Aromatic compound, pharmaceutical composition containing aromatic compound and application of aromatic compound

Abstract

The invention discloses an aromatic compound, a pharmaceutical composition containing the aromatic compound and application of the aromatic compound. The aromatic compound is a compound with a formula (I), and can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways. The compound and the pharmaceutical composition have very good application prospects in IRAK4-mediated diseases including immune diseases, tumors, Alzheimer's disease, fibrosis diseases and the like, and a new choice is provided for clinical screening and / or preparation of drugs for diseases related to IRAK4 activity.

Description

Aromatic compound, pharmaceutical composition containing same and use thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202310859092.8 filed with the Chinese Patent Office on July 13, 2023, entitled Aromatic compounds, pharmaceutical compositions containing same, and their uses, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of drug synthesis, and in particular relates to an aromatic compound, a pharmaceutical composition containing the aromatic compound and applications thereof. Background Art

[0004] 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.

[0005] 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.

[0006] Currently, over 600 E3 ubiquitin ligases have been identified that promote the in vivo ubiquitination of diverse proteins. These 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 over 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.

[0007] 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.

[0008] 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.

[0009] 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 suppress the release of IL-6 and TNF-α in response to IL-1β stimulation. Furthermore, IRAK4 knockout effectively abolished inflammatory responses 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.

[0010] 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.

[0011] Summary of the Invention

[0012] The purpose of the present invention is to address the deficiencies of the prior art and provide a PROTAC drug targeting IRAK4.

[0013] The present invention provides a compound represented by Formula I, or its enantiomers, diastereomers, racemates, mixtures thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof:

[0014] in,

[0015] PTM is selected from

[0016] Ring D is selected from

[0017] And when the D ring is selected from When PTM is not selected

[0018] Q is selected from CR 2a , N;

[0019] V' is selected from C, N;

[0020] U' is selected from CR 2 NR 2 ;

[0021] W' is selected from CR 3 , N;

[0022] X' is selected from C, CR 4 , N;

[0023] Y' is selected from C, CR5 , N;

[0024] Z' is selected from C, CR 6 , N;

[0025] U is selected from C, CR U , N;

[0026] W is selected from C, CR W , N;

[0027] T is selected from C, CR T , N;

[0028] X is selected from C, CR X , N;

[0029] Y is selected from C, CR Y , N;

[0030] Z is selected from C, CR Z , N;

[0031] Indicates a single bond or a double bond;

[0032] V is selected from C and N;

[0033] R 1 、R 1’ are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, 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 C1-C6 straight or branched alkylamino group, 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; 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;

[0034] 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 heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0035] R 2a 、R 2 、R 3 、R4 、R 5 、R 6 、R U 、R W 、R T 、R X 、R Y 、R Z 、R e 、R 7 are 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;

[0036] L1 is selected from none,

[0037] a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are independently selected from 0 to 6;

[0038] 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 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 RL111 、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 、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 、R27 、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;

[0039] L b’ 、L c’ 、L d’ 、L i’ Independently selected from N, CR 38 ;

[0040] R 38 、R L11 、R L12 、R L13 、R L14 、R L15 、R L16 、R L17 、R L18 、R L19 、R L110 、RL111 、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 SO2NR 33 R 34 -、

[0041] 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 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 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 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 SO2NR 33 R 34 -、

[0042] 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;

[0043] L2 is selected from none,

[0044] 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;

[0045] 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 ;

[0046] L 2b’ 、L 2c’ 、L 2d’ 、L 2i’ Selected from N, CR 44 ;

[0047] 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 、R L230 、R L241 、RL242 、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 、RL22 、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 、RL220 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 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 -、-R23 SO2R 24 -、-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 -、 or R 44 With R L211 、R L212 、R L213 、R L214 、R L223 、R L224 、R L225 、R L226 、RL227 、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 SO2NR 33 R 34 -、

[0048] The C ring is selected from the group consisting of no, 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 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 a linear or branched alkyl group, a C2-C6 linear or branched unsaturated hydrocarbon group, a C1-C6 linear or branched alkoxy group, a halogen-substituted C1-C6 linear or branched alkyl group, a halogen-substituted C2-C6 linear or branched unsaturated hydrocarbon group, a halogen-substituted C1-C6 linear or branched alkoxy group, a 3-10 membered cycloalkyloxy group, a C1-C6 linear or branched alkylamino group, a 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 -、 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;

[0049] Selected from: A single cis-trans isomer thereof or a mixture containing the same;

[0050] For example

[0051] Each of the halogens is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine;

[0052] The C1-C6 alkyl group in each of the substituted or unsubstituted C1-C6 linear or branched alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl; for example, methyl, ethyl or propyl;

[0053] The 3-10 membered cycloalkyl in each of the substituted or unsubstituted 3-10 membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,

[0054] The 4-10 membered heterocyclic group in each of the substituted or unsubstituted 4-10 membered heterocyclic groups can be independently For example

[0055] The C3-C10 heterospirocyclic group in each of the substituted or unsubstituted C3-C10 heterospirocyclic groups 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

[0056] The C5-C12 hetero-bridged ring group in each of the substituted or unsubstituted C5-C12 hetero-bridged ring groups is independently octahydrocyclopenta[C]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl; for example

[0057] Each of the substituted or unsubstituted 5-10 membered aromatic heterocycles may be independently

[0058] In some embodiments of the present invention, the D ring is selected from

[0059] In some embodiments of the present invention, the compound of Formula I is represented by Formula Ia:

[0060] in,

[0061] Ring D is selected from

[0062] U is selected from N, W is selected from C, CR W , T is selected from C, CR T ;

[0063] Alternatively, W is selected from N, and U is selected from C, CR U , T is selected from C, CR T ;

[0064] Among X, Y and Z, at most one is N;

[0065] R 1is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl; 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; for example, R 1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, and cyclopropyloxymethyl;

[0066] for

[0067] R U 、R W 、R T 、R X 、R Y 、R Z 、R e Each of the following groups is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy; for example, H, F or methyl;

[0068] Ring A is independently selected from the following rings:

[0069] R 7 Selected from:

[0070] In some preferred embodiments of the present invention:

[0071] Ring D is selected from:

[0072] Among them, the * end is connected to the C ring;

[0073] for

[0074] Ring A is selected from:

[0075] R e is hydrogen or methyl.

[0076] Furthermore, the compound represented by Formula Ia is as follows:

[0077] in,

[0078] R 7 Selected from

[0079] R C Selected from hydrogen, deuterium, 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 cycloalkoxy, C1-C6 straight chain or branched alkylamino.

