatory signaling pathways. In human skin fibroblasts, ATP-competitive small molecule inhibition of IRAK4 was unable to effectively inhibit the release of IL-6 and TNF-α in response to IL-1β stimulation. In addition, IRAK4 knockout effectively abolished the inflammatory response mediated by IL-1, IL-8, and TLR ligands. Therefore, ATP-competitive small molecule inhibitors cannot completely eliminate the inflammatory signaling pathways mediated by the IRAK4 protein. Therefore, targeting IRAK4 with small molecule inhibitors has its therapeutic limitations.

[0009] Protein degradation targeting chimeras (PROTACs) are an effective means of degrading pathogenic proteins. Small molecules that can bind to target proteins are linked to small molecules that can bind to E3 ligases including CRBN, VHL, MDM2, DRAF, etc. to form heterobifunctional molecules. By simulating the ubiquitin-proteasome pathway (UPP), the target protein is ubiquitinated, thereby achieving degradation of the target protein by the proteasome. Compared with small molecule inhibitors, a potential advantage of protein degradation targeting chimeras is that they can remove all functions of pathogenic proteins. In addition, GSK scientists have demonstrated that protein degradation targeting chimeras (PROTACs) can achieve IRAK4 protein degradation by combining IRAK4 small molecule inhibitors with ligands of E3 ligases CRBN and VHL through linker fragments. At the same time, Kymera and Avinas have designed corresponding PROTACs for IRAK4. These emerging technologies provide a new therapeutic approach for targeting IRAK4. Summary of the Invention

[0010] Provided herein are compounds containing E3 ligand fragments, pharmaceutical compositions containing the same, and uses thereof. The degrader is composed of a CRBN ligand, a linker, and a target protein ligand. Compounds containing E3 ligand fragments of this type can be used to prepare PROTAC compounds, which can recruit the target protein to the CRBN E3 ubiquitin ligase and degrade it or otherwise inhibit the activity of the target protein. Also provided herein are compounds that are degraders of the enzyme IRAK4, pharmaceutical compositions containing such compounds, and uses thereof. The degrader can recruit IRAK4 to the E3 ubiquitin ligase and degrade it or otherwise inhibit the activity of IRAK4. The compound has a structure shown in Formula I, I', Ia-e, II, III, IV, or V, or is a pharmaceutically acceptable salt, metabolite, prodrug, or derivative thereof.

[0011] The present invention solves the above technical problems through the following technical solutions.

[0012] First aspect

[0013] The present invention provides a compound represented by Formula I and a pharmaceutically acceptable composition thereof, which is effective as an IRAK4 degradation agent. The present invention solves the above technical problems through the following technical solutions.

[0014] The present invention provides a compound represented by formula (I), its enantiomers, diastereomers, racemates and mixtures, or pharmaceutically acceptable salts thereof.

[0015]

[0016] in,

[0017] Q is selected from CR 2a , N;

[0018] V is selected from C and N;

[0019] U selected from CR 2 NR 2 (e.g. N);

[0020] W is selected from CR 3 , N;

[0021] X is selected from C (when connected to L), CR 4 , N;

[0022] Y is selected from C (when connected to L), CR 5 , N;

[0023] Z is selected from C (when connected to L), CR 6 , N;

[0024] R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cycloalkyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0025] Ring A is independently selected from 0-4 R 7 Substituted 5-10 membered aromatic heterocycle; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0026] R e 、R 2a 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkane substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, substituted or unsubstituted C1-C6 straight or branched alkanoyl group substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-; the heterocyclic group, heterobridged ring group, heterospirocyclic group, or aromatic heterocyclic ring contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0027] L is selected from linking groups that are non-hydrogen.

[0028] in, Indicates a single bond or a double bond.

[0029] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I, its enantiomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof are defined as follows (unmentioned groups are the same as those described in any embodiment of the present application, hereinafter referred to as "in a certain embodiment"), and the compound of Formula I is as shown in Formula Ia or Formula Ib,

[0030]

[0031] For example, as shown in Formula Ic or Formula Id,

[0032]

[0033] Also shown as (Ie), (If) and (Ig):

[0034]

[0035] In one embodiment, U is selected from CR 2 、N.

[0036] In one embodiment, U is selected from NR 2 .

[0037] In one scenario, R 1 Selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, 3-10 membered cycloalkyl, wherein the substituents are independently selected from deuterium, halogen, hydroxyl, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy; the number of the substitutions is 1, 2 or 3;

[0038] For example, R 1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl; for example -CF2.

[0039] In one plan, for

[0040] In one plan, In the equation, V is selected from N and U is selected from CR. 2 , W is selected from CR 3 、N.

[0041] In one scenario, R e 、R 2a 、R 2 、R 3 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy; for example, H substituted or unsubstituted C1-C6 straight chain or branched alkyl, and for example H or methyl.

[0042] In one embodiment, X is selected from CR 4 、N;Y is selected from CR 5 、N;Z is selected from C、CR 6 , N; and at most one of X, Y and Z is N.

[0043] In one scenario, R 4 、R 5 、R 6are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy; for example, H, halogen or substituted or unsubstituted C1-C6 straight chain or branched alkyl, and for example, H, F or methyl.

[0044] In one scenario, R 4 、R 5 、R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy; for example, H or substituted or unsubstituted C1-C6 straight chain or branched alkyl, and for example, H or methyl.

[0045] In one embodiment, ring A is independently selected from 0-4 R 7 Substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle;

[0046] For example, the A ring is independently selected from the following: 7 Substituted rings:

[0047]

[0048] R 7 The number of substitutions is 0-4; for example

[0049]

[0050] In one embodiment, Ring A is independently selected from:

[0051]

[0052] In one scenario, R 7 Selected from substituted or unsubstituted 4-10 membered heterocyclic groups, substituted or unsubstituted C5-C12 heterobridged ring groups, substituted or unsubstituted C3-C10 heterospirocyclic groups, substituted or unsubstituted C1-C6 straight or branched chain alkylamino groups;

[0053] The substituents may be independently selected from deuterium, halogen, C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched alkoxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight chain or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

[0054] In one scenario, R 7Selected from substituted or unsubstituted 4-10 membered heterocyclic groups, substituted or unsubstituted C5-C12 heterobridged ring groups, substituted or unsubstituted C3-C10 heterospirocyclic groups, substituted or unsubstituted C1-C6 straight or branched chain alkylamino groups;

[0055] The substituents may be independently selected from deuterium, halogen, C1-C6 straight or branched alkyl, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

[0056] In one scenario, R 7 Selected from:

[0057]

[0058] For example

[0059]

[0060] In one scheme, L is in,

[0061] L1 is selected from none,

[0062] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0063] La, Lb, Lc, Ld, Le, L a’ 、L e’ 、L f’ 、L g’ 、L h’ are independently selected from none, O, S, -N(R 8 )-、-C(=O)-R 9 -、-SO2R 10 -;R 8 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、

[0064] R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37and independently selected from anhydrous, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered Cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkylamino group, a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkanoyl group, a 4-10-membered heterocyclic group, a C5-C12 heterobridged ring group, a C3-C10 heterospirocyclic group, a 6-10-membered aromatic ring, or a 5-10-membered aromatic heterocycle; wherein the heterocyclic group, heterobridged ring group, heterospirocyclic group, or aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0065] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0066] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、

[0067] The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28-、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、

[0068] Ring B is selected from the group consisting of: none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0069] L2 is selected from none,

[0070]

[0071] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, and 2s are independently selected from 0 to 6;

[0072] L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 39 、COR 40 、-SO2R 41 ;

[0073] L 2b’ 、L 2c’ 、L 2d’ 、L 2i’ Selected from N, CR 44 ;

[0074] R 39 、R 40 、R 41 、R 44 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、RL229 、R L230 、R L241 、R L242 、R L243 、R L244 、R L245 、R L246 R is independently selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 39 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28-、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L221 、R L222 、R L223 、R L224 、R L225 、R L226Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R 44 With R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L231 、R L232 A substituted or unsubstituted 3-10 membered ring can be formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、

[0075] The C ring is selected from the group consisting of no, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0076] In one scheme, L is

[0077] Wherein, L1 is selected from none,

[0078] f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0, 1, or 2;

[0079] Ld and Le are independently selected from the group consisting of no (connecting bond), -C(=O)-R 9 -or-N(R 8 )-;R 8R is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; 9 Selected from zero, substituted or unsubstituted C1-C6 straight or branched alkyl groups;

[0080] L a’ 、L e’ 、L f’ 、L g’ 、L h’ are independently selected from none (linking bond);

[0081] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0082] R 38 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

[0083] Ring B is selected from none (representing a connecting bond), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl;

[0084] L2 is selected from none,

[0085]

[0086] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, and 2s are independently selected from 0, 1, 2, or 3;

[0087] L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, and L2n are independently selected from the group consisting of: none (linking bond), -C(=O), -R 40 -, O, S or -N(R 39 )-;R 39 R is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; 40 Selected from zero, substituted or unsubstituted C1-C6 straight or branched alkyl groups;

[0088] L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none; L 2b’ 、L 2c’ 、L 2d’ 、L 2i’ Selected from N, CR 44 ;

[0089] R 44 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L241 、R L242 、R L243 、R L244 、R L245 、RL246 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; or R 44 With R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L231 、R L232 A substituted or unsubstituted 3-10 membered ring can be formed through C, N, O, and S;

[0090] The C ring is selected from none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 5-10 membered aromatic heterocycle;

[0091] The substituents are independently selected from deuterium, halogen, C1-C6 straight or branched alkyl;

[0092] And at least one of L1, B ring, L2 and C ring is not absent.

[0093] In one scheme, L is in,

[0094] L1 is selected from none,

[0095] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0096] La, Lb, Lc, Ld, Le, L a’ 、L e’ 、L f’ 、L g’ 、L h’ Independently selected from none, O, S, NR 8 (-N(R 8 )-)、COR 9 (-C(=O)-R 9 -),-SO2R 10 -;R 8is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、RL125 、R L126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R33 、R 34 、R 35 、R 36 、R 37 and independently selected from anhydrous, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered Cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkylamino group, a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkanoyl group, a 4-10-membered heterocyclic group, a C5-C12 heterobridged ring group, a C3-C10 heterospirocyclic group, a 6-10-membered aromatic ring, or a 5-10-membered aromatic heterocycle; wherein the heterocyclic group, heterobridged ring group, heterospirocyclic group, or aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0097] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0098] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、RL117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28-、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、

[0099] Ring B is selected from the group consisting of: no, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, deuterium, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0100] L2 is selected from none,

[0101]

[0102] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, and 2s are independently selected from 0 to 6;

[0103] L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 39 (-N(R 39 )-)、COR 40 (-C(=O)-R 40 -),-SO2R 41 ; R 39 、R 40 、R 41 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L241 、R L242 、R L243 、R L244 、RL244 、R L245 R is independently selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 37 Can be respectively with R L21 、R L22 、R L23 、R L24 、RL25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L221 、R L222 、R L223 、R L224 、R L225 、R L226 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、

[0104] The C ring is selected from the group consisting of no, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0105] In a certain embodiment, at least one of L1, B ring, L2 and C ring is not absent; for example, two, three or four of L1, B ring, L2 and C ring are not absent.

[0106] In one scheme, L, L 2b’ 、L 2c’ 、L 2d’ 、L 2i’ Selected from N, CR 44 ; R 44independently selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 39 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、RL27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 R L221 、R L222 、R L223 、R L224 、R L225 、R L226 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 or R 44 With R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228、R L229 、R L230 、R L231 、R L232 A substituted or unsubstituted 3-10 membered ring can be formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、

[0107] In one solution, L, R 39 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、

[0108] In one scheme, L is

[0109] Wherein, L1 is selected from none,

[0110] f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0, 1, or 2;

[0111] Ld and Le are independently selected from the group consisting of no (connecting bond), -C(=O)-R 9 -or-N(R 8 )-;R 8 R is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; 9 Selected from zero, substituted or unsubstituted C1-C6 straight or branched alkyl groups;

[0112] L a’ 、L e’ 、L f’ 、L g’ 、L h’ are independently selected from none (linking bond);

[0113] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0114] R 38 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

[0115] Ring B is selected from none (representing a connecting bond), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl;

[0116] L2 is selected from none,

[0117]

[0118] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, and 2s are independently selected from 0, 1, 2, or 3;

[0119] L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, and L2n are independently selected from the group consisting of: none (linking bond), -C(=O), -R 40 -, O, S or -N(R 39 )-;R 39R is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; 40 Selected from zero, substituted or unsubstituted C1-C6 straight or branched alkyl groups;

[0120] L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none;

[0121] R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L241 、R L242 、R L243 、R L244 、R L245 、R L246 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

[0122] The C ring is selected from none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 5-10 membered aromatic heterocycle;

[0123] The substituents are independently selected from deuterium, halogen, C1-C6 straight or branched alkyl;

[0124] And at least one of L1, B ring, L2 and C ring is not absent.

[0125] In one plan, for

[0126] In one plan, for For example

[0127] For example

[0128] In one plan, for

[0129] In one plan,

[0130] Selected from:

[0131]

[0132]

[0133]

[0134] In one embodiment, Ring A is selected from:

[0135] In one embodiment, L is selected from: (connected to V on the left)

[0136]

[0137]

[0138]

[0139] Its single cis- or trans-isomers or mixtures thereof;

[0140] For example

[0141]

[0142] In one embodiment, the compound represented by formula I is

[0143] in,

[0144] V is selected from C and N;

[0145] U selected from CR 2 , N;

[0146] W is selected from CR 3 , N;

[0147] X is selected from CR 4 , N;

[0148] Y is selected from CR 5 , N;

[0149] Z is selected from CR 6 , N;

[0150] R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cycloalkyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0151] Ring A is independently selected from 0-4 R 7 Substituted 5-10 membered aromatic heterocycle; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0152] R 2 、R 3 、R 4 、R 5 、R 6 、R 7and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cyclic Alkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0153] L is selected from a linking group that is non-hydrogen;

[0154] For example, the compound represented by formula I is a compound of formula (Ia) shown below,

[0155]

[0156] In a certain embodiment, in the compound,

[0157] V is selected from C and N;

[0158] U selected from CR 2 , N;

[0159] W is selected from CR 3 , N;

[0160] X is selected from CR 4 , N;

[0161] Y is selected from CR 5 , N;

[0162] Z is selected from CR 6 , N;

[0163] R1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0164] Ring A is independently selected from 0-4 R 7 Replaces:

[0165]

[0166] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cyclic Alkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0167] L is selected from a non-hydrogen linking group; for example, the compound represented by formula I is a compound of formula (Ia) as shown below,

[0168]

[0169] In a certain embodiment, in the compound,

[0170] V is selected from C and N;

[0171] U selected from CR 2 , N;

[0172] W is selected from CR 3 , N;

[0173] X is selected from CR 4 , N;

[0174] Y is selected from CR 5 , N;

[0175] Z is selected from CR 6 , N;

[0176] R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0177] Ring A is independently selected from 0-4 R 7 Replaces:

[0178]

[0179] R 2 、R 3 、R 4 、R 5 、R 6 、R 7and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight a C1-C6 straight-chain or branched alkylamino group, a 3-10-membered cycloalkylamino group, a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkanoyl group, a 4-10-membered heterocyclic group, a C5-C12 heterobridged ring group, a C3-C10 heterospirocyclic group, a 6-10-membered aromatic ring, or a 5-10-membered aromatic heterocycle; wherein the heterocyclic group, heterobridged ring group, heterospirocyclic group, or aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0180] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0181]

[0182] L1 is selected from none,

[0183] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0184] La, Lb, Lc, Ld, Le, L a’ 、L e’ 、L f’ 、L g’ 、L h’ Independently selected from none, O, S, NR 8 、COR 9 、-SO2R 10 ; R 8is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、R L125 、RL126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R35 、R 36 、R 37 are independently selected from anhydrous, hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered Cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0185] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0186] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、RL119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、

[0187] Ring B is selected from the group consisting of: no, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0188] L2 is selected from none,

[0189] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, and 2p are independently selected from 0 to 6;

[0190] L2a, L2b, L2c, L2d, L2e, L2f, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 39 、COR 40 、-SO2R 41 ; R 39 、R 40 、R 41 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 37 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L221 、R L222 、R L223 、R L224 、R L225 、R L226Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、

[0191] The C ring is selected from the group consisting of no, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0192] For example, the compound represented by formula I is a compound of formula (Ia) shown below,

[0193]

[0194] Among them, L 2b’ 、L 2c’ 、L 2d’ 、L 2i’ Selected from N, CR 44 ; R 44 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or R44 With R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L231 、R L232 A substituted or unsubstituted 3-10 membered ring can be formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2 NR 33 R 34 -、

[0195] R 39 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、RL213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、

[0196] In one plan,

[0197] The structures of the compounds are shown in (II) and (III):

[0198]

[0199] V is selected from C and N;

[0200] X is selected from CR 4 , N;

[0201] Y is selected from CR 5 , N;

[0202] Z is selected from CR 6 , N;

[0203] R1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0204] Ring A is independently selected from 0-4 R 7 Replaces:

[0205]

[0206] R 4 、R 5 、R 6 、R 7 and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cyclic Alkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0207] R 42 、R 43selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkanoyl alkyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0208] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0209]

[0210] The fragments are selected from:

[0211]

[0212]

[0213] Or, also:

[0214]

[0215] In one plan,

[0216] The structure of the compound is shown in (IV), (V) or (VI):

[0217]

[0218] X is selected from CR 4 , N;

[0219] Y is selected from CR 5 , N;

[0220] Z is selected from CR 6 , N;

[0221] R 1is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0222] R 4 、R 5 、R 6 and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cyclic Alkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0223] C1-C6 straight chain or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight chain or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight chain or branched alkyl, C2-C6 straight chain or branched unsaturated hydrocarbon, C1-C6 straight chain or branched alkoxy, 3-10 membered cyclo Alkoxy, C1-C6 straight-chain or branched alkylamino, 3-10-membered cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0224] R 42 、R 43 selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkanoyl alkyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0225] Ring A is independently selected from 0-4 R 7 Replaces:

[0226]

[0227] R 7 Selected from:

[0228]

[0229] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0230] The fragments are selected from:

[0231]

[0232]

[0233] Alternatively, it can be:

[0234]

[0235] Another aspect of the present invention provides a compound as shown in formula I', its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof,

[0236]

[0237] in,

[0238] V is selected from C and N;

[0239] U selected from CR 2 , N;

[0240] W is selected from CR 3 , N;

[0241] X is selected from CR 4 , N;

[0242] Y is selected from CR 5 , N;

[0243] Z is selected from CR 6 , N;

[0244] R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched cycloalkyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0245] Ring A is independently selected from 0-4 R 7 Substituted 5-10 membered aromatic heterocycle; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0246] R 2 、R 3 、R 4 、R 5 、R 6 、R 7are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, substituted or unsubstituted unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0247] L is selected from linking groups that are non-hydrogen.

[0248] In one plan,

[0249] wherein V is selected from C and N;

[0250] U selected from CR 2 , N;

[0251] W is selected from CR 3 , N;

[0252] X is selected from CR 4 , N;

[0253] Y is selected from CR 5 , N;

[0254] Z is selected from CR 6 , N;

[0255] R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0256] Ring A is independently selected from 0-4 R 7 Replaces:

[0257]

[0258] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, substituted or unsubstituted unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0259] L is selected from linking groups that are non-hydrogen.

[0260] In one plan,

[0261] in,

[0262] V is selected from C and N;

[0263] U selected from CR 2 , N;

[0264] W is selected from CR 3 , N;

[0265] X is selected from CR 4 , N;

[0266] Y is selected from CR 5 , N;

[0267] Z is selected from CR 6 , N;

[0268] R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0269] Ring A is independently selected from 0-4 R 7 Replaces:

[0270]

[0271] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, substituted or unsubstituted unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0272] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0273]

[0274] L1 is selected from none,

[0275] a, b, and d are independently selected from 1-6;

[0276] c, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0277] La, Lb, Lc, Ld, Le, L a’ 、L e’ 、L f’ 、L g’ 、L h’ Independently selected from none, O, S, NR 8 ; R 8 is selected from hydrogen, a substituted or unsubstituted C3-C10 heterocyclic group, a substituted or unsubstituted C3-C10 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted C5-10 aromatic ring, a substituted or unsubstituted C5-10 aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted C1-C6 cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted C1-C6 cycloalkylamino group, 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 The substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight-chain or branched alkyl, C2-C6 straight-chain or branched unsaturated hydrocarbon, C1-C6 straight-chain or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight-chain or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、

[0278]

[0279] R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, substituted or unsubstituted unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0280] L b’ 、L c’ 、L d’、L i’ Independently selected from N, CR 36 ;

[0281] R 36 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 The substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight-chain or branched alkyl, C2-C6 straight-chain or branched unsaturated hydrocarbon, C1-C6 straight-chain or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight-chain or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 36 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2NR 31 R 32 、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2NR 31 R 32 、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2NR 31 R 32 、

[0282]

[0283] Ring B is selected from the group consisting of: none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclic group, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring; the substituents are independently selected from the group consisting of halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0284] L2 is selected from none,

[0285]

[0286] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, and 2p are independently selected from 0 to 6;

[0287] L2a, L2b, L2c, L2d, L2e, L2f, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 37 ; R 37 is selected from hydrogen, a substituted or unsubstituted C3-C10 heterocyclic group, a substituted or unsubstituted C3-C10 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted C5-10 aromatic ring, a substituted or unsubstituted C5-10 aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted C1-C6 cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted C1-C6 cycloalkylamino group, 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28SO2R 29 、-R 30 SO2 NR 31 R 32 、 The substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight-chain or branched alkyl, C2-C6 straight-chain or branched unsaturated hydrocarbon, C1-C6 straight-chain or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight-chain or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 37 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 R L221 、R L222 、R L223 、R L224 、R L225 、R L226Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、

[0288] The C ring is selected from the group consisting of none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclic group, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring; the substituents are independently selected from the group consisting of halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, C1-C6 cycloalkyloxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 、-R 11 OCOR 12 、-R 13 COOR 14 、-R 15 NR 16 COR 17 、-R 18 CONR 19 R 20 、-R 21 SO2R 22 、-R 23 OSO2R 24 、-R 25 SO2OR 26 、-R 27 NR 28 SO2R 29 、-R 30 SO2 NR 31 R 32 、 C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0289] In a certain embodiment, the compound of formula (I'), its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof,

[0290] in,

[0291] The structures of the compounds are as follows (II') and (III'):

[0292]

[0293] V is selected from C and N;

[0294] X is selected from CR 4 , N;

[0295] Y is selected from CR 5 , N;

[0296] Z is selected from CR 6 , N;

[0297] R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0298] Ring A is independently selected from 0-4 R 7 Replaces:

[0299]

[0300] R 4 、R 5 、R 6 、R 7are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, substituted or unsubstituted unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0301] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0302]

[0303] The preferred fragments are:

[0304]

[0305] Among them, R 38 and R 39 The definition of R 2 In one embodiment,

[0306] Wherein, the structure of the compound is as shown in (IV') and (V'):

[0307]

[0308] X is selected from CR 4 , N;

[0309] Y is selected from CR 5 , N;

[0310] Z is selected from CR 6 , N;

[0311] R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0312] R 4 、R 5 、R 6 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted C1-C6 straight or branched cycloalkyl group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted C1-C6 cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted C1-C6 cycloalkylamino group, substituted or unsubstituted unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 straight or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 straight or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0313] Ring A is independently selected from 0-4 R 7 Replaces:

[0314]

[0315] R 7 Selected from:

[0316]

[0317] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0318] The preferred fragments are:

[0319]

[0320]

[0321] Among them, R 38 and R 39 The definition of R 2 As stated.

[0322] In the present invention, each of the halogens may independently be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0323] In the present invention, each of the substituted or unsubstituted C1-C6 linear or branched C1-C6 alkyl groups may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including various isomers of hexyl); for example, methyl, ethyl or propyl.

[0324] In the present invention, the 3-10 membered cycloalkyl in each of the substituted or unsubstituted 3-10 membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,

[0325] In the present invention, each of the substituted or unsubstituted C1-C6 cycloalkyl groups in a straight or branched C1-C6 cycloalkyl group, the C1-C6 cycloalkyl group in a C1-C6 cycloalkylamino group, the C1-C6 cycloalkyl group in a substituted or unsubstituted C1-C6 cycloalkoxy group, and the C1-C6 cycloalkyl group in a C1-C6 cycloalkanoyl group may independently be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclobutyl group.

[0326] In the present invention, each of the substituted or unsubstituted 4-10 membered heterocyclic groups can be independently For example

[0327] In the present invention, each of the substituted or unsubstituted C3-C10 heterocyclic groups may be independently For example

[0328] In the present invention, each of the substituted or unsubstituted C3-C10 heterospirocyclic groups in the C3-C10 heterospirocyclic group can independently be 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 6-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example

[0329] In the present invention, each of the substituted or unsubstituted C5-C12 hetero-bridged ring groups is independently an octahydrocyclopenta[C]pyrrolyl, an octahydropyrrolo[3,4-c]pyrrolyl, a 3-azabicyclo[3.1.0]hexyl, a 2-oxa-5-azabicyclo[2.2.1]heptyl, or a 8-oxa-3-azabicyclo[3.2.1]octyl group; for example

[0330] In the present invention, each of the 6-10-membered aromatic rings in the substituted or unsubstituted 6-10-membered aromatic rings and the C5-10 aromatic ring in the substituted or unsubstituted C5-10 aromatic rings is independently a benzene ring or a naphthalene ring.

[0331] In the present invention, each of the substituted or unsubstituted 5-10 membered aromatic heterocycles can be independently

[0332]

[0333] In the present invention, each of the substituted or unsubstituted C5-10 aromatic heterocycles may be independently

[0334]

[0335] In a certain embodiment, the compound represented by Formula I or Formula I' is selected from:

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351] In one embodiment, the pharmaceutically acceptable salt of the present invention is a salt formed by the direct reaction of the compound of formula (I) or (I') with an inorganic acid, an organic acid or an inorganic base.

[0352] Second aspect

[0353] The present invention provides an aromatic compound as shown in formula E, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof.

[0354]

[0355] in, Indicates a single bond or a double bond;

[0356] R a is halogen, H, OH, O= or C1-C6 linear or branched alkyl-O-;

[0357] L is selected from a linking bond or a non-hydrogen linking group;

[0358] V, U, W, X, Y, Z, Q, R e The definitions of V, U, W, X, Y, Z, Q, R, and R in the compound of formula I or formula I' are as described above. e defined by any of the schemes.