[0080] In some specific embodiments of the present invention, the compound is selected from the following structures:

[0081] In some preferred embodiments of the present invention, the compound of formula I is as shown in formula Ib or formula Ic:

[0082] in,

[0083] Ring D is selected from

[0084] Q is selected from CR 2a , N;

[0085] U is selected from N, W is selected from C, CR W , T is selected from C, CR T ;

[0086] Alternatively, W is selected from N, and U is selected from C, CR U , T is selected from C, CR T ;

[0087] Among X, Y and Z, at most one is N;

[0088] V' is selected from N or C, and U' is selected from CR 2 or NR 2 , W' is selected from CR 3 , N;

[0089] 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;

[0090] R 1’selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C1-C6 straight or branched alkylamino; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight or branched alkyl-C(═O)-, 3-10 membered cycloalkyl-C(═O)-; the number of the substitutions is 1, 2 or 3;

[0091] 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, R 1’ Selected from:

[0092] R 2a 、R 2 、R 3 、R 4 、R 5 、R 6 、R U 、R W 、R T 、R X 、R Y 、R Z 、R e Each of the following groups is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, and substituted or unsubstituted 3-10 membered cycloalkyl; for example, H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy or methyl;

[0093] Ring A is independently selected from the following rings:

[0094] R 7selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C1-C6 straight or branched alkylamino; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight or branched alkyl-C(═O)-, 3-10 membered cycloalkyl-C(═O)-; the number of the substitutions is 1, 2 or 3;

[0095] For example, R 7 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl; for example, R 7 Selected from:

[0096] In some preferred embodiments, the D ring is selected from

[0097] In some preferred embodiments of the present invention:

[0098] Ring D is selected from: Among them, * end is connected to C ring; Among them, R 2 、R 4 、R 5 、R 6 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl; preferably, R 2 、R 4 、R 5 、R 6 Each of the following groups is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy or methyl;

[0099] Ring A is selected from:

[0100] Furthermore, the compound represented by formula Ib is as follows:

[0101] in,

[0102] R 2 、R 4 、R 5 、R 6 Each of the following groups is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy or methyl;

[0103] R 1’ Selected from hydrogen, deuterium, methyl, ethyl, propyl, hydroxymethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, amino, monomethylamino, dimethylamino, deuterated monomethylamino, deuterated dimethylamino,

[0104] R 7 Selected from hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl,

[0105] In some preferred embodiments of the present invention, the compound is selected from the following compounds:

[0106] The present invention also provides the use of the aforementioned compound, its enantiomers, diastereomers, racemates, mixtures containing the same, or pharmaceutically acceptable salts thereof in the preparation of a medicament; the medicament may be a medicament 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); or, the medicament may be a medicament for treating and / or preventing autoimmune diseases and / or cancer or proliferative diseases.

[0107] Furthermore, in the aforementioned use

[0108] The diseases 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 diseases, lesions caused by T cell activation, and cardiovascular diseases;

[0109] The cancer or proliferative disease may be selected from the group consisting of 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 carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's or non-Hodgkin's lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma, ABC DLBCL, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, or intravascular large B-cell lymphoma; epidermal hyperproliferative disorders, psoriasis, prostatic hyperplasia, IL-1-driven diseases, MyD88-driven diseases;

[0110] The MyD88-driven disease may be selected from ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia;

[0111] The neurodegenerative disease may be selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, traumatic neurodegenerative disease, and graft-versus-host disease;

[0112] The inflammatory disease can be selected from ocular allergies, 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 an 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 syndrome inflammatory bowel disease, 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 syndromes, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, anaphylaxis , 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-Schönlein 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.

[0113] The compounds and derivatives provided 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.

[0114] 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.

[0115] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0116] “Can be further substituted” means that “substitution” can but does not have to occur, and the description includes situations where it occurs or does not occur.

[0117] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0118] The term "alkyl" as used herein refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1～6 Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups, such as C 1～6 Alkoxy.

[0119] The "alkylene" mentioned in the present invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. a～b "Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, "C 1～6 The term "alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structures: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0120] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon group having a specified number of carbon atoms and at least one vinyl unsaturated site (>C=C<). a-bAlkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0121] The term "alkynyl" as used herein refers to a linear monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0122] The "halogen" mentioned in the present invention is fluorine, chlorine, bromine or iodine.

[0123] The "halogen alkyl" and "halogen substituted alkyl" mentioned in the present invention refer to alkyl groups in which the hydrogen atoms may be substituted by one or more halogen atoms. 1～4 Halogenalkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms, such as trifluoromethyl and difluoromethyl.

[0124] The substituents such as “═O” and “═S” described in the present invention refer to an oxygen atom or a sulfur atom replacing two hydrogen atoms to form a double bond, or replacing a lone pair of electrons to form a double bond.

[0125] The "-OR", "-NRR" and the like described in the present invention refer to that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0126] In the "-C(O)R", "-S(O)2R", "-P(O)RR" and the like described in the present invention, the oxygen atom is double-bonded to a carbon atom, a sulfur atom or a phosphorus atom, and R is single-bonded to a carbon atom or a sulfur atom. In the "-C(O)NRR", "-S(O)2NRR" and the like described in the present invention, the oxygen atom is double-bonded to a carbon atom or a sulfur atom, the nitrogen atom is single-bonded to a carbon atom or a sulfur atom, and R is single-bonded to a nitrogen atom. In the "-NRC(O)R", "-NRS(O)2R" and the like described in the present invention, one R is single-bonded to a nitrogen atom, the other R is single-bonded to a carbon atom or a sulfur atom, the nitrogen atom is single-bonded to a carbon atom or a sulfur atom, and the oxygen atom is double-bonded to a carbon atom or a sulfur atom.

[0127] "Cycloalkyl" as used herein refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spirocyclic and adamantane systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl) is used when the point of attachment is located at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. Two such bicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Bicyclohexyl. Adamantyl includes but is not limited to the following structures: Specific examples of the bridged ring (bridged cycloalkyl) of the present invention include Etc. Specific examples of the spiro ring of the present invention include wait.

[0128] As used herein, "heterocycle" and "heterocycloalkyl" refer to saturated or non-aromatic unsaturated rings containing at least one heteroatom; wherein a heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, or the like. Generally, it refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic refers to two rings consisting of two rings sharing two ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyls are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyls are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, examples of partially unsaturated heterocycloalkyls are dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl or dihydropyranyl. Other examples include, but are not limited to: (For example ), (For example ), (For example ) (For example ), (For example ), (For example ), (For example ). Another example of a bicyclic ring includes octahydrocyclopenta[C]pyrrolyl (e.g. ), octahydropyrrolo[3,4-c]pyrrolyl (e.g. ), 3-azabicyclo[3.1.0]hexane (e.g. ).

[0129] The "heterospirocyclic group" and "heterospiro ring" described in the present invention refer to a group containing at least one heteroatom, 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. ).

[0130] The "heterobridged cyclic group" and "heterobridged ring" described in the present invention refer to a group containing at least one heteroatom and having two rings sharing two non-adjacent carbon atoms or heteroatoms, wherein the heterobridged cyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. It includes saturated or partially unsaturated non-aromatic heterobridged cyclic groups; for example, 2-oxa-5-azabicyclo[2.2.1]heptyl (for example ), 8-oxa-3-azabicyclo[3.2.1]octanyl (e.g. ).

[0131] As used herein, "aromatic ring" or "aryl" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups typically include monocyclic, bicyclic, or tricyclic aromatic groups. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0132] The "aromatic heterocycle" and "aromatic heterocyclic group" described in the present invention refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, and S heteroatoms. Preferably, there are one to three heteroatoms. Heterocyclic aromatic groups are represented by pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl. Other examples include but are not limited to

[0133] "Stereoisomers" include enantiomers and diastereomers;

[0134] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0135] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0136] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0137] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0138] The beneficial effects of the present invention are:

[0139] The present invention discloses compounds represented by Formula I, which can effectively degrade IRAK4 or inhibit IRAK4 activity in other ways. These compounds have promising applications in IRAK4-mediated diseases, including immune diseases (such as psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, alcoholic liver disease, autoimmune liver disease, acne, etc.), tumors (such as multiple myeloma, lymphocytic leukemia and lymphoma, etc.), Alzheimer's disease, and fibrotic diseases.

[0140] Compared with the positive compound (Kymera Therapeutics, Inc. patent, patent number WO2020113233), the compound of the present invention has advantages in the following aspects, including: the inhibitory effect on the IL-6 secretion level of PBMC cells induced by R848, the inhibitory effect on the IL-6 secretion level of PBMC cells induced by LPS+IL-1β, the effect of degrading IRAK4 protein in THP1 cells, stability in liver microsomes, the therapeutic effect on IMQ-induced psoriatic skin thickening and ear thickening, and oral bioavailability. Therefore, the compounds disclosed in the present invention provide a new option for clinical screening and / or preparation of drugs for diseases related to IRAK4 activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0141] FIG1 shows the therapeutic effect of the compounds of the present invention on IMQ-induced psoriasis skin thickening;

[0142] FIG2 shows the significant therapeutic effect of the compound of the present invention on IMQ-induced psoriatic ear thickening. DETAILED DESCRIPTION

[0143] 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.

[0144] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0145] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-25° C. All temperatures are expressed in degrees Celsius.

[0146] Overnight is 14±1h.

[0147] High-performance liquid chromatography (HPLC) conditions: Waters high-pressure liquid chromatograph (e2695 / e2487). Analytical HPLC conditions: C18 column (3.5 μm, 4.6 x 75 mm), UV detection at 220 and 254 nm, elution: 5-95% acetonitrile (containing 0.1% v / v TFA or 10 mmol NH₄CO₃) gradient over 10 minutes.

[0148] Reverse-phase purification was performed using a Gilson GX-281 reverse-phase preparative chromatograph or a Biotage IsoLera One rapid purification system.

[0149] NMR measurements were performed using a Bruker Avance III 400 or 600 NMR spectrometer. The NMR shift (δ) was measured at 10 -6 The unit of concentration is ppm. The solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCL3) and deuterated methanol (CD3OD), etc. The internal standard is tetramethylsilane (TMS).

[0150] 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 Chengdu Jinshan Chemical Reagent Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd.

[0151] 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 Chengdu Jinshan Chemical Reagent Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd.

[0152] 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-fluorenyl Methoxyformyl; MsCl is methanesulfonyl chloride; Ms is methanesulfonyl; TBSCl is tert-butyldimethylsilyl chloride; TBS is tert-butyldimethylsilyl chloride; TBDPSCl is tert-butyldiphenylsilyl chloride; 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; NMM is nitrogenmethylmorpholine.

[0153] Example

[0154] Synthesis of intermediate IM-1

[0155] Step 1: Synthesis of intermediate 1b

[0156] Compound 1a (850 g, 3.47 mmol) was added to methanol, followed by the addition of 1 / 200 concentrated sulfuric acid. The reaction was refluxed at 65°C for 12 h. After the reaction was complete, a saturated sodium carbonate solution was added to adjust the pH to 7. The mixture was filtered and concentrated. 2000 mL of EA was added, and the mixture was extracted three times with saturated brine (400 mL x 3), dried over anhydrous sodium sulfate, and concentrated to afford compound 1b (900 g), which was directly used in the next step.

[0157] Step 2: Synthesis of intermediate 1c

[0158] Compound 1b (900 g) was added to THF (6000 mL), and 150 g of lithium aluminum hydride was added in small portions at -20°C. After the reaction was complete, an equal amount of water and an equal amount of 15% aqueous sodium hydroxide solution were added, followed by quenching with 3 times the amount of aqueous solution. The mixture was filtered and concentrated to obtain compound 1c (410 g).

[0159] Step 3: Synthesis of intermediate 1d

[0160] Under an ice-water bath, compound 1c (400 g) was added to DCM (6000 mL), and compound 4 (251 g) was added dropwise with a solution of 521 g of TBSCl in DCM. The mixture was reacted at room temperature for 12 h. After completion of the reaction, the mixture was concentrated, washed three times with water (2000 mL), and twice with DCM. The organic phase was extracted once with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1d (737 g).

[0161] Step 4: Synthesis of intermediate 1e

[0162] Compound 1d (720 g, 2.95 mol) was dissolved in DCM (10 L). A solution of 940 g of TsCl in dichloromethane (2 eq) was quickly added dropwise, followed by a solution of DMAP in DCM. The mixture was allowed to react at 30°C for 12 h. After the reaction was complete, 2 L of water was added, and the mixture was extracted twice with 2 L of DCM. The organic phase was extracted once with 10% citric acid, washed once with saturated NaHCO₃ and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford compound 6 (760 g).