[0359] In certain preferred embodiments of the present invention, certain groups in the compound as shown in Formula E are defined as follows (unmentioned groups are the same as those described in any embodiment of the present application, hereinafter referred to as "in a certain embodiment"), wherein,

[0360] Indicates a single bond or a double bond;

[0361] R a Halogen, H, OH, O= (when geminal hydrogen is substituted) or C1-C6 linear or branched alkyl-O-;

[0362] L is selected from a linking bond or a non-hydrogen linking group;

[0363] Q is selected from CR 2a , N;

[0364] V is selected from C and N;

[0365] U selected from CR 2 NR 2 (e.g. N);

[0366] W is selected from CR 3 , N;

[0367] X is selected from C (when connected to L), CR 4 , N;

[0368] Y is selected from C (when connected to L), CR 5 , N;

[0369] Z is selected from C (when connected to L), CR 6 , N;

[0370] R 2 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cycloalkyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon, hydroxy, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, and substituted or unsubstituted amino; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, amino, C1-C6 straight-chain or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 straight-chain or branched alkylamino, 3-10-membered cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, 3-10-membered cycloalkanoyl, 3-10-membered cycloalkyl, and 4-10-membered heterocyclic group; wherein the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0371] R e 、R 2a 、R3 、R 4 、R 5 and R 6 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamine alkyl, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. In certain preferred embodiments of the present invention, certain groups in the compound shown in Formula E are defined as follows (unmentioned groups are the same as those described in any embodiment of the present application, hereinafter referred to as "in a certain embodiment"), the compound shown in Formula I is shown in Formula Ea or Formula Eb,

[0372]

[0373] For example, as shown in Formula Ec, Formula Ed or Ee,

[0374]

[0375] In one scenario, R a When it is a halogen, it may be bromine or chlorine.

[0376] In one scenario, R a When it is a C1-C6 straight chain or branched chain alkyl-O-, the C1-C6 straight chain or branched chain alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0377] In one scenario, R 2 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, wherein the substituents are independently selected from deuterium, halogen, hydroxyl, amino, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl; the number of the substitutions is 1, 2 or 3;

[0378] For example, R 2 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutanamine-1-yl, 2-oxetanyl, 3-oxetanyl, 2-azetidinyl, 3-azetidinyl.

[0379] In one plan, U is selected from CR 2a 、N;X is selected from C、CR 4 、N;Y is selected from C、CR 5 、N;Z is selected from C、CR 6 , N; and at most two of X, Y and Z are N; one or two of U, V and W are N.

[0380] In one scenario, R 4 、R 5 、R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy; for example, H, halogen or substituted or unsubstituted C1-C6 straight chain or branched alkyl, and for example, H, F or methyl.

[0381] In one scenario, R e 、R 2a 、R 3 、R 4 、R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy; for example, H or methyl.

[0382] In one plan, for For example

[0383] For example

[0384] In one plan, for For example

[0385] In one plan,

[0386] Selected from:

[0387]

[0388]

[0389] In the present invention, when L is a non-hydrogen linker, it can be a conventional linker in PROTAC in the art.

[0390] In one embodiment, when L is a non-hydrogen linking group, L is as defined above in any embodiment of L in the compound of Formula I or Formula I'.

[0391] In one embodiment, L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0392] in,

[0393] L1 is selected from none,

[0394]

[0395] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0396] La, Lb, Lc, Ld, Le, Lf, Lg, L a’ 、L e’ 、L f’ 、L g’ 、L h’ Independently selected from none, O, S, NR 8 (-N(R 8 )-)、COR 9 (-C(=O)-R 9 -),-SO2R 10 ; R 8is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5-10 membered aromatic heterocyclic group, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (radical) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、RL125 、R L126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R34 、R 35 、R 36 、R 37 and independently selected from anhydrous, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane amino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino , 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (group), 5-10 membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (group) contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0397] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0398] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、RL117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 、R L133 、R L134 R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、

[0399]

[0400] Ring B is selected from the group consisting of none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of oxo (O=), deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (group), 5-10 membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0401] L2 is selected from none,

[0402] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, and 2s are independently selected from 0 to 6;

[0403] L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 39 (-N(R 39 )-)、COR 40 (-C(=O)-R 40 -),-SO2R 41 (-SO2-R 41 -);L 2b’ 、L 2c’ 、L 2d’ 、L 2i’ Selected from N, CR 44 ; R 39 、R 40 、R 41 、R 44 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、RL230 、R L241 、R L242 、R L243 、R L244 、R L245 、R L246 R is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (radical) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 39 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L221 、R L222 、R L223 、R L224 、R L225 、R L226Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R 44 With R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 、R L231 、R L232 A substituted or unsubstituted 3-10 membered ring can be formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -、-R 13 OCOR 14 -、-R 15 COOR 16 -、-R 17 NR 18 COR 19 -、-R 20 CONR 21 R 22 -、-R 23 SO2R 24 -、

[0404]

[0405] The C ring is selected from none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocycle (group); the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (group), 5-10 membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (group) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; and at least one of L1, B ring, L2 and C ring is not absent.

[0406] In one embodiment, two, three or four of L1, B ring, L2 and C ring are not absent.

[0407] In one scheme, L is

[0408] Wherein, L1 is selected from none,

[0409] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0410] La, Lb, Lc, Ld, Le, L a’ 、L e’ 、L f’ 、L g’ 、L h’ Independently selected from none, O, S, NR 8 、COR 9 、-SO2R 10 ; R 8 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R 9 、R 10 、R 11 、R12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 and independently selected from anhydrous, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered Cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkylamino group, a C1-C6 straight-chain or branched alkanoyl group, a 3-10-membered cycloalkanoyl group, a 4-10-membered heterocyclic group, a C5-C12 heterobridged ring group, a C3-C10 heterospirocyclic group, a 6-10-membered aromatic ring, or a 5-10-membered aromatic heterocycle; wherein the heterocyclic group, heterobridged ring group, heterospirocyclic group, or aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0411] L b’ 、L c’ 、L d’ 、Li’ Independently selected from N, CR 38 ;

[0412] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R34 、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、

[0413] Ring B is selected from the group consisting of: none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0414] L2 is selected from none,

[0415] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, and 2p are independently selected from 0 to 6;

[0416] L2a, L2b, L2c, L2d, L2e, L2f, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 39 、COR 40 、-SO2R 41 ; R 39 、R 40 、R 41 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 37 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L221 、R L222 、R L223 、R L224 、R L225 、RL226 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2NR 33 R 34 、

[0417] The C ring is selected from the group consisting of no, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle; the substituents are independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0418] In one embodiment, L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0419]

[0420] Its fragment is: (connected to T on the left)

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427] or a single cis-trans isomer or a mixture thereof (when cis-trans isomers exist);

[0428] For example

[0429]

[0430] In one embodiment, the compound represented by Formula E or a pharmaceutically acceptable salt thereof is selected from the following structures:

[0431]

[0432]

[0433]

[0434]

[0435] The third aspect

[0436] The present invention provides a ligand of a ubiquitin ligase connected to a ligand-linker for targeting protein degradation as shown in formula E3,

[0437]

[0438] Among them, Q, U, V, W, X, Y, Z and R e The definitions of Q, U, V, W, X, Y, Z and R in the aromatic compound represented by formula E, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof are as described above. e defined.

[0439] The present invention provides a ligand for ubiquitin ligase, which comprises a structure as shown in formula E3,

[0440]

[0441] Among them, Q, U, V, W, X, Y, Z and R e The definitions of Q, U, V, W, X, Y, Z and R in the aromatic compound represented by formula E, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof are as described above. e defined.

[0442] The ligand of the ubiquitin ligase is connected to the linker and further connected to the targeted degradation protein ligand.

[0443] In one embodiment, position 1 is connected to a linker,

[0444]

[0445] The fourth aspect of the present invention provides a linker-ubiquitin ligase ligand connected to a ligand targeted for protein degradation as shown in Formula E2,

[0446]

[0447] Among them, L, Q, U, V, W, X, Y, Z and R e The definitions of L, Q, U, V, W, X, Y, Z and R in the aromatic compound represented by formula E, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof are as follows: e defined.

[0448] The present invention provides a linker-ubiquitin ligase ligand comprising a structure as shown in Formula E2,

[0449]

[0450] Among them, L, Q, U, V, W, X, Y, Z and R e The definitions of L, Q, U, V, W, X, Y, Z and R in the aromatic compound represented by formula E, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof are as follows: e defined.

[0451] The linker-ubiquitin ligase ligand is connected to the targeted degradation protein ligand through the linker.

[0452] In one embodiment, position 1 is connected to a ligand that targets protein degradation.

[0453]

[0454] The fifth aspect

[0455] The present invention provides an aromatic compound as shown in Formula E as described above, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, a ligand of a ubiquitin ligase of a ligand-linker as described above (linked to a targeted degradation protein as shown in Formula E3), or a ligand of a linker-ubiquitin ligase as described above (linked to a ligand of a targeted degradation protein as shown in Formula E2) for preparing a ligand-drug conjugate; wherein the E3 fragment shown below can be used as a (recruiting) ligand of the E3 ubiquitin ligase,

[0456]

[0457] The (recruiting) ligand of the E3 ubiquitin ligase can bind to the Cereblon (CRBN) ligase.

[0458] Wherein, the ligand-drug conjugate can be a protein targeted degradation chimera (PROTAC) or an antibody-drug conjugate (ADC).

[0459] The sixth aspect

[0460] The present invention provides an aromatic compound (PROTAC compound) as represented by formula X, its enantiomers, diastereomers, racemates and mixtures, or pharmaceutically acceptable salts thereof.

[0461]

[0462] Wherein, T is the ligand group that targets protein degradation;

[0463] L, Q, U, V, W, X, Y, Z and R e The definitions of L, Q, U, V, W, X, Y, Z and R in the aromatic compound represented by formula Y above are as follows: e As stated.

[0464] In certain preferred embodiments of the present invention, certain groups in the compound represented by Formula X are defined as follows (unmentioned groups are the same as those described in any embodiment of the present application, hereinafter referred to as “in a certain embodiment”), and the compound represented by Formula X is represented by Formula Xa or Formula Xb,

[0465]

[0466] For example, as shown in Formula Xc, Formula Xd or Formula Xe,

[0467]

[0468] In a certain embodiment, T is selected from the following:

[0469] The MAT2A targeting ligand group can be:

[0470]

[0471] The SOS1 targeting ligand group can be:

[0472]

[0473] The DGKα targeting ligand group can be:

[0474]

[0475] SIK2 and SIK3 targeting ligand groups can be:

[0476]

[0477] The KRAS G12D targeting ligand group can be:

[0478]

[0479] The POLθ targeting ligand group can be:

[0480]

[0481] The Cbl-b targeting ligand group can be:

[0482]

[0483] PARG targeting ligand groups can be:

[0484]

[0485] DNA-PK targeting ligand groups can be:

[0486]

[0487] The ATR targeting ligand group can be:

[0488]

[0489] The NMT targeting ligand group can be:

[0490]

[0491] STAT3 targeting ligand groups can be:

[0492]

[0493] In one embodiment, the ligand group T that targets the protein for degradation is Its definition is as described in any one of the above formula I or formula I',

[0494] For example, V is selected from C and N;

[0495] R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cycloalkyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0496] Ring A is independently selected from 0-4 R 7 Substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle; the aromatic heterocycle (group) contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl , substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkoxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, substituted or unsubstituted C1-C6 straight or branched alkanoyl group substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, a 4-10 membered heterocyclic group, a C5-C12 heterobridged ring group, a C3-C10 heterospirocyclic group, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered cycloalkyl, a C1-C6 straight or branched alkyl-C(=O)-, a 3-10 membered cycloalkyl-C(=O)-; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0497] In one embodiment, the ligand group T that targets the protein for degradation is Among them, R 1 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, 3-10 membered cycloalkyl, wherein the substituents are independently selected from halogen, hydroxyl, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy; the number of the substitutions is 1, 2 or 3;

[0498] For example, R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl; for example -CF2.

[0499] In one embodiment, the ligand group T that targets the protein for degradation is in, for

[0500] In one embodiment, the ligand group T that targets the protein for degradation is wherein the A ring is independently selected from 0-4 R 7 Substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle;

[0501] For example, ring A is independently selected from 0-4 R 7 Replaces:

[0502]

[0503] For example

[0504]

[0505] In one embodiment, Ring A is independently selected from:

[0506]

[0507] In one scenario, R 7 Selected from substituted or unsubstituted 4-10 membered heterocyclic groups, substituted or unsubstituted C5-C12 heterobridged ring groups, substituted or unsubstituted C3-C10 heterospirocyclic groups, substituted or unsubstituted C1-C6 straight or branched chain alkylamino groups;

[0508] The substituents may be independently selected from deuterium, halogen, C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched alkoxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight chain or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

[0509] In one scenario, R 7 Selected from: a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted C1-C6 straight or branched chain alkylamino group;

[0510] The substituents may be independently selected from halogen, C1-C6 linear or branched alkyl, 4-10 membered heterocyclyl, substituted or unsubstituted 3-10 membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

[0511] In one scenario, R 7 Selected from:

[0512]

[0513] For example,

[0514]

[0515] In one plan, for

[0516] In one embodiment, Ring A is selected from:

[0517]

[0518] In one embodiment, the ligand group T that targets the protein for degradation is When , it is an IRAK4 targeting ligand group.