[0163] Step 5: Synthesis of intermediate 1f

[0164] 3-(Difluoromethyl)-4-nitro-1H-pyrazole (73.64 g) was added to DMF (1 L) and cesium carbonate (1.4 eq), and the reaction was continued for 10 min. Compound 1e (180 g) was added, and the reaction was continued at 60°C for 12 h. 2500 mL of water was added, and the mixture was extracted three times with 500 mL of petroleum ether, washed twice with 500 mL of water, and washed once with 500 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and passed through a chromatography column to obtain compound 1f (52.6 g).

[0165] Step 6: Synthesis of intermediate 1g

[0166] Compound 8 (52.6 g) was added with 500 mL of methanol, 1 eq of triethylamine, and 3 eq of (Boc)2O. The mixture was stirred at room temperature for 10 min, and 0.05 eq of palladium on carbon was added. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was filtered and concentrated to obtain compound 9 (62 g).

[0167] Step 7: Synthesis of intermediate 1h

[0168] Compound 1g (62g) was added to 300mL of THF. HF.py (2eq) was added dropwise under an ice-water bath. The mixture was allowed to warm naturally and stirred for 12h. After the reaction was complete, the mixture was extracted three times with water and EA. The organic phase was washed once with saturated sodium bicarbonate and once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and filtered through a chromatography column to obtain the compound (39.6g). ESI-LCMS: m / z 346 [M+1], 1.45min.

[0169] Step 8: Synthesis of intermediate IM-1

[0170] Compound 1h (39.6 g) was added to 250 mL of DCM. DMP (1.3 eq) was added in small portions under an ice-water bath and stirred for 3 h. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was filtered, separated, dried over anhydrous sodium sulfate, concentrated, and filtered through a chromatography column to obtain compound 1 (31 g). ESI-LCMS: m / z 344 [M+1], 1.55 min.

[0171] Synthesis of intermediate IM-2

[0172] Step 1: Synthesis of intermediate 2b

[0173] 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 of ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate. LCMS (ESI) m / z: [M+1] = 277.

[0174] Step 2: Synthesis of intermediate IM-2

[0175] Ethyl 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2.55 g, 9.2 mmol) was dissolved in 20 ml of methanol, followed by the addition of a solution of sodium hydroxide (800 mg) in water (10 ml) and stirring at room temperature for 16 hours. After the reaction was complete, 1 M dilute hydrochloric acid was added to adjust the pH to approximately 5-6, and a solid precipitated. The organic solvent was removed under reduced pressure, followed by filtration and the solid rinsed with water. The solid was collected and dried to yield 2.01 g of 5-morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid. LCMS (ESI) m / z: [M+1] = 249.

[0176] Synthesis of intermediates IM-3 to IM-13: The preparation methods of intermediates IM-3 to IM-13 were similar to those of intermediate IM-2, as shown in Table 1.

[0177] Table 1 Compound numbers and structures

[0178] Synthesis of intermediate IM-15

[0179] Step 1: Synthesis of Intermediate IM-15b: Dissolve IM-15a (15 g), triphenylphosphine (31 g), and phthalimide (12.9 g) in 200 mL of THF. Slowly add diisopropyl azodicarboxylate (23.5 mL) at 0°C. Allow to react overnight at room temperature, concentrate, and column chromatography to yield a yellow solid (20 g). LCMS (ESI) m / z: [M+1] = 316.9.

[0180] Step 2: Synthesis of intermediate IM-15c

[0181] IM-15b (20 g) was dissolved in 200 mL of ethanol, and 10 mL of hydrazine hydrate was added. The mixture was heated and refluxed for 5 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The organic layer was extracted with EA. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+1] = 186.9.

[0182] Step 3: Synthesis of intermediate IM-15d

[0183] Dissolve IM-15c (10 g) in 100 mL of dichloromethane, add 11 mL of triethylamine, cool, and add 6 mL of acetic anhydride dropwise at 0°C. After addition, react at room temperature for 2 h. Add 20 mL of water, extract with dichloromethane, collect the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 8 g of crude product, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+1] = 228.9.

[0184] Step 4: Synthesis of intermediate IM-15e

[0185] IM-15d (8 g) was dissolved in 60 mL of phosphorus oxychloride and refluxed overnight. The reaction mixture was concentrated, and the residue was added to ice, neutralized with saturated sodium carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography yielded 5 g of the product. LCMS (ESI) m / z: [M+1] = 210.9.

[0186] Step 5: Synthesis of intermediate IM-15f

[0187] Dissolve IM-15e (5 g) in 50 mL of concentrated sulfuric acid. Add 1.8 mL of concentrated nitric acid dropwise in an ice bath and allow to react overnight. Slowly add ice to the reaction mixture to remove a yellow solid. Filter, wash with water, and collect the filter cake. Dry under vacuum to obtain the desired product. LCMS (ESI) m / z: [M+1] = 255.9.

[0188] Step 6: Synthesis of intermediate IM-15g

[0189] IM-15f (2 g) was dissolved in 20 mL of trifluoroacetic acid, followed by the addition of 2.7 mL of trifluoroacetic anhydride and 2.55 g of zinc powder. The reaction was allowed to react at room temperature. After completion, the reaction solution was concentrated, and the residue was extracted with EA. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography afforded 1.8 g of the desired product. LCMS (ESI) m / z: [M+1] = 321.9.

[0190] Step 7: Synthesis of intermediate IM-15h

[0191] Dissolve 1.5 g of IM-15 in 20 mL of methanol, add 1.3 g of potassium carbonate, and heat under reflux. After the reaction is complete, filter and concentrate the filtrate to obtain the desired product, which is used in the next step without further purification. LCMS (ESI) m / z: [M+1] = 225.9.

[0192] Step 8: Synthesis of intermediate IM-15i

[0193] Dissolve IM-15h (1 g) in 10 mL of ethanol, then add 2 mL of trifluoromethanesulfonic acid and 4.8 mL of ethyl acrylate. Heat under reflux. After completion of the reaction, concentrate and extract with EA. The organic layer is washed sequentially with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography afforded 900 mg of the desired product. LCMS (ESI) m / z: [M+1] = 327.2.

[0194] Step 9: Synthesis of intermediate 15j

[0195] IM-15i (900 mg) was dissolved in 6 mL of MeOH / THF / H₂O (v / v / v = 4 / 1 / 1), and 165 mg of sodium hydroxide was added. The reaction was allowed to react at room temperature. After completion, the reaction was concentrated, the organic solvent was evaporated, and the aqueous phase was adjusted to pH 4. A white solid was separated and filtered. The filter cake was collected and dried to yield 800 mg of a white solid. LCMS (ESI) m / z: [M+1] = 298.0.

[0196] Step 10: Synthesis of intermediate IM-15k

[0197] Disperse IM-15j (800 mg) in 10 mL of dioxane, then add 255 mg of ammonium bicarbonate, 0.33 mL of pyridine, and 703 mg of Boc anhydride. Heat to 60°C and react for 3 hours. Concentrate, add water, and a white solid is removed. Filter and dry to obtain 750 mg of the desired product. LCMS (ESI) m / z: [M+1] = 297.0.

[0198] Step 11: Synthesis of intermediate IM-15

[0199] IM-15k (500 mg), 1.36 g carbonyldiimidazole, and 1.64 g cesium carbonate were dispersed in 5 mL of acetonitrile, refluxed, and concentrated. Extraction with dichloromethane was completed, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography afforded 360 mg of the desired product. LCMS (ESI) m / z: [M+1] = 323.1.

[0200] Synthesis of intermediate IM-16

[0201] The preparation method of intermediate IM-16 is similar to that of intermediate IM-15.

[0202] Synthesis of intermediate IM-17

[0203] Step 1: Synthesis of intermediate IM-17b

[0204] IM-17a (5 g) was dissolved in 30 mL of DME and 3.1 g of dichloroacetaldehyde was added. The mixture was heated and reacted for 6 hours. The solid was collected by filtration to obtain 5.2 g of a yellow solid. LCMS (ESI-MS): 178 [M+H] +

[0205] Step 2: Synthesis of intermediate IM-17c

[0206] IM-17b was dissolved in 50 mL of DMF, and 4.98 g of NBS was added in portions. The mixture was reacted at room temperature for 2 hours and filtered to obtain 4.8 g of a yellow solid. LCMS (ESI-MS): 256 [M+H] + .

[0207] Step 3: Synthesis of intermediate IM-17d

[0208] IM-17c (4.8 g) was dissolved in MeOH / H₂O (V / V = 3 / 1), and 10 g of ammonium chloride and 10.5 g of iron powder were added under nitrogen. The mixture was reacted at 80°C for 2 hours. The mixture was filtered, the filtrate was concentrated, and the residue was extracted with EA. The organic layers were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurried with dichloromethane to obtain a white solid. LCMS (ESI-MS): 226 [M+H] + ; 1HNMR (400MHz, CD3OD) δ7.44 (s, 1H), 6.48 (d, J = 7.6Hz, 1H), 6.40 (d, J = 7.5Hz, 1H), 2.94 (s, 3H).

[0209] Steps 4 to 7: Synthesis of intermediate IM-17

[0210] Steps 4 to 7 were similar to steps 8 to 11 for preparing IM-15. LCMS (ESI-MS): 323.0 [M+H] + .

[0211] Synthesis of intermediate IM-18

[0212] The preparation method of intermediate IM-18 is similar to that of intermediate IM-17.

[0213] Synthesis of intermediate IM-19

[0214] Step 1: Synthesis of intermediate IM-19b

[0215] IM-17a (5 g) was dissolved in 30 mL of DME, and 5.9 g of 1-bromopropan-2-one was added. The mixture was heated and reacted for 6 hours. The solid was collected by filtration to obtain 5.2 g of a yellow solid.

[0216] Step 2: Synthesis of intermediate IM-19c

[0217] IM-19b (4 g) was dissolved in 40 mL of DMF, and 4.8 g of NBS was added in batches. The mixture was reacted at room temperature for 2 hours. 500 mL of water was added to the reaction solution, and the mixture was filtered to obtain 5 g of a yellow solid.

[0218] Step 3: Synthesis of intermediate IM-19d

[0219] IM-19c (5 g) was dissolved in 100 mL of MeOH / H₂O (V / V = 3 / 1), and 11 g of ammonium chloride and 12 g of iron powder were added. The mixture was stirred at 80°C for 2 hours under nitrogen. The mixture was filtered, the filtrate was concentrated, and the residue was extracted with EA. The organic layers were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the desired product. LCMS (ESI-MS): 226 [M+H] + ; 1 HNMR (400MHz, DMSO) δ7.48(d,J=6.6Hz,1H),6.77(t,J=7.0Hz,1H),6.31(d,J=7.4Hz,1H),5.71(s,2H),2.32(s,3H).

[0220] Steps 4 to 7: Synthesis of intermediate IM-19

[0221] Steps 4 to 7 were similar to steps 8 to 11 for preparing IM-15. LCMS (ESI-MS): 323.0 [M+H] +

[0222] Synthesis of intermediate IM-20

[0223] The preparation method of intermediate IM-20 is similar to that of intermediate IM-19. LCMS (ESI-MS): 323.0 [M+H] +

[0224] Synthesis of intermediate IM-21

[0225] The preparation method of intermediate IM-21 is similar to that of intermediate IM-19. LCMS (ESI-MS): 323.0 [M+H] +

[0226] Synthesis of intermediate IM-22

[0227] Step 1: Synthesis of intermediate IM-22b

[0228] Compound MSH (31.00 g) was added to DCM (150 mL), and compound IM-22a (15 g) was slowly added, and the mixture was stirred overnight and monitored by LCMS. The reaction solution was concentrated to obtain crude compound IM-22b.

[0229] Step 2: Synthesis of intermediate IM-22c

[0230] The crude product from the previous step was added to DMF (150 mL), and potassium carbonate (26 g) and methyl but-2-ynoate (18 g) were added under ice-cooling. The mixture was stirred at room temperature overnight. LCMS monitoring, concentration, and column chromatography afforded compound IM-22c (5 g). ESI-LCMS: m / z 268.9 [M+H] + .

[0231] Step 3: Synthesis of intermediate IM-22d

[0232] IM-22c (5 g) was dissolved in 25 mL of acetic acid, and a 10 mg solution of hydrobromic acid (48%) in water was added. The mixture was heated to 100°C overnight. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Column chromatography afforded 3.5 g of the desired product. ESI-LCMS: m / z 210.9 [M+H] + .

[0233] Steps 4 to 9: Synthesis of intermediate IM-22

[0234] Steps 4 to 9 for preparing intermediate IM-22 are similar to steps 2 to 7 for preparing intermediate IM-20. ESI-LCMS: m / z 323.0 [M+H] + .