[0519] In one embodiment, said target degradation protein is selected from SOS1, SIK2, SIK3, IRAK4, MAT2A, HPK1, menin, MLL, Cbl-b, POLθ, DNA-PK, STAT3, PARG, KIT, EPHA2, PDE4D, SRC, BRAF, KYN, ITK, PARP 1、EPHB2、BLK、IGF1R、TGFBR1、AKT2、AKT1、PTK2、MAPK1、MAPK14、MCL1、BRD3、BRD4、AKT3、PAK4、MAPKAPK2、TNK2、SIRT2、DAPK1、ABL2、PRKAA2、KAT2A、PBR M1、EIF2AK2、MAP3K7、MAPT、RIPK1、IRAQ1、MAP4K1、MARK4、BRD9、RIPK2、LIMK1、STK38、TRIM24、SMARCA4、PRKAA1、TBK1、KRAS、SMARCA2、PCNA、BRD7、SUZ1 2、IKZF1、HTT、SNCA、SLC9A1、FER、MAP4K2、DLG4、IKZF3、SMAD3、PDE4A、HMGCR、ABL1、RARA、FLT3、RARGFLT1、EZH2、EPHA1、AURKB、PLK4、PLK1、WEE1、CHEK1 、CDC7、MDM2、MAPK6、BUB1、ESRRA、BCL6、MAPK12、CRABP2、HIPK1、ADRM1、CDC20、BUB1B、CD274、PDCD1、ERBB2、EPHA3、PIK3CG、MAP2K1、LCK、MAP2K2、PDE6D 、GSK3B、PRKCI、FKBP1A、DHODH、PIK3CA、PDE4B、FYN、TYK2、PDK1、PDK2、PDK3、YES1、GSK3A、CSNK2A1、PTK2B、MAPK10、MAPK9、MAPK8、METAP2、BRD、2、MAPK3 、MAPK3K11、RPS6KB1、CSK、MERTK、STK17B、CSNK2A2、RPS6KA1、MAPK13、GAK、CLK1、STK4、EIF4E、STK10、LRRK2、TAOK3、MARK2、CSNK1D、AAK1、IRAK3、CAMKK 1、EED、CSNK1A1、NEK1、BMP2K、MAPK7、ULK1、RPS6KA3、PTPN11、LIMK2、CSNK1E、EIF2AK4、MAP2K5、MAP4K5、SNRK、EEF2K、SGK3、AHR、NEK4、NEK9、CIT、LATS1、<h2 style=";text-align:left;direction:ltr">MINK1、RPS6KA4、NEK3、MAST3、STK32C、EPHB4、PARP2、PTK6、PARP3、BRDT、MA PKAPK5、MAPKAPK5、MAP3K1、TTK、PIM2、PKMYT1、MKNK2、KAT2B、NEK2、HASPIN PIR, CYP1B1, ERN1, MELK, COQ8A, RIOK2, RPS6KA6, MAP3K20, MAPKAPK3, ULK3, MAP3K21, COQ8B, TNK1, BMPR1A, STK17A, TESK2, NLK, STK35, PKN3, STK33, S BK1、SLC9A2、CSNK2A3、TACC3、GSPT1、SLC9A7、RPS6KC1、TBCK、CRABP1、BCKD K、TRPM7、TRIB3、UHMK1、PDIK1L、STK40、SLC9A4、EPHB3、MAP3K12、DDR2、RARB 、PDE4C、IDO1、SLC9B1、PEAG1、TOP1、TOP2A、CXCR4、ERBB4、HCK、SYK、ACLY、I MPDH2、TOP2B、KEAP1、NR3C1、DNMT1、TXNRD1、PDGFRA、TUBB、TUBB2B、GABRA5、 EPHB1、KCNQ2、GRIK2、CALM1、DNMT3A、KIF5B、POLD1、CUL4A、TUBB2A、PDGFRB 、FGR、PRKCG、SCN3A、BACE1、HSP90AA1、HSP90AB1、PDPK1、BIRC2、CHEK2、MAP3 K5、CASP1、NAE1、PIK3R1、IKBKB、PSMA1、ITGB1、PRKDC、PIK3R2、FGF2、ZAP70 、PIP4K2B、GAPDH、FASN、PKM、VCP、KDM1A、TAB1、EP300、VRK1、RPS6KA5、UBA2、 LDHA、TKT、HPRT1、KDM2A、EHMT1、CAMK1D、WDR5、EHMT2、RAC1、OGT、NCOA1、PH GDH、ARHGDIA、RBBP4、BPTF、KAT5、NOTCH1、PPIA、FKBP4、CREBBP、POLB、APEX1 、CCNT1、EIF4A1、USP7、CTNNB1、TXN、DDX3X、NLRP3TNKS、PAK3、PKN1、CISD1、 WNK1、BRD1、XIAP、PRDX1、KMT2A、KDM5C、RPA1、CAMK1、EIF4A3、TAF1、ALKBH3、MAP3K2、RELA、NCOR2、PRPF4B、RPS3、RPSA、RPS27A、RPS20、RPL18、RPS5、RPL6、RPLP0、RPL3、RPL18A、RPL28、RPL19、RPL34、RPS13、RPL14、RPS15、RPL5、BPS10、RPL35、RPS6、RPS24、RPS2、RPL11、RPS8、RPL32、RPS3A、RPL10、RPL7A、RPL30、RPL8、RPL26、RPS14、RPL13、RPS9、RPS21、RPS7、RPL38、RPL4、RPL15、RPS17、RPS23、RPL14、RPL12、RPS4X、RPL23A、RPL10A、RPS18、SLC7A5、ORAI1PI4K2A、SUMO1、HSPA8、HSPD1、CSNK2B、PPP2CA、FSCN1、BID、DCUN1D1、USP28、TP53BP1、KDM5B、KDM5A、BAZ2A、UBE2I、SPIN1、TDP2、RBBP5、PRMT1、MLLT1、SETDB1、ARNT、SNRNP200、WRN、ATAD2、SQSTM1、DPY30、JMJD1C、MDM4、L3MBTL3、LDLR、GLUL、HRAS、APOBEC3G、TSG101、LRP6、ENO1、ANXA2、SOD1、KAT6A、CBS、RUVBL1、UHRF1、HSPA5、SQLE、NEDD4、RBBP7、UBE2N、NRAS、PTEN、RHOA、RNF31、PIN4、TPI1、PPIG、NCOA2、FOXO1、PSIP1、MACROD2、SETD2、NFKBIA、PLA2G4A、ICAM1、ACVR1B、CYBB、STAMBP、NFKB1、PAK2、ITPR1、ELAVL1、NFKB2、STAT1、RIPK3、STAT5A、BRSK2、ERCC4、NPM1、IKBKG、PBK、CD22、APC、PLCG1、ING2、ERCC1、KDM2B、ETV6、CBX4、USP25、HSF1、TRIM33、HNRNPA1、TERF2、PTBP1、NR2C2、NOTCH2、USP8、RGS12、ATF1、PPM1B、PDCD4、LMNA、MITF、ADCY3、EEF1A1、MYH9、BCL3、XRCC6、USP10、MAGI3、DVL1、VDAC2、MDH1、CBX5、CBX1、BRD8、TSNAX、CREB1、RBCK1, UBA1, MACROD1, PELP1, BAP1, TERF2IP, LARP7, UBA7, SUMO2, SUMO3, G ICYF2, S100A10, GRIK3, TLR8, DYRK2, NOS1, WNK3, TLR2, BCL2L11, SLC11A2, A BCB11, ITGAL, CA12, PDE2A, EPHA1, PRKCA, CA2, EPHA4, ACE, RAF1, GLA, MAOB AKR1B1, GSR, UMPS, THRA, GART, FDPS, ADH5, RXRB, DHFR, PDE10A, IDH1, ITGB 2. COMT, PRKCQ, IMPDH1, TUBB3, TUBA1A, ADA, GABRG2, GABBR2, GABRB2, GABR B3, GABBR1, PRKCE, SIGMAR1, MTOR, SLC29A1KCNJ11, GAA, PRKCH, PIK3CD, MAO A. SOAT1, BCR, PSMB5, XPO1, MALT1, IDH2, RRM1, NDUFA10, EPHA5, TUBB4A, TU BB1, TUBB6, TUBA4A, TUBA1C, CACNB1, ATP1A2, ATP1A3, GRIA1, GABRB1, and ATP1A 1. KCNQ5, PRKCD, CACNA1H, GRIA4, KCNA3, S1PR3, NISCH, PRKCB, TLR7, CACNA 18. CACNA2D2, CPT2, FAAH, UGCG, PDE1A, HPD, CA5B, CA5A, ANO1, DHCR24, CCDC 6. EML4, KCNA2, KCNB2, PLA2G2A, MIF, GBA, INSR, GSTP1, PNP, FDFT1, CASP8. CASP9, CASP6, CASP7, CASP3, ERAP1, UBA3, PSEN1, FNTA, METAP1, CASP2, ITGA 4. ABCB1, NTSR1, GRM3, LNPEP, APH1A, NCSTN, PSMB1, PSMA2, PSMA7, PSMB7 SMA5, PSMA4, PSMA3, PSMA6, PSMB2, EGLN1, PSMB6, PSMB4, PSMB8, PSMB9, PSMB 10. FNTB, PSMB3, ERAP2, DNPEP, STS, SELL, CCR1, PIK3CB, PORCN, P4HTM, ATR. CASP10, NPEPPS, RNPEP, LAP3, DPYD, XPNPEP1, NAMPT, PRKACA, PSMD14, ARAF.PRKACB、ITGAV、TGM2、ACE2、PAK1、CAPN1、CDC42、NMT1、CAMK2D、AKR1B10、P4HB、CDC42BPB、CAMK2G、PTP4A1、G6PD、LSS、ALB、ECE1、CTSD、CTSB、ILK、MGLL、CASK、ADAM17、PYGL、ATIC、HSD17B10、SRPK1、LTA4H、STK16、ADK、GRK6、ACVR1、CES1、CSNK1G3、CAMK2A、BCAT1、MAP2K4、ACACB、MTAP、AHCY、STK24、GALK1、MAP2K6、DCPS、SAE1、CARM1、CAMK4、TNIK、DCK、PHKG2、DYRK1A、CBR1、DAPK3、FEN1、OXSR1、CLK3、UPP1、AKR1C1、AKR1C3、CD38、SORT1、GALNT2、LGALS1、HK2、HK1、HMOX1、PARP14、GRB2、HMOX2、DDAH1、PARP12、OAT、SIRT6、PGK1、KAT8、SPR、CTH、SIRT5、GSTO1、PFKFB3、CTBP2、PARP10、SMYD3、SULT1A1、AKR1C4、GSTM2、STRADA、BMPR2、PIK3C2A、PTPN1、IDE、CAPNS1、GLO1、UCHL1、NPC1、FES、CSNK1G1、SLK、MAP2K7、PIK3C3、HAO1、PASK、STK25、KYNU、DUT、PTPN22、NEK7、NNMT、NRP1、RPS27、DDR1、LPL、ABCC1、ASIC1、SLC2A1、PTPRS、ABCG2、SLC1A3、ALC1A1、TRPM2、GRM1、MLKL、RAB7A、AHCYL1、NAAA、CAMK2B、NT5E、CTSL、HSPA1A、FABP5、CTSC、ACVR2A、MMP14、HSP90B1、GLB1、PTPRF、ST14、PKN2、AGR1、PGAM1、PPP1CA、PTP4A2、MAST1、PI4KB、VRK2、SCD、MUDT1、CSNK1G2、EBP、EIF2AK3、ATP2A2、MAN1B1、CDKL5、MAP4K4、DPP8、MKNK1、PREP、FKBP5、SIRT1、STK3、LIG1、DUSP3、CAMKK2、PRKAB1、MTR、UCHL3、ESRRB、RIOK、TRAP1、PIN1、<h2 style=";text-align:left;direction:ltr">ALDH1A2、PAK6、AOX1、DPP9、ACP1、PTPN7、TLK2、SMG1、YWHAZ、ALDH1A1、PHF8 、PRKAG1、PEMT3、SF3B3、AKT1S1、CHUK、RPL36A、RPL31、RPL19、RPL16、RPL22 、RPL12、RPL25、RPL21、RPL23、RPL36、RPS4Y1、RPL27、RPS15A、RPS11、RPL13 A、RPL37、RPL7、RPL29、RPL27A、RPL35A、RPS26、RPL37A、RPS29、RPS28、RPL17 、FAU、SLC2A3、ASAH1、BTN3A1、NMT2、PI4KA、GNG2、GNA11、PRMT8、LYPLA1、LG ALS3、UBE2D3、S100A4、LGALS9、PIP4K2A、LGMN、GNB1、HINT1、FTO、BRPF1、ST6 GAL1、INPPL1、PI4K2B、PARP16、HEXA、SGPL1、MGAT2、LGALS8、ASH2L、SARM1、 LYPLA2、ASNS、PABPC1、PRMT5、DNPH1、WDR48、WDR77、ATAD2B、COPS5、PFKFB2、 KDM4B、PRKAB2、MEN1、PMM2、RPTOR、MLST8、DTYMK、PTPN9、SHMT2、PARG、GLS、 APAF1、KSR2、SORD、SMS、GALE、PGD、HNMT、QDPR、GSTK1、SRM、FARS2、GNAI3、CL TC、RHOC、DNM1、GALNT10、MTHFD1、RAB2A、USP5、GDA、UCK2、HIF1AN、MDH2、YW HAG、CFPT1、FN1、PLAUR、NCS1、GNAI1、HCN2、QSOX1、TLR1、USP14、KSR1、RAB9A CCR7, PLCG2, GFR, PTPRG, FUT8, POR, RECQL, UNG, CAD, NCOA3, CTSDP1, KDM1B, TEAD1, DDO, SLC1A5, CD81, GGT1, ADIPOR1, RAP1A, RAB29, GOPC, UTRN, GNA O1、DDOST、PYGB、RABGTB、VAV1、SDHA、QTRT1、CISD2、DHPS、PPP2R5A、PANK2 、NEDD8、DOHH、UBE2M、RNASEL、SYNJ1、DUS2、CYCS、PPP1CC、HMBS、PNPO、PPIF、<h2 style=";text-align:left;direction:ltr">DPP7、MARK1、PRCP、PIP4K2C、AKR1A1、ME1、ACACA、CD74、NFATC1、RUNX1、PTP RC、CAPN2、RB1、ITGA5、ITGA2、ADAM10、DAGLB、SLC16A1、ABCC2、SCARB1、DAG LA, SLC47A1, PIK3C2B, GBA2, NCEH1, WNK2, LIPE, SLC27A1, PTPRA, PTPN2, ITGB5, CTSH, MAN2B1, ITPR2, ITPR3, ABHD12, CTSZ, SL6A12, SL6A11, KCNN3, SLC 27A4、PTPN6、AMPD3、PLEC、PLD1、PAM、PRKD2、TYRO3、RYR2、PIP5K1C、LIPA、P PIB、ATP2A3、CPT1A、ICMT、HSD17B7、ELOVL6、DHCR7、ATP2A1、RIOK3、HSPB1、 PTPN12、PLAA、MPI、MATK、UBA6、MAP2K3、RPS6KA2、MAP3K4、PARP4、EIF4H、TE SK1、MLX、NEK6、ALDH1B1、ATM、CDYL、TAOK1、STAT6、MGMT、PPID、STAT5B、TXNR D2, TXNRD3, STK39, STK38L, CDC42BPA, ATG4B, DCLK2, TUBAL3, MAP3K3, PPME1, RPLP1, GSDMD, C9, HMGB1, DAB2IP, PHLPP1, PHKA2, PHKA1, PHKB, EWSR1, SL C16A3, PTPRE, NEU1, PCSK6, ANTXR2, STIM1, DNM2, SDHB, MAPKAP1, PTGES2, TMEM97, SPPL2A, SLC7A11, ABHD6, DGKA, NAPRT, BAX, SPTLC1, SPTLC2, MGAT1, E PHX1、FADS1、ABHD5、CBFB、POLR1A、MPG、GYS1、PRKAG2、ASF1A、MED23、PFKFB 4、KDM3A、USP9X、MAX、MBD2、CBX8、FLI1、ATRIP、RICTOR、UBLCP1、DCTPP1、TC F4、CNOT7、OGFRL1、MVD、IL6ST、DOCK2、C3、PPM1A、SHC1DVL2、NPR3、GSTM1、P PP3CA、SLC12A2、ABCC3、ABCC4、GGH、HCN3、ADCY1、ADCY5、HKDC1、PPT1、PRNP、CXCR5, SMPD2, SLC6A15, MANBA, AGPAT2, ABHD16A, GCLC, HAGH, SENP1, DNAJA1, SCP2, AMPD2, ERCC5, SENP7, NADK, RBBP9, CD2, CD44, CD47, CD63, SLC27A2, PLEKHA1, ITGA 3. SPPL2B, PLTP, SLC20A2, ADCY6, IGF2R, EZR, GNAQ, INPP5A, CRACR2A, LANCL2, SMPD3, EHD1, PDIA6, CHN2, CDH2, TFPI, CD58, SLC2A8, PTPRM, STIM2, ADCY7, SLC20A1, IT GA1, RABGGTA, MAP1B, PAFAH1B2, RIN1, PLCD1, RGS19, PNPLA2, ST3GAL3, GALNT1, ATP6V1B2, ATP6AP1, PHLPP2, GNPAT, PPP3CB, SLC25A20, ELOVL1, MAN2A1, SLC33A1, GAB 1. ARHGEF12, MAP2, MBTD1, PNKP, NLRP1, TXN2, EEF1A2, GOT1, PRMT7, MYH10, TPP2, EYA3, SSU72, AMDHD2, CLPX, MECP2, KPNA2, PSMG1, CBX6, PPP2R2A, UBE2V1, PPIC, PGK2. ,