[0235] Synthesis of intermediate IM-23

[0236] Step 1: Synthesis of intermediate IM-23a

[0237] Dissolve IM-22d (1.5 g) in 10 mL of methanol, add triethylamine (1.1 mL) and 150 mg of palladium on carbon, replace the mixture three times under a hydrogen balloon, and react at room temperature overnight. Filter with suction, concentrate the filtrate, and perform column chromatography to obtain the desired product (600 mg).

[0238] Step 2: Synthesis of intermediate IM-23b

[0239] IM-23a (600 mg) was dissolved in 6 mL of anhydrous tetrahydrofuran, cooled to -78°C, and 4.3 mL of n-butyl lithium (1.6 M) was added dropwise. After completion of the addition, the mixture was allowed to react for 30 minutes. 2.2 g of 1,2-dibromotetrachloroethane was added and the reaction continued for 30 minutes. The mixture was slowly warmed to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography yielded 700 mg of the desired product. ESI-LCMS: m / z 210.9 [M+H] + .

[0240] Steps 3 to 8: Synthesis of intermediate IM-23

[0241] Steps 3 to 8 for preparing intermediate IM-23 are similar to steps 2 to 7 for preparing intermediate IM-20. ESI-LCMS: m / z 323.0 [M+H] + .

[0242] Synthesis of intermediate IM-24

[0243] Step 1: Synthesis of intermediate IM-24c

[0244] Dissolve IM-24a (4 g) in 30 mL of DME and add 3.7 g of IM-24b. Heat and react for 6 hours. Filter and collect the solid, then redissolve in 30 mL of methanol. Heat to 80°C and react overnight. Concentrate to obtain the title compound. LCMS (ESI-MS): 285 [M+H] +

[0245] Step 2: Synthesis of intermediate IM-24d

[0246] Dissolve IM-24c (4.9 g) in 30 mL of tetrahydrofuran, 15 mL of methanol, and 7.5 mL of water. Add 1.3 g of lithium hydroxide and react at room temperature for 3 h. Concentrate and evaporate to remove the organic solvent. Adjust the pH to 4-5, remove the solid, and filter the filter cake to obtain 2.9 g of a white solid. LCMS (ESI-MS): 255 [M+H] + .

[0247] Step 3: Synthesis of intermediate IM-24e

[0248] Dissolve IM-24d in 30 mL of tert-butanol, add 4.4 g of DIEA and 6.1 g of DPPA, and heat to 80°C under nitrogen for overnight reaction. Add 50 mL of water to the reaction solution and extract with ethyl acetate. The organic layer is washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography yielded 950 mg of the desired product as a white solid. LCMS (ESI-MS): 326 [M+H] + , 1 HNMR (400MHz, CD3OD) δ8.11(d,J=7.2Hz,1H),7.67(d,J=1.4Hz,1H),7.11(dd,J=7.2,2.0Hz,1H),2.40(s,3H),1.54(s,9H).

[0249] Steps 4 to 7: Synthesis of intermediate IM-24

[0250] Steps 4 to 7 were similar to steps 8 to 11 for preparing IM-15. LCMS (ESI-MS): 323.0 [M+H] +

[0251] Synthesis of intermediate IM-25

[0252] The preparation method of intermediate IM-25 is similar to that of intermediate IM-24. LCMS (ESI-MS): 323.0 [M+H] +

[0253] Synthesis of intermediate IM-26

[0254] Step 1: Synthesis of intermediate IM-26b

[0255] To 200 mL of anhydrous tetrahydrofuran was added 15 mL of acetonitrile, cooled to -78°C, and n-butyllithium (178 mL, 1.6 M) was added. The reaction mixture was allowed to react at -78°C for 45 minutes, and IM-26a (20 g) was slowly added. After the addition, the reaction mixture was warmed to -30°C and allowed to react for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution, 200 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography yielded 16 g of the desired product. LCMS (ESI-MS): 196.9 [M+H] +

[0256] Step 2: Synthesis of intermediate IM-26c

[0257] Dissolve 16g of the product in 100mL of DMF. In an ice-water bath under nitrogen, add NaH (6.5g, 60%) portionwise. Stir for 15 minutes, followed by 15.4mL of dimethyl sulfate. After addition, warm the reaction mixture to room temperature, allow to react overnight, and then quench with water. Extract with ethyl acetate, and wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Column chromatography yielded 14g of the desired product. LCMS (ESI-MS): 210.9 [M+H] +

[0258] Step 3: Synthesis of intermediate IM-26d

[0259] The synthesis of step 3 is similar to that of step 1 for preparing intermediate IM-22.

[0260] Step 4: Synthesis of intermediate IM-26e

[0261] IM-26d (20 g) was dissolved in 100 mL of methanol, and KCO (13 g) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated, and water was added to the residue. The mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography afforded 9.7 g of the desired product. LCMS (ESI-MS): 225.9 [M+H] +

[0262] Steps 5 to 8: Synthesis of intermediate IM-26

[0263] Steps 5 to 8 were similar to those of steps 8 to 11 for preparing IM-15. LCMS (ESI-MS): 323.0 [M+H] +

[0264] Synthesis of intermediate IM-27

[0265] The preparation method of intermediate IM-27 is similar to that of intermediate IM-26. LCMS (ESI-MS): 323.0 [M+H] +

[0266] Synthesis of intermediate IM-28

[0267] Step 1: Synthesis of intermediate IM-28b

[0268] IM-15 (500 mg), IM-28a (876 mg), and K3PO4 (985 mg) were dispersed in 5 mL of dioxane and 1 mL of water. Under nitrogen, Pd(PPh3)4 (89.4 mg) was added. The nitrogen atmosphere was replaced three times, and the mixture was heated at 90°C for 18 h. The mixture was concentrated and the residue was purified by column chromatography to obtain the desired product (420 mg). LCMS (ESI-MS): 494.2 [M+H] +

[0269] Step 2: Synthesis of intermediate IM-28

[0270] IM-28b was added to a 4M HCl-dioxane solution, and after the starting material disappeared, the solvent was removed by rotary evaporation to obtain IM-28, which was used directly in the next step reaction without purification. LCMS (ESI) m / z: [M+1] = 394.2.

[0271] Synthesis of intermediates IM-29 to IM-42: The preparation methods of intermediates IM-29 to IM-42 were similar to those of intermediate IM-28, as shown in Table 2.

[0272] Table 2 Compound numbers and structures

[0273] Synthesis of intermediate IM-43

[0274] Step 1: Synthesis of intermediate 43b

[0275] IM-15 (150 mg) was dissolved in 5 ml of DMF, followed by the addition of N-Boc-4-propargyloxypiperidine (124 mg), ditriphenylphosphine palladium dichloride (33 mg), and cesium carbonate (306 mg). The reaction system was then protected with nitrogen and stirred at 100°C overnight. After completion of the reaction, 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 purified by column chromatography to obtain the title compound. LCMS (ESI) m / z: [M+1] = 482.2.

[0276] Step 2: Synthesis of intermediate IM-43

[0277] IM-43b was dissolved in dioxane, and 4M HCl in dioxane was added. After the starting material disappeared, the solvent was removed by rotary evaporation to obtain IM-43 hydrochloride, which was used in the next reaction without purification. LCMS (ESI) m / z: [M+1] = 382.2.

[0278] Synthesis of intermediate IM-44

[0279] Step 1: Synthesis of intermediate IM-44a

[0280] IM-1 (700 mg) was dissolved in DMF / THF (1.0 mL / 15.0 mL). The reaction mixture was cooled to -10°C, and IM-28 (776 mg) and TEA (412 mg) were added. The mixture was stirred under argon for 0.5 h. HOAc (367 mg) and NaBH(OAc)3 (1.3 g) 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 combined organic layers were washed with saturated brine. The organic layers were then dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column (DCM / MeOH = 100 / 1 to 20 / 1) to yield a white solid in 77% yield. LCMS (ESI) m / z: [M+1] = 721.4.

[0281] Step 2: Synthesis of intermediate IM-44

[0282] IM-44a (1 g) was dissolved in 10 mL of dioxane, and a 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 5 h. 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] = 621.3.

[0283] Synthesis of intermediates IM-45 to IM-58b: The preparation method of intermediates IM-45 to IM-58b is similar to that of intermediate IM-44, as shown in Table 3.

[0284] Table 3 Compound numbers and structures

[0285] Synthesis of intermediate IM-59

[0286] Step 1: Synthesis of intermediate IM-59b

[0287] IM-59a (2g), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.5g), and K2CO3 (1.72g) were dispersed in 20mL of dioxane and 5mL of water. Under nitrogen, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (725mg) was added. The air in the reaction system was replaced with nitrogen, and the reaction was continued at 90°C under nitrogen for 18 hours. 20mL of dioxane was added to the reaction solution, and after ultrasonic dispersion, the mixture was filtered through celite. The filtrate was concentrated, and the residue was dispersed in 20mL of acetonitrile. CDI (5g) was added, and the mixture was refluxed at 80°C. After completion of the reaction, the mixture was concentrated, and column chromatography yielded 900mg of the desired product. LCMS (ESI) m / z: [M+1] = 425.3.

[0288] Step 2: Synthesis of intermediate IM-59c

[0289] IM-59b (900 mg) was dissolved in 15 mL of ethanol, and 100 mg of Pd / C was added. The mixture was heated to 60°C under hydrogen for 18 hours. The filtrate was filtered through Celite and concentrated to afford 700 mg of the desired product, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+1] = 427.2.

[0290] Step 3: Synthesis of intermediate IM-59

[0291] IM-59c (500 mg) was dissolved in 5 mL of dioxane, and a 4 M solution of dioxane hydrochloride was added. The reaction mixture was stirred at room temperature for 5 h. 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] = 327.2.

[0292] Synthesis of intermediates IM-60 to IM-72: The preparation method of intermediates IM-60 to IM-72 is similar to that of intermediate IM-59, as shown in Table 4.

[0293] Table 4 Compound numbers and structures

[0294] Synthesis of intermediate IM-73

[0295] Step 1: Synthesis of intermediate IM-73a

[0296] IM-59a (5 g) was dissolved in 50 mL of tetrahydrofuran and cooled in an ice-water bath. Sodium hydroxide (931 mg) was added portionwise and stirred in an ice-water bath for 10 minutes. SEM-Cl (3 g) was then added. After addition, the reaction mixture was allowed to warm to room temperature and allowed to react overnight. The reaction was quenched with saturated ammonium chloride solution. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography yielded 5.6 g of the desired product. LCMS (ESI-MS): 452.1 [M+H]. +

[0297] Step 2: Synthesis of intermediate IM-73b

[0298] IM-73a (3 g), Cs2CO3 (4.3 g), and Ruphos (609 mg) were dispersed in 30 mL of dioxane. Pd2(dba)3 (607 mg) was added under nitrogen, and the air in the reaction system was replaced with nitrogen. The reaction was continued at 100°C under nitrogen for 18 hours. 20 mL of dioxane was added to the reaction solution, and after ultrasonic dispersion, the solution was filtered through celite. The filtrate was concentrated, and the residue was purified by column chromatography to obtain 1.8 g of the desired product. LCMS (ESI) m / z: [M+1] = 558.7.

[0299] Step 3: Synthesis of intermediate IM-73

[0300] IM-73b (500 mg) was dissolved in 8 mL of dichloromethane, and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 4 h. 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] = 328.2.

[0301] Synthesis of intermediate IM-74

[0302] The preparation method for the synthesis of intermediate IM-74 is similar to that of IM-73. LCMS (ESI) m / z: [M+1] = 354.2. Synthesis of intermediates IM-75 to IM-81: The preparation methods of intermediates IM-75 to IM-81 are similar to those of intermediate IM-73, as shown in Table 5.

[0303] Table 5 Compound numbers and structures

[0304] Synthesis of intermediate IM-82

[0305] Step 1: Synthesis of IM-82b

[0306] 2,6-Dihydroxyacetophenone (5.6 g, 36.83 mmol) was dissolved in 56 mL of ethylene glycol, and 28 mL of hydrazine hydrate was added. The reaction mixture was stirred at 160°C for 3 hours. After completion of the reaction, ethyl acetate was added for extraction. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The desired product was obtained by column chromatography (PE / EA = 10 / 1 to 5 / 1) in a 77% yield. LCMS (ESI) m / z: [M+1] = 149.2.