[0520] In the present invention, each of the halogens may independently be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0521] In the present invention, each of the substituted or unsubstituted C1-C6 linear or branched C1-C6 alkyl groups may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including various isomers of hexyl); for example, methyl, ethyl or propyl.

[0522] In the present invention, the 3-10 membered cycloalkyl in each of the substituted or unsubstituted 3-10 membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,

[0523] In the present invention, each of the substituted or unsubstituted C1-C6 cycloalkyl groups in a straight or branched C1-C6 cycloalkyl group, the C1-C6 cycloalkyl group in a C1-C6 cycloalkylamino group, the C1-C6 cycloalkyl group in a substituted or unsubstituted C1-C6 cycloalkoxy group, and the C1-C6 cycloalkyl group in a C1-C6 cycloalkanoyl group may independently be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclobutyl group.

[0524] In the present invention, each of the substituted or unsubstituted 4-10 membered heterocyclic groups can be independently

[0525] For example

[0526] In the present invention, each of the substituted or unsubstituted C3-C10 heterocyclic groups may be independently

[0527] For example

[0528] In the present invention, each of the substituted or unsubstituted C3-C10 heterospirocyclic groups in the C3-C10 heterospirocyclic group can independently be 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 6-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example

[0529] In the present invention, each of the substituted or unsubstituted C5-C12 hetero-bridged ring groups is independently an octahydrocyclopenta[C]pyrrolyl, an octahydropyrrolo[3,4-c]pyrrolyl, a 3-azabicyclo[3.1.0]hexyl, a 2-oxa-5-azabicyclo[2.2.1]heptyl, or a 8-oxa-3-azabicyclo[3.2.1]octyl group; for example

[0530] In the present invention, each of the 6-10-membered aromatic rings in the substituted or unsubstituted 6-10-membered aromatic rings and the C5-10 aromatic ring in the substituted or unsubstituted C5-10 aromatic rings is independently a benzene ring or a naphthalene ring.

[0531] In the present invention, each of the substituted or unsubstituted 5-10 membered aromatic heterocycles can be independently

[0532] In the present invention, each of the substituted or unsubstituted C5-10 aromatic heterocycles may be independently

[0533] In certain preferred embodiments of the present invention, certain groups in the aromatic compound represented by Formula X, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof are defined as follows (unmentioned groups are the same as those described in any embodiment of the present application, hereinafter referred to as "in a certain embodiment"), and the compound represented by Formula X is represented by the compound represented by Formula I as described in any of the previous embodiments, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, or by the compound represented by Formula I' as described in any of the previous embodiments, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof.

[0534] In a certain embodiment, in the compound represented by formula X,

[0535] Q is selected from CR 2a , N;

[0536] V is selected from C and N;

[0537] U selected from CR 2 , N;

[0538] W is selected from CR 3 、N

[0539] X is selected from CR 4 , N;

[0540] Y is selected from CR 5 , N;

[0541] Z is selected from CR 6 , N;

[0542] R 2 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutan-1-yl, 2-oxetanyl, 3-oxetanyl, 2-azetidinyl, 3-azetidinyl;

[0543] R e 、R 2a 、R3 、R 4 、R 5 and R 6 and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group. substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino ... -10-membered cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5-10-membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (group) containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0544] L is selected from a linking group that is non-hydrogen;

[0545] T is a ligand that targets proteins for degradation.

[0546] In a certain embodiment, in the compound represented by formula X,

[0547] Q is selected from CR 2a , N;

[0548] V is selected from C and N;

[0549] U selected from CR 2 , N;

[0550] W is selected from CR 3 、N

[0551] X is selected from CR 4 , N;

[0552] Y is selected from CR 5 , N;

[0553] Z is selected from CR 6 , N;

[0554] R 2 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutan-1-yl, 2-oxetanyl, 3-oxetanyl, 2-azetidinyl, 3-azetidinyl;

[0555] R e 、R 2a 、R 3 、R 4 、R 5 and R 6 and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group. substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino ... -10-membered cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5-10-membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (group) containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0556] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0557]

[0558] L1 is selected from none,

[0559] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0560] La, Lb, Lc, Ld, Le, L a’ 、L e’ 、L f’ 、L g’ 、L h’ Independently selected from none, O, S, NR 8 、COR 9 、-SO2R 10 ; R 8 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring (group), a substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (radical) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 Can be respectively with R L111 、R L112 、R L113 、R L114 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R 9 、R 10 、R11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 and independently selected from anhydrous, hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane amino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (group), 5-10 membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (group) containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0561] L b’ 、L c’、L d’ 、L i’ Independently selected from N, CR 38 ;

[0562] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L25 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 Can be used with R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 、R L121 、R L122 、R L123 、R L124 、R L125 、R L126 、R L127 、R L128 、R L129 、R L130 、R L131 、R L132 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L111 、R L112 、R L113 、R L114 、R L115 、R L116 、R L117 、R L118 、R L119 、R L120 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32SO2 NR 33 R 34 、 R L121 、R L122 、R L123 、R L124 、R L125 、R L126 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L127 、R L128 、R L129 、R L130 、R L131 、R L132 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、

[0563]

[0564] Ring B is selected from none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocycle (group); the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight chain or branched alkyl, C2-C6 straight chain or branched unsaturated hydrocarbon group, C1-C6 straight chain or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight chain or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (group), 5-10 membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0565] L2 is selected from none,

[0566] 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, and 2p are independently selected from 0 to 6;

[0567] L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L 2a’ 、L 2e’ 、L 2f’ 、L 2g’ 、L 2h’ Independently selected from none, O, S, NR 39 、COR 40 、-SO2R 41 ; R 39 、R 40 、R 41 is selected from hydrogen, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted C5-C12 heterobridged ring group, a substituted or unsubstituted C3-C10 heterospirocyclic group, a substituted or unsubstituted 6-10 membered aromatic ring (group), a substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted 3-10 membered cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted 3-10 membered cycloalkyloxy group, a substituted or unsubstituted C1-C6 straight or branched alkylamino group, a substituted or unsubstituted 3-10 membered cycloalkylamino group, 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (radical), 5-10 membered aromatic heterocyclic ring (radical); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 37 Can be respectively with R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L210 、R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、R L227 、R L228 、R L229 、R L230 A substituted or unsubstituted 3-10 membered ring is formed by C, N, O, and S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L211 、R L212 、R L213 、R L214 、R L215 、R L216 、R L217 、R L218 、R L219 、R L220 Any two groups can form a substituted or unsubstituted 3-12 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L221 、R L222 、R L223 、R L224、R L225 、R L226 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 R L227 、R L228 、R L229 、R L230 、R L231 、R L232 Any two groups can form a substituted or unsubstituted 3-10 membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、

[0568] The C ring is selected from none, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged ring group, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocycle (group); the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight chain or branched alkyl, C2-C6 straight chain or branched unsaturated hydrocarbon group, C1-C6 straight chain or branched alkoxy, 3-10 membered cycloalkyloxy, C1-C6 straight chain or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 、-R 13 OCOR 14 、-R 15 COOR 16 、-R 17 NR 18 COR 19 、-R 20 CONR 21 R 22 、-R 23 SO2R 24 、-R 25 OSO2R 26 、-R 27 SO2OR 28 、-R 29 NR 30 SO2R 31 、-R 32 SO2 NR 33 R 34 、 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10 membered aromatic ring (group), 5-10 membered aromatic heterocyclic group (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic group (group) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0569] T is a ligand that targets proteins for degradation.

[0570] In one plan,

[0571] Q is selected from CR 2a , N;

[0572] V is selected from C and N;

[0573] U selected from CR 2 , N;

[0574] W is selected from CR 3 , N;

[0575] X is selected from C, CR 4 , N;

[0576] Y is selected from C, CR 5 , N;

[0577] Z is selected from C, CR 6 , N;

[0578] R 2 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutan-1-yl, 2-oxetanyl, 3-oxetanyl, 2-azetidinyl, 3-azetidinyl;

[0579] R e 、R 2a 、R 3 、R 4 、R 5 and R 6and independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring (group), substituted or unsubstituted 5-10 membered aromatic heterocyclic ring (group), substituted or unsubstituted C1-C6 straight or branched alkyl group, substituted or unsubstituted 3-10 membered cycloalkyl group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group. substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino ... -10-membered cycloalkylamino, C1-C6 straight-chain or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5-10-membered aromatic heterocyclic ring (group); the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (group) containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0580] L is selected from a non-hydrogen linking group; the general formula of the linking group is:

[0581]

[0582] The fragment is:

[0583]

[0584]

[0585]

[0586]

[0587]

[0588] A single cis-trans isomer or a mixture thereof;

[0589] T is a ligand that targets proteins for degradation.

[0590] Seventh aspect

[0591] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a substance B and one or more pharmaceutically acceptable carriers; the substance B is a compound represented by formula I according to any one of claims 1 to 5 or 8, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; a compound represented by formula I' according to any one of claims 6 to 8, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; an aromatic compound represented by formula E according to any one of claims 9 to 12, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; or an aromatic compound represented by formula X according to any one of claims 16 to 18, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof. The pharmaceutical composition can be used to treat and prevent diseases associated with or mediated by kinase 4 (IRAK4); the kinase 4 (IRAK4) can be tumor necrosis factor α (TNFα) and / or interleukin-1 receptor-associated kinase 4 (IRAK4); the disease associated with or mediated by tumor necrosis factor α (TNFα) and / or interleukin-1 receptor-associated kinase 4 (IRAK4) can be an autoimmune disease or cancer.

[0592] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I) or (I') as described above, its enantiomers, diastereomers, racemates, mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers (or pharmaceutical excipients, such as diluents or excipients). The pharmaceutical composition can be used to treat and prevent autoimmune diseases or cancers associated with or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4).

[0593] The present invention provides a pharmaceutical composition for treating and preventing autoimmune diseases or cancers associated with or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), comprising a compound of general formula (I) or (I'), its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0594] Furthermore, the pharmaceutically acceptable salt thereof accounts for 1 to 99 wt % of the total weight of the composition.

[0595] The present invention provides a use of a substance B in the preparation of a medicament; the substance B is a compound represented by the general formula (I) or formula I' as described above, its enantiomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof; a compound represented by the general formula E as described above, its enantiomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof; or a compound represented by the general formula X as described above, its enantiomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof. The medicament can be a medicament for treating and / or preventing diseases related to or mediated by one or more of the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, the interleukin-6 (IL-6) receptor, and tumor necrosis factor alpha (TNFα).

[0596] The present invention provides a use of a substance C in preparing a drug; the substance C is a compound represented by the general formula (I) or formula I' as described above, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, or a compound represented by the general formula X as described above, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; the drug can be used to treat and / or prevent interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor and tumor necrosis factor α. (TNFα); the drug can be a drug for treating and / or preventing cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, cardiovascular diseases, such as drugs for treating and / or preventing autoimmune diseases and / or cancer or proliferative diseases.

[0597] The present invention provides a use of a substance X in the preparation of a medicament; the substance X is a compound represented by the general formula (I) or formula I' as described above, its enantiomers, diastereomers, racemates, mixtures thereof, or pharmaceutically acceptable salts thereof. The medicament can be used to treat and prevent diseases associated with or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

[0598] The present invention provides the use of a compound of general formula (I) or (I'), its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating and preventing diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

[0599] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an aromatic compound, enantiomers, diastereomers, racemates, and mixtures thereof, as described above, as represented by Formula E or Formula X, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (or pharmaceutical excipients, such as diluents or excipients). The pharmaceutical composition can be used to treat and prevent diseases associated with or mediated by the interleukin-6 (IL-6) receptor, such as autoimmune diseases or cancer.

[0600] The present invention provides the use of a substance A in the preparation of a medicament. The substance A is an aromatic compound, enantiomer, diastereomer, racemate, or mixture thereof, as described above, such as Formula E or Formula X, or a pharmaceutically acceptable salt thereof. The medicament can be used to treat or prevent diseases associated with or mediated by the interleukin-6 (IL-6) receptor.

[0601] The present invention provides a pharmaceutical composition for treating and preventing diseases associated with or mediated by interleukin-6 (IL-6) receptors (e.g., autoimmune diseases or cancer), comprising a compound of formula E or formula X, its enantiomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0602] Furthermore, the pharmaceutically acceptable salt thereof accounts for 1 to 99 wt % of the total weight of the composition.

[0603] The present invention provides a pharmaceutical composition for treating and preventing autoimmune diseases or cancers associated with or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), comprising a compound of general formula X, its enantiomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0604] Furthermore, the pharmaceutically acceptable salt thereof accounts for 1 to 99 wt % of the total weight of the composition.

[0605] The present invention provides a use of a substance X in the preparation of a medicament; the substance X is a compound represented by the general formula X described above, its enantiomers, diastereomers, racemates, mixtures thereof, or pharmaceutically acceptable salts thereof. The medicament can be used to treat and prevent diseases associated with or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

[0606] The present invention provides the use of a compound of general formula X, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating and preventing diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

[0607] Furthermore, the diseases described in any of the above schemes include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver disease, lesions caused by T cell activation, and cardiovascular diseases.

[0608] Further, the cancer or proliferative disease is selected from brain cancer, kidney cancer, liver cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, esophageal cancer, lung cancer, prostate cancer, pancreatic cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, head and neck cancer, epidermoid cancer, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's or non-Hodgkin's lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, plasmacytoma, or intravascular large B-cell lymphoma; epidermal hyperproliferative disorders, psoriasis, prostatic hyperplasia, IL-1-driven diseases, MyD88-driven diseases.

[0609] Furthermore, the MyD88-driven disease is selected from ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma and chronic lymphocytic leukemia.

[0610] Furthermore, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, traumatic neurodegenerative disease, and graft-versus-host disease.

[0611] Furthermore, the inflammatory disease is selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, phlebitis conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red blood cell anemia, idiopathic thrombocytopenia, skin acne; or another inflammatory disease caused by autoimmune reaction, selected from systemic lupus erythema, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel Irritation syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Graves disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, uveitis keratoconjunctivitis, interstitial fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, allergies reactions, sinusitis, chronic obstructive pulmonary disease, lung disease, cystic fibrosis, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis , otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, enteritis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, dermatitis herpetiformis, subcutaneous dermatitis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigus, pemphigus vulgaris, pemphigus leaf, epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis.

[0612] The compounds and derivatives described in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0613] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0614] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography. Stereoisomers of the compounds of the present invention may be (R)- or (S)-isomers.

[0615] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0616] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0617] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0618] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0619] In this application, "pharmaceutically acceptable excipients (or carriers)" include but are not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant government regulatory authorities as acceptable for human or livestock use.

[0620] As used herein, the terms "prophylactic," "prevention," and "preventing" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

[0621] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0622] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0623] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0624] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0625] (iv) Alleviate the symptoms of the disease or condition.

[0626] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0627] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods by which a compound or composition can be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0628] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0629] "Substitution" refers to the replacement of a hydrogen atom in a molecule with another atom or chemical group. When the number of substituents is not specified, one or more substituents may be present. When the position of the substituent is not specified, substitution may occur at any position, but is permitted only if the result is a stable or chemically viable compound.

[0630] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0631] As used herein, the terms "moiety," "moiety," "chemical moiety," "group," and "chemical group" refer to specific segments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0632] 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-.

[0633] When a substituent is listed without indicating the atom via which it is bonded in a chemical formula (including but not specifically mentioned compounds), such substituent may be bonded via any atom thereof. Combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0634] 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", it should be understood that the "alkyl" represents a linking alkylene group.

[0635] In some specific structures, when an alkyl group is clearly indicated as a linking group, the alkyl group represents a linked alkylene group, for example, the C1-C6 alkyl in the group "halo-C1-C6 alkyl" should be understood as a C1-C6 alkylene.

[0636] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0637] It is to be understood that as used herein, the singular forms, such as "a," "an," and the like, include plural referents unless otherwise specified.

[0638] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0639] Those skilled in the art will understand that according to the conventions used in the art, the structural formulas used in this application to describe groups and It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0640] "Hydroxy" refers to an -OH group.

[0641] "Carbonyl" refers to a -C(=O)- group. When R is a carbonyl group, for

[0642] "Cyano" refers to -CN.

[0643] "Amino" refers to -NH2.

[0644] "Carboxyl" refers to -COOH.

[0645] "Halogen" refers to a halogen radical: fluorine, chlorine, bromine, or iodine.

[0646] The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix, for example, the prefix (C1-C6)alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1-C6alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.

[0647] In the present invention, "alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups can be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including various isomers of hexyl). Alkyl groups can also be part of other groups, such as C1-C6 alkylamino groups. In this application, "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both situations where the event or situation occurs and situations where it does not occur.

[0648] In the present invention, a C-C unsaturated hydrocarbon group refers to an aliphatic hydrocarbon group containing from "a" to "b" carbon atoms and containing one or more olefinic bonds and one or more acetylenic bonds. Unsaturated hydrocarbon groups include branched and straight chain groups. Olefinic bonds include cis double bonds and trans double bonds.

[0649] In the present invention, the Ca-Cb alkoxy group refers to a group formed by connecting an alkyl group containing "a" to "b" carbon atoms to the corresponding oxygen atom.

[0650] In the present invention, the Ca-Cb alkylamino group refers to a group formed by connecting an alkyl group containing "a" to "b" carbon atoms to the corresponding nitrogen atom.

[0651] In the present invention, the Ca-Cb alkanoyl group refers to a group formed by linking an alkyl group containing "a" to "b" carbon atoms with the corresponding acyl group.

[0652] In the present invention, ab-membered cycloalkyl refers to a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms. For example, 3-10-membered cycloalkyl, and another example is cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,

[0653] In the present invention, the cycloalkyl group of C1-C6 refers to a saturated hydrocarbon ring containing "a" to "b" carbon atoms. For example, the cycloalkyl group of C1-C6 refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclobutyl.

[0654] In the present invention, the ab-membered unsaturated cyclic hydrocarbon group refers to an unsaturated cyclic hydrocarbon containing "a" to "b" carbon atoms and containing one or more olefinic bonds or one or more acetylenic bonds.

[0655] In the present invention, an ab-membered cycloalkoxy group refers to a group formed by linking a saturated hydrocarbon ring containing from "a" to "b" carbon atoms to the corresponding oxygen atoms. A Ca-Cb-cycloalkoxy group refers to a group formed by linking a saturated hydrocarbon ring containing from "a" to "b" carbon atoms to the corresponding oxygen atoms.

[0656] In the present invention, an ab-membered cycloalkylamino group refers to a group formed by linking a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms to the corresponding nitrogen atom. A Ca-Cb-cycloalkylamino group refers to a group formed by linking a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms to the corresponding nitrogen atom.

[0657] In the present invention, an ab-membered cycloalkanoyl group refers to a group formed by linking a saturated cyclic hydrocarbon containing from "a" to "b" carbon atoms with the corresponding acyl group. A Ca-Cb-cycloalkanoyl group refers to a group formed by linking a saturated cyclic hydrocarbon containing from "a" to "b" carbon atoms with the corresponding acyl group.

[0658] In the present invention, the ab-membered heterocyclic group refers to a group consisting of a to b carbon atoms and heteroatoms, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the Ca-Cb heterocyclic group refers to a group consisting of a to b carbon atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; including saturated or partially unsaturated groups; for example, a 4-10 membered heterocycloalkyl group may be (For example (For example (For example (For example (For example (For example ), (For example ).

[0659] In the present invention, the aromatic heterocyclic ring of ab members refers to an aromatic ring composed of a to b carbon atoms and heteroatoms. The heterocyclic group of Ca-Cb refers to an aromatic ring composed of a to b carbon atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. For example

[0660] In the present invention, the ab-membered aromatic ring refers to an aromatic ring consisting of a to b carbon atoms, such as a benzene ring and a naphthalene ring.

[0661] The heterospirocyclic group of Ca-Cb in the present invention refers to a group containing "a" to "b" carbon atoms, wherein one carbon atom is shared by two rings, and the heterospirocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; including saturated or partially unsaturated non-aromatic heterospirocyclic groups; for example, 4-10 membered heterospirocycloalkyl groups, which may be 2-azaspiro[3.3]heptyl (for example ), 7-azaspiro[3.5]nonyl (e.g. ), 2-azaspiro[3.5]nonyl (e.g. ), 2,7-diazaspiro[3.5]nonyl (e.g. ), 6-azaspiro[3.4]octyl (e.g. ), 4-oxa-7-azaspiro[2.5]octanyl (e.g. ), 5-oxa-8-azaspiro[3.5]nonyl (e.g. ), 2-oxa-6-azaspiro[3.3]heptyl (e.g. ), 2-oxa-6-azaspiro[3.4]octanyl (e.g. ), 4,7-diazaspiro[2.5]octanyl (e.g. ).

[0662] In the present invention, the hetero-bridged ring group of Ca-Cb refers to a group containing "a" to "b" carbon atoms, and having two rings sharing two carbon atoms or heteroatoms, wherein the hetero-bridged ring group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. It includes saturated or partially unsaturated non-aromatic hetero-bridged ring groups; for example, 4-10 membered hetero-bridged cycloalkyl groups; and may be octahydrocyclopenta[C]pyrrolyl (for example ), octahydropyrrolo[3,4-c]pyrrolyl (e.g. ), 3-azabicyclo[3.1.0]hexane (e.g. ), 2-oxa-5-azabicyclo[2.2.1]heptyl (e.g. ), 8-oxa-3-azabicyclo[3.2.1]octanyl (e.g. ).

[0663] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0664] The reagents and raw materials used in the present invention are commercially available.

[0665] The positive advances of the present invention are that the aromatic compounds provided herein can be used as E3 ligands to prepare PROTAC compounds that effectively degrade IRAK4 or otherwise inhibit IRAK4 activity, as well as intermediates for interleukin-6 (IL-6) receptor inhibitors (CRBN ligand-linker compounds). These interleukin-6 (IL-6) receptor inhibitors and PROTAC compounds exhibit excellent activity, providing a new option for clinical screening and / or preparation of drugs for related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0666] Figure 1 Comparison of the middle ear thickness effect for test case 11.

[0667] Figure 2 This is a comparison of the psoriasis effects in Test Example 11. DETAILED DESCRIPTION

[0668] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0669] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-25° C. All temperatures are expressed in degrees Celsius.

[0670] Overnight is 14±1h.

[0671] High-performance liquid chromatography (HPLC) analysis conditions: Shimadzu LC-20A. Analytical HPLC conditions: C18 column (5 μm, 4.6 x 150 mm), UV detection at 214 and 254 nm, elution: 0-90% acetonitrile (containing 0.03% v / v TFA) gradient over 30 min.

[0672] Reverse-phase purification was performed using a Gilson GX-281 reverse-phase preparative chromatograph or a Biotage Isolera One rapid purification system.

[0673] NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer. NMR shifts (δ) are reported in units of 10⁻⁶ (ppm). Solvents included deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). The internal standard was tetramethylsilane (TMS).

[0674] The hydrogenation reaction requires vacuuming to expel the air, filling with hydrogen, then vacuuming to expel the gas, filling with hydrogen, and repeating the operation three times.

[0675] The known starting materials, reagents and solvents of the present invention can be synthesized by methods known in the art, or can be purchased from Shaoyuan Chemical Technology, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd.

[0676] In the above discussion and the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has the generally accepted meaning. MPLC is medium pressure preparative chromatography; TLC is thin layer chromatography; MeOH is methanol; EtOH is ethanol; DMAP refers to 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMA is N,N-dimethylacetamide; EA is ethyl acetate; THF is tetrahydrofuran; DMSO is dimethyl sulfoxide; DCM is dichloromethane; DCE is dichloroethane; MTBE is methyl tert-butyl ether; Boc2O is di-tert-butyl dicarbonate; Boc is tert-butyloxycarbonyl; SEMCl is 2-(trimethylsilyl)ethoxymethyl chloride; SEM is 2-(trimethylsilyl)ethoxymethyl; CbzCl is benzyloxycarbonyl chloride; Cbz is benzyloxycarbonyl; FmocCl is 9-fluorenylmethyl chloroformate; Fmoc is 9-fluorenylmethoxycarbonyl; MsCl is methanesulfonyl chloride; Ms is methanesulfonyl; TBSCl is tert-butyldimethylchlorosilane; TBS is tert-butyldimethylchlorosilyl; TBDPSCl is tert-butyldiphenylchlorosilane; TBDPS is tert-butyldiphenylsilyl; TBAF is tetrabutylammonium fluoride; NBS is N-bromosuccinimide; TFA is trifluoroacetic acid; DBU is 1,8-diazabicycloundec-7-ene; DIPEA is N,N-diisopropylethylamine; TEA is triethylamine; HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HBTU is 2-(benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0677] Example

[0678] Synthesis of Intermediate 1: ((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol

[0679]

[0680] Step 1: Synthesis of cis-4-methanesulfonyloxycyclohexyl-1-methylcarboxylate

[0681] Methyl cis-4-hydroxycyclohexyl-1-carboxylate (10 g, 63.2 mmol) was dissolved in 100 ml of dichloromethane. Triethylamine (12.5 g, 123 mmol) and methanesulfonyl chloride (10.9 g, 94.8 mmol) were then added under an ice bath. The mixture was gradually warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction was extracted with dichloromethane and water. The aqueous phase was washed twice with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed. This yielded methyl cis-4-methanesulfonyloxycyclohexyl-1-carboxylate (12.45 g, 83% yield).

[0682] Step 2: Synthesis of (trans)-4-(3-formyl)-1H-pyrazol-1-yl-cyclohexylcarboxylic acid methyl ester

[0683] Methyl cis-4-methanesulfonyloxycyclohexyl-1-carboxylate (6.22 g, 26.3 mmol) and 3-formyl-1H-pyrazole (1.68 g, 17.5 mmol) were dissolved in 50 ml of DMF, and cesium carbonate (10.26 g, 31.6 mmol) was added, followed by stirring at 80°C overnight. After the reaction was complete, the reaction was extracted with ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate, and the organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was then purified by column chromatography to obtain 2.1 g (8.9 mmol, 51% yield) of methyl (trans)-4-(3-formyl)-1H-pyrazol-1-yl-cyclohexanecarboxylate. LCMS (ESI) m / z: [M+1] = 237.

[0684] Step 3: Synthesis of (trans)-4-(3-difluoromethyl)-1H-pyrazol-1-yl-cyclohexylcarboxylic acid methyl ester

[0685] Methyl (trans)-4-(3-formyl)-1H-pyrazol-1-yl-cyclohexanecarboxylate (2.1 g, 8.9 mmol) was dissolved in 20 ml of dichloromethane, and then DAST (2.87 g, 17.8 mmol) was added at 0°C, and then stirred overnight from room temperature to room temperature. After the reaction was completed, methanol was added at 0°C to quench the reaction, and then the reaction was extracted with ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate, and the organic phase was collected and washed once with saturated brine. The product was then dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The residue was purified by column chromatography to obtain 1.8 g (7.0 mmol, 78% yield) of (trans)-4-(3-difluoromethyl)-1H-pyrazol-1-yl-cyclohexanecarboxylic acid methyl ester. LCMS (ESI) m / z: [M+1] = 259. Step 4: Synthesis of (trans)-4-(3-difluoromethyl)-4-nitro-1H-pyrazol-1-yl-cyclohexanecarboxylic acid

[0686] Methyl (trans)-4-(3-difluoromethyl)-1H-pyrazol-1-yl-cyclohexanecarboxylate (1.8 g, 7.0 mmol) was dissolved in 10 ml of concentrated sulfuric acid, and then 65% concentrated nitric acid (1.55 g, 16 mmol) was added under ice-cooling. The temperature was raised to 100° C. and stirred for 4 hours. After the reaction was complete, the reaction was extracted with ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate, and the organic phase was collected and the solvent was removed by rotary evaporation. The residue was then purified by reverse phase MPLC to obtain 1.3 g (4.5 mmol, 64% yield) of (trans)-4-(3-difluoromethyl)-4-nitro-1H-pyrazol-1-yl-cyclohexanecarboxylic acid. LCMS (ESI) m / z: [M+1]=290.

[0687] Step 5. Synthesis of (trans)-4-(3-difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-cyclohexylmethanol

[0688] Dissolve (trans)-4-(3-difluoromethyl)-4-nitro-1H-pyrazol-1-yl-cyclohexanecarboxylic acid (1.3 g, 4.5 mmol) in 10 ml of tetrahydrofuran and cool to -10°C. Add isobutyloxychloride (0.59 mL, 5.34 mmol) and then add N-methylmorpholine (0.56 mg, 5.5 mmol). After stirring at this temperature for 10 minutes, add sodium borohydride (570 mg, 15 mmol), then raise the temperature to 0°C and add dropwise 2 ml of methanol was added and the reaction was continued for 30 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator, and the reaction was extracted with ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate, and the organic phase was collected and the solvent was removed using a rotary evaporator. The residue was then purified by reverse phase MPLC to obtain 1.1 g (3.9 mmol, 87% yield) of (trans)-4-(3-difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-cyclohexylmethanol. LCMS (ESI) m / z: [M+1] = 276.

[0689] Step 6. Synthesis of (trans)-4-(3-difluoromethyl-4-amino-1H-pyrazol-1-yl)-cyclohexylmethanol

[0690] (Trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylmethanol (1.1 g, 3.9 mmol) was dissolved in 10 ml of tetrahydrofuran, and 100 mg of 20% palladium-carbon catalyst was added. The mixture was stirred at room temperature overnight in hydrogen, and then the palladium-carbon catalyst was removed by filtration. The filtrate was collected and the solvent was removed to obtain 864 mg (3.44 mmol, 88% yield) of (trans)-4-(3-difluoromethyl-4-amino-1H-pyrazol-1-yl-cyclohexylmethanol. LCMS (ESI) m / z: [M+1] = 246.

[0691] Synthesis of Intermediate 2: tert-Butyl (3-(difluoromethyl)-1-((trans)-4-formylcyclohexyl)-1H-pyrazol-4-yl)carbamate

[0692]

[0693] Step 1. Synthesis of tert-butyl (3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)-cyclohexyl)-1H-pyrazol-4-yl)carbamate

[0694] (trans)-4-(3-Difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-cyclohexylmethanol (1 g, 3.6 mmol) was dissolved in 20 mL of ethanol, and Pd / C (0.5 g) and Boc2O (1.6 g, 7.2 mmol) were added. The mixture was vacuumed and switched to hydrogen. The reaction was stirred at room temperature for 16 h, filtered, and the filtrate was concentrated. The target product was obtained by column chromatography (PE / EA = 10 / 1 to 5 / 1) as a white solid in 88% yield. LCMS (ESI) m / z: (M+H)+ = 346.1.

[0695] Step 2: Synthesis of tert-butyl (3-(difluoromethyl)-1-((trans)-4-formylcyclohexyl)-1H-pyrazol-4-yl)carbamate

[0696] Tert-butyl (3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)-cyclohexyl)-1H-pyrazol-4-yl)carbamate (1.1 g, 3.2 mmol) was dissolved in 30 mL of dichloromethane and Dess-Martin periodinane (1.8 g, 4.1 mmol) was added at 0°C. The reaction was stirred at room temperature for 4 hours. The reaction solution was purified by column chromatography (PE / EA = 100 / 1 to 5 / 1) to obtain 0.8 g of the desired product in a 73% yield. LCMS(ESI)m / z:(M+H)+=344.1; 1H NMR (400MHz, CDCl3) δ9.68 (s, 1H), 7.93 (s, 1H), 6.86-6.54 (m, 2H), 4.01 (ddd, J = 11.9, 8.1,3.8Hz,1H),2.41-2.08(m,5H),1.92-1.68(m,3H),1.43(td,J=13.0,3.1Hz,11H).

[0697] Synthesis of Intermediate 3: Synthesis of N-Boc-4-propargyloxypiperidine

[0698]

[0699] N-Boc-4-hydroxypiperidine (4.02 g, 20 mmol) was dissolved in 30 ml of anhydrous tetrahydrofuran, and then sodium hydride (1.20 g, 30 mmol) was added at 0°C. After stirring for 30 minutes, propargyl bromide (3.56 g, 30 mmol) was added and stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride was added to quench the reaction, and the organic solvent was removed by rotary evaporation, followed by extraction with ethyl acetate. The product was then dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The residue was then purified by column chromatography to obtain 3.91 g (1.63 mmol, 82% yield) of N-Boc-4-propargyloxypiperidine. LCMS (ESI) m / z: [M+1] = 240.

[0700] Synthesis of Intermediate 4: N-(3-(difluoromethyl)-1-((trans)-4-(formyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[0701]

[0702] Step 1: Synthesis of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0703] Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.25 g, 10 mmol) was dissolved in 10 ml of acetonitrile, followed by the addition of morpholine (1.31 g, 15 mmol) and DIPEA (2.58 g, 20 mmol). The mixture was then heated under reflux for 2 hours. After the reaction was complete, 10 ml of water was added to precipitate a solid. After cooling, the solid was filtered, and the filter cake was rinsed with water. The solid was collected and dried to yield 2.55 g (9.2 mmol, 92% yield) of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate. LCMS (ESI) m / z: [M+1] = 277.

[0704] Step 2: Synthesis of 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0705] 5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (2.55 g, 9.2 mmol) was dissolved in 20 ml of methanol, and then a solution of sodium hydroxide (800 mg) in water (10 ml) was added and stirred at room temperature for 16 hours. After the reaction was complete, 1 M dilute hydrochloric acid was added to adjust the pH to about 5-6 and solid precipitated. The organic solvent was removed under reduced pressure, and then filtered and the solid was rinsed with water. The solid was collected and dried to obtain 2.01 g (8.1 mmol, yield 88%) of 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid. LCMS (ESI) m / z: [M+1] = 249. Step 3. Synthesis of N-(3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[0706] 5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.01 g, 8.1 mmol) and (trans)-4-(3-difluoromethyl-4-amino-1H-pyrazol-1-yl)-cyclohexylmethanol 2.03 g (8.1 mmol) were dissolved in 30 ml of DMF, and then HATU (3.42 g 9 mmol) and DIPEA (2.04 g, 16 mmol) were added. Water and ethyl acetate were then added for extraction, and the mixture was washed with water and ethyl acetate. The aqueous phase was washed twice with ethyl acetate, and the organic phase was collected and the solvent removed on a rotary evaporator. The residue was then purified by reverse phase MPLC to yield 1.91 g (4.0 mmol, 49% yield) of N-(3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m / z: [M+1] = 476.

[0707] Step 4. Synthesis of N-(3-(difluoromethyl)-1-((trans)-4-(aldehyde)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[0708] N-(3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide (1.91 g, 4.0 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of Dess-Martin periodinane (2.54 g, 6.0 mmol). The mixture was allowed to react overnight at room temperature. After completion, the reaction was extracted with aqueous sodium bicarbonate. The aqueous phase was washed twice with dichloromethane, and the organic phase was collected and the solvent removed using a rotary evaporator. The residue was then purified by column chromatography to yield 1.43 g (3.0 mmol, 75% yield) of N-(3-(difluoromethyl)-1-((trans)-4-(formyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m / z: [M+1]=474.

[0709] Synthesis of Intermediate 5: 4-(3-(difluoromethyl)-4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine

[0710]

[0711] Step 1 to Step 3, Synthesis of tert-butyl 4-(3-(difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0712] Substitute cis-4-hydroxycyclohexyl-1-carboxylic acid methyl ester for N-Boc-4-hydroxyoxypiperidine. The remaining raw materials, reagents, and preparation methods are the same as those for Intermediate 4, steps 1 to 3. The product is isolated and purified by flash column chromatography, yielding a 21% overall yield over three steps. LCMS (ESI) m / z: [M+1] = 302.

[0713] Step 4: Synthesis of tert-butyl 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0714] tert-Butyl 4-(3-(difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (903 mg, 3 mmol) was dissolved in 5 ml of concentrated sulfuric acid. 65% concentrated nitric acid (0.77 g, 8 mmol) was then added under ice-cooling. The mixture was heated to 100°C and stirred for 4 hours. After the reaction was complete, the reaction solution was slowly poured into 50 ml of ice water. Sodium hydroxide was slowly added until the pH reached approximately 10. Boc2O (1.09 g, 5 mmol) and sodium carbonate (0.53 g, 5 mmol) were then added. The reaction mixture was then extracted with ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate. The organic phase was collected and the solvent removed on a rotary evaporator. The residue was then purified by silica gel column chromatography to obtain 466 mg (1.35 mmol, 45% yield) of tert-butyl 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate. LCMS (ESI) m / z: [M+1]=347.

[0715] Step 5. Synthesis of tert-butyl 4-(3-(difluoromethyl)-4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0716] tert-Butyl 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (466 mg, 1.35 mmol) was dissolved in 10 ml of tetrahydrofuran, and 40 mg of 20% palladium-carbon catalyst was added. The mixture was stirred at room temperature overnight under hydrogen atmosphere, and then the palladium-carbon catalyst was removed by filtration. The filtrate was collected and the solvent was removed to obtain 402 mg (1.27 mmol, 94% yield) of tert-butyl 4-(3-(difluoromethyl)-4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate. LCMS (ESI) m / z: [M+1] = 317.

[0717] Step 6. Synthesis of tert-butyl 4-(3-(difluoromethyl)-4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0718] 5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (315 mg, 1.27 mmol) and tert-butyl (4-(3-(difluoromethyl)-4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (402 mg, 1.27 mmol) were dissolved in 5 ml of DMF, and then HATU (569 mg, 1.5 mmol) and DIPEA (581 mg, 4.5 mmol) were added and reacted at 80°C for 16 hours. The product was extracted with water and ethyl acetate, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and the solvent removed on a rotary evaporator. The residue was then purified by silica gel column chromatography to obtain 610 mg (1.12 mmol, 88% yield) of tert-butyl 4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine-1-carboxylate. LCMS (ESI) m / z: [M+1] = 547.

[0719] Step 7. Synthesis of 4-(3-(difluoromethyl)-4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine

[0720] Dissolve tert-butyl 4-(3-(difluoromethyl)-4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine-1-carboxylate (610 mg, 1.12 mmol) in 5 ml of 2M HCl in ethyl acetate, then add 2 ml of methanol and stir overnight at room temperature. After completion of the reaction, remove the solvent using a rotary evaporator to yield 580 mg (1.12 mmol, 100% yield) of 4-(3-(difluoromethyl)-4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine hydrochloride. LCMS (ESI) m / z: [M+1] = 447.

[0721] Synthesis of Intermediate 6: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-aldehydecyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0722]

[0723] Steps 1 to 4, Synthesis of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4-aldehydecyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide: Replace morpholine with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane. The remaining starting materials, reagents, and preparation methods were the same as those for Steps 1 to 4 of Intermediate 2. The total yield across the three steps was 36%. LCMS (ESI) m / z: [M+1] = 486.

[0724] Synthesis of Intermediate 7: 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine

[0725]

[0726] Step 1. Synthesis of 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0727] 3-Methyl-4-bromoindazole (210 mg, 1 mmol) was dissolved in 5 mL of anhydrous THF / DMSO (1 / 1) mixture. Sodium hydride (120 mg, 3 mmol, 60% purity) was then added at 0°C. After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (288 mg, 1.5 mmol) and potassium iodide (133 mg, 0.8 mmol) were added, and the mixture was stirred at room temperature overnight. After completion, the reaction was quenched with 10 mL of saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The product was then dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography to obtain 151 mg (0.47 mmol, 48% yield) of (3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione). LCMS (ESI) m / z: [M+1] = 322 / 324.

[0728] Step 2: Synthesis of tert-butyl 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine-1-carboxylate.

[0729] (3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (151 mg, 0.47 mmol) was dissolved in 5 ml of DMF, and then N-Boc-4-propargyloxypiperidine (124 mg, 0.52 mmol), ditriphenylphosphine palladium dichloride (33 mg, 47 umol) and cesium carbonate (306 mg, 0.94 mmol) were added. The reaction system was then protected with nitrogen and stirred at 100 ° C overnight. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The reaction mixture was separated and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The residue was then purified by column chromatography to obtain 144 mg (0.30 mmol, 64% yield) of tert-butyl 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine-1-carboxylate. LCMS (ESI) m / z: [M+1] = 481.

[0730] Step 3. Synthesis of 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine

[0731] Dissolve tert-butyl 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine-1-carboxylate in dioxane, then add 4M HCl in dioxane. After the starting material disappears, remove the solvent on a rotary evaporator to obtain 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine hydrochloride. LCMS (ESI) m / z: [M+1] = 381.

[0732] Synthesis of Intermediate 8: 3-(4-(3-((1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0733]

[0734] Step 1. Synthesis of tert-butyl (3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1-1H-indazol-4-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)carbamate

[0735] Intermediate 7 (700 mg, 2.0 mmol) was dissolved in DMF / THF (1.0 mL / 15.0 mL). The reaction mixture was cooled to -10°C, and Intermediate 2 (776 mg, 2.0 mmol) and TEA (412 mg, 4 mmol) were added. The mixture was stirred under argon for 0.5 h. HOAc (367 mg, 6 mmol) and NaBH(OAc)3 (1.3 g, 6 mmol) were then added to the reaction mixture, and the mixture was stirred for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layer was then dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column (MeOH / DCM = 100 / 1 to 20 / 1) to afford a white solid in 77% yield. LCMS (ESI) m / z: [M+1] = 708.0.

[0736] Step 2. Synthesis of 3-(4-(3-((1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione: The product from Step 1 (1 g, 1.4 mmol) was dissolved in 5 mL of dioxane. 4 M dioxane hydrochloric acid solution was added, and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated to obtain the desired product, which was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] == 608.0.

[0737] Synthesis of Intermediate 9: 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine

[0738]

[0739] Step 1: 3-(4-bromo-3-methyl-1H-indol-1-yl)piperidine-2,6-dione

[0740] 3-Methyl-4-bromoindole was substituted for 3-methyl-4-bromoindole. The remaining raw materials, reagents, and preparation methods were the same as those in Step 1 of the synthesis of Intermediate 5. The product was isolated and purified by rapid column chromatography with a yield of 23%. LCMS (ESI) m / z: [M+1] = 321 / 323.

[0741] Step 2: 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine

[0742] (3-(4-Bromo-3-methyl-1H-indol-1-yl)piperidine-2,6-dione (161 mg, 0.5 mmol) was dissolved in 3 ml of DMF, and then 4-propargyloxypiperidine (208 mg, 0.75 mmol), bistriphenylphosphine palladium dichloride (35 mg, 50 umol) and cesium carbonate (325 mg, 1.0 mmol) were added. The reaction system was then protected with nitrogen and stirred at 100° C. overnight. After completion of the reaction, the product was purified by reverse phase MPLC to obtain 96 mg (0.25 mmol, 51% yield) of 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine. LCMS (ESI) m / z: [M+1]=380.

[0743] Synthesis of Intermediate 10: 3-(3-methyl-4-(3-(piperidin-1-yloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidine-2,6-dione trifluoroacetate

[0744]

[0745] Step 1 to Step 3, Synthesis of 3-(3-methyl-4-(3-(piperidin-1-yloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidine-2,6-dione trifluoroacetate

[0746] 4-Bromo-3-methyl-indazole was replaced with 4-bromo-3-methyl-7-azaindole. The remaining raw materials, reagents, and preparation methods were the same as those for Steps 1 to 3 of the synthesis of Intermediate 5. The total yield of the three steps was 25%. LCMS (ESI) m / z: [M+1] = 381.

[0747] Synthesis of Intermediate 11: (1r,4r)-4-((3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexane-1-carbaldehyde

[0748]

[0749] Step 1. Synthesis of trans-4-(tert-butyldimethylsilyloxymethyl)cyclohexanol

[0750] Trans-4-(hydroxymethyl)cyclohexanol (1.3 g, 10 mmol) was dissolved in 15 ml of DMF, and then TBSCl (1.51 g, 10 mmol), imidazole (1.36 g, 20 mmol), and DMAP (122 mg, 1 mmol) were added at 0°C. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The residue was then purified by column chromatography to obtain 1.41 g (5.80 mmol, 58% yield) of trans-4-(tert-butyldimethylsilyloxymethyl)cyclohexanol.

[0751] Step 2: Synthesis of trans-4-(tert-butyldimethylsilyloxymethyl)cyclohexyl propargyl ether

[0752] Trans-4-(tert-butyldimethylsilyloxymethyl)cyclohexanol (1.41 g, 5.80 mmol) was dissolved in ultra-dry DMF, and then sodium hydride (580 mg, 14.5 mmol) was added at 0°C and stirred for 0.5 hours. Finally, propargyl bromide (1.38 g, 11.6 mmol) was added, and the mixture was returned to room temperature and stirred overnight. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was then purified by column chromatography to obtain 716 mg (2.53 mmol, 44% yield) of trans-4-(tert-butyldimethylsilyloxymethyl)cyclohexyl propargyl ether.

[0753] Step 3: Synthesis of trans-(4-hydroxymethyl)cyclohexyl propargyl ether

[0754] trans-4-(tert-Butyldimethylsilyloxymethyl)cyclohexyl propargyl ether (716 mg, 2.53 mmol) was dissolved in 5 ml of tetrahydrofuran, followed by the addition of a 2M TBAF solution in tetrahydrofuran (5 ml, 10 mmol). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to obtain 317 mg (1.89 mmol, 75% yield) of trans-(4-hydroxymethyl)cyclohexyl propargyl ether.

[0755] Step 4. Synthesis of 3-(4-(3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0756] (3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (322 mg, 1 mmol) was dissolved in 5 ml of DMF, and then trans-(4-hydroxymethyl)cyclohexyl propargyl ether (168 mg, 1 mmol), bistriphenylphosphine palladium dichloride (70 mg, 0.1 mmol), and cesium carbonate (650 mg, 2.0 mmol) were added. The reaction system was then protected with nitrogen and stirred at 100° C. overnight. After completion of the reaction, the product was purified by reverse phase MPLC to obtain 3-(4-(3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione, 312 mg (0.76 mmol, 76% yield). LCMS (ESI) m / z: [M+1]=410.

[0757] Step 5. Synthesis of (1r,4r)-4-((3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexane-1-carbaldehyde

[0758] 3-(4-(3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (312 mg, 0.76 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of Dess-Martin periodinane (356 mg, 0.84 mmol) and the reaction was allowed to react at room temperature overnight. After completion, the reaction was extracted with aqueous sodium bicarbonate. The aqueous phase was washed twice with dichloromethane, and the organic phase was collected and the solvent removed by rotary evaporation. The residue was then purified by column chromatography to obtain (1r,4r)-4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexane-1-carbaldehyde (0.66 mmol, 87% yield). LCMS (ESI) m / z: [M+1]=408.

[0759] Synthesis of Intermediate 12: 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine hydrochloride

[0760]

[0761] Step 1. Synthesis of tert-butyl 4-(2-(methylsulfonyloxyethyl)piperidine-1-carboxylate

[0762] tert-Butyl 4-(2-(hydroxyethyl)piperidine-1-carboxylate (4.59 g, 20 mmol) was dissolved in 50 ml of dichloromethane, and triethylamine (4.04 g, 40 mmol) and methanesulfonyl chloride (2.52 g, 22 mmol) were added under ice-cooling. The mixture was gradually warmed to room temperature and stirred for 2 hours. After the reaction was completed, the reaction was extracted with dichloromethane and water, and the aqueous phase was washed twice with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed. tert-Butyl 4-(2-(methylsulfonyloxyethyl)piperidine-1-carboxylate (5.92 g, 19.3 mmol, 96% yield) was obtained.

[0763] Step 2: Synthesis of tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate

[0764] tert-Butyl 4-(2-(methylsulfonyloxyethyl)piperidine-1-carboxylate (5.92 g, 19.3 mmol) and 3-bromo-1H-pyrazole (2.94 g, 20 mmol) were dissolved in 50 ml of DMF, and cesium carbonate (13.0 g, 40 mmol) was added, followed by stirring at 80° C. overnight. After the reaction was complete, the reaction was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was then purified by column chromatography to obtain tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (4.97 g, 13.9 mmol, 72% yield). LCMS (ESI) m / z: [M+1]=359.

[0765] Step 3: Synthesis of tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate

[0766] Dissolve tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (4.97 g, 13.9 mmol) and pinacol diboron (7.06 g, 27.8 mmol) in 80 ml of ethylene glycol dimethyl ether, then add potassium acetate (2.95 g, 30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (509 mg, 0.7 mmol). Add 20 ml of water, replace the air in the reaction system with nitrogen, and then reflux under nitrogen for 16 hours. After the reaction is complete, extract with ethyl acetate and water. Wash the aqueous phase twice with ethyl acetate. Collect the organic phase and wash it once with saturated brine, then dry it over anhydrous sodium sulfate and remove the solvent using a rotary evaporator. The residue was purified by column chromatography to give tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (3.90 g, 9.6 mmol, 69% yield). LCMS (ESI) m / z: [M+1] = 406.

[0767] Step 4. Synthesis of tert-butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate

[0768] tert-Butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (3.90 g, 9.6 mmol) and 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (3.09 g, 9.6 mmol) were dissolved in 30 ml of N,N-dimethylformamide, and then sodium carbonate (204 g, 19.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (703 mg, 0.96 mmol) were added, and the air in the reaction system was replaced with nitrogen, and then the reaction was protected with nitrogen and reacted at 90°C for 4 hours. After the reaction was complete, the reaction was extracted with ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The residue was then purified by column chromatography to obtain tert-butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (876 mg, 1.68 mmol, 18% yield). LCMS (ESI) m / z: [M+1] = 521.

[0769] Step 5. Synthesis of 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine hydrochloride

[0770] tert-Butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (876 mg, 1.68 mmol) was dissolved in 4 mL of tetrahydrofuran, and 4 mL of a 4M hydrochloric acid and ethyl acetate solution was added. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the solvent was removed by rotary evaporation to obtain 770 mg (1.68 mmol, 100% yield) of 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine hydrochloride. LCMS (ESI) m / z: [M+1] = 421.

[0771] Synthesis of Intermediate XIII: 3-(3-methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0772]

[0773] Step 1. Synthesis of tert-butyl 4-((p-tolyloxy)methyl)piperidine-1-carboxylate

[0774] N-Boc-4-piperidinemethanol (5.0 g, 23.3 mmol) was dissolved in 30 mL of dichloromethane, and Et3N (7.1 g, 69.9 mmol) was added. p-Toluenesulfonyl chloride (6.7 g, 35.0 mmol) was then added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was extracted with dichloromethane and washed twice with water. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the desired product, which was used direc...

Claims

1. A compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that: The compound represented by formula I is selected from the following structures:

2. A compound represented by formula I', its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that: The compound represented by the formula I' is selected from the following structures:

3. A pharmaceutical composition comprising a therapeutically effective amount of a substance B and one or more pharmaceutically acceptable carriers; the substance B is the compound of formula I as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, or the compound of formula I' as claimed in claim 2, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof.

4. Use of a substance B in preparing a drug, wherein the substance B is the compound of formula I as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, or the compound of formula I' as claimed in claim 2, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, and the drug can be a drug for treating and preventing diseases related to or mediated by one or more of the interleukin-1 receptor associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor and tumor necrosis factor α (TNFα); The disease is selected from tumors, autoimmune diseases or inflammatory diseases; The tumor is selected from multiple myeloma, leukemia or lymphoma; The autoimmune disease is selected from rheumatoid arthritis and systemic lupus erythematosus; The inflammatory disease is selected from hidradenitis suppurativa, psoriasis, atopic dermatitis, acne, hepatitis, nephritis, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel diseases.

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