[0307] Step 2: Synthesis of IM-82c

[0308] 3-Methyl-1H-indazol-4-ol (4.2 g, 28.37 mmol) was dissolved in 42 mL of tetrahydrofuran, and tert-butyl 4-hydroxypiperidine-1-carboxylate (6.28 g, 31.22 mmol), PPh3 (9.67 g, 36.87 mmol), and DIAD (8.6 g, 42.53 mmol) were added sequentially. The reaction mixture was refluxed overnight, filtered, and the filtrate was concentrated and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to give 4.5 g of the product. Yield: 48%. LCMS (ESI) m / z: [M+1] = 332.19.

[0309] Step 3: Synthesis of IM-82d

[0310] Compound IM-82c (4.5 g, 13.59 mmol) was dissolved in DMSO / THF (v / v = 25 mL / 25 mL). NaH (1.63 g, 67.92 mmol) was added portionwise at 0°C under nitrogen. The mixture was stirred for 30 min. A solution of KI (1.8 g, 10.86 mmol) in 20 mL of DMSO and a solution of 3-bromopiperidine-2,6-dione (5.19 g, 27.18 mmol) in tetrahydrofuran (20 mL) were then added. The mixture was gradually warmed to room temperature and stirred for 1 hour. After completion of the reaction, the temperature was lowered to 0-10°C, and 2M HCI was added to adjust the pH to 6-7. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The product was purified by column chromatography (PE / EA = 3 / 1) to obtain 2.5 g of the desired product in a 42% yield. LCMS (ESI) m / z: [M+1] = 443.22.

[0311] Step 4: Synthesis of IM-82

[0312] IM-82d (100 mg) was dissolved in 4 mL of dichloromethane, and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 4 h. 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] = 343.17.

[0313] Synthesis of intermediate IM-83

[0314] Step 1: Synthesis of intermediate IM-83a

[0315] Disperse IM-2 (2 g), pyridine (1.3 g), and ammonium bicarbonate (1.3 g) in 15 mL of dioxane, and add Boc2O (2.6 g). After addition, heat the reaction mixture to 60°C and react for 3 hours. Add 45 mL of water to the reaction mixture, filter, and wash the filter cake with a small amount of dioxane. Collect the solid and dry to obtain 1.85 g of a white solid. LCMS (ESI) m / z: [M+1] = 248.1.

[0316] Step 2: Synthesis of intermediate IM-83c

[0317] IM-83b (1.56 g, preparation method adapted from WO2020 / 264499), IM-83a (1.25 g), Cs2CO3 (3.60 g), and Xantphos (532 mg) were dispersed in 20 mL of dioxane. Under nitrogen, Pd2(dba)3 (421 mg) was added, and the air in the reaction system was replaced with nitrogen. The reaction was continued at 80°C under nitrogen for 72 hours. 20 mL of dioxane was added to the reaction solution, and after ultrasonic dispersion, the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by column chromatography to obtain 320 mg of the desired product. LCMS (ESI) m / z: [M+1] = 506.2.

[0318] Step 3: Synthesis of intermediate IM-83

[0319] Compound IM-83c (100 mg) was dissolved in 3 mL of DCM, and DMP (1.3 eq) was added under ice-water bath and stirred for 3 h. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was filtered, separated, dried over anhydrous sodium sulfate, concentrated, and filtered through a chromatography column to obtain compound IM-80 (80 mg). LCMS (ESI) m / z: [M+1] = 504.2.

[0320] Synthesis of intermediates IM-84 to IM-87: The preparation methods of intermediates IM-84 to IM-87 were similar to the preparation of intermediate IM-83, as shown in Table 6.

[0321] Table 6 Compound numbers and structures

[0322] Synthesis of intermediate IM-88

[0323] Step 1: Synthesis of IM-88b

[0324] 5-Bromo-4-fluoro-2-nitrobenzaldehyde (15g) and dimethylamine hydrochloride (9.86g) were dissolved in 150mL of DMSO, and diisopropylethylamine (15.63g) was added. The reaction mixture was allowed to react overnight at 90°C. After completion, the mixture was diluted with water (600mL) and extracted with EA (100mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (PE / DCM = 5 / 1) to obtain 7.53g of the desired product. LCMS (ESI) m / z: [M+1] = 272.98.

[0325] Step 2: Synthesis of IM-88

[0326] IM-88b (2.5 g) was dissolved in 30 mL of isopropanol, followed by the addition of IM-85c (1.43 g). The mixture was reacted at 80°C under nitrogen for four hours, then cooled to 25°C. Tributylphosphine (5.56 g) was then added to the reaction mixture, and the mixture was reacted at 80°C under nitrogen for 16 hours. After completion of the reaction, the organic solvent was removed by vortexing, the mixture was diluted with water (100 mL), and extracted with EA (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 1:1) afforded 4.5 g of the product. LCMS (ESI) m / z: [M+1] = 352.1.

[0327] Synthesis of intermediates IM-89 to IM-98: The preparation methods of intermediates IM-89 to IM-98 were similar to that of intermediate IM-88, as shown in Table 7.

[0328] Table 7 Compound numbers and structures

[0329] Synthesis of intermediate IM-99

[0330] Step 1: Synthesis of IM-99b

[0331] Dissolve pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.5 g, 9.20 mmol) in 15 mL of 1,4-dioxane and stir until clear. Add pyridine (0.727 g, 9.19 mmol), BOC anhydride (3.01 g, 13.79 mmol), and NH4HCO3 (1.45 g, 18.34 mmol). Stir the reaction mixture in a water bath at room temperature for 12 hours. After completion, filter through celite, wash with water, then with 1,4-dioxane, and dry in a vacuum oven to constant weight to obtain the desired product in a 67% yield. LCMS (ESI) m / z: [M+1] = 163.19.

[0332] Step 2: Synthesis of IM-99c

[0333] IM-99b (1 g, 6.17 mmol), IM-86 (2.21 g, 5.60 mmol), CS2CO3 (4.38 g, 13.44 mmol), and Xantphos (0.649 g, 1.12 mmol) were dissolved in 19 mL of 1,4-dioxane. Pd2(dba)3 (0.513 g, 0.56 mmol) was quickly added. The atmosphere was purged with nitrogen five times and the reaction was continued at 100°C for 16 h. After completion, the reaction was filtered through Celite, dried under vacuum, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to obtain the desired product (1.168 g, yield 61.47%). LCMS (ESI) m / z: [M+1] = 476.49.

[0334] Step 3: Synthesis of IM-99

[0335] Oxalyl chloride (0.434 g, 3.42 mmol) was added to DCM (18 mL). DMSO (0.544 g, 6.96 mmol) in DCM (1 mL) was added dropwise in a dry ice-ethanol bath at -70°C. The mixture was stirred for 0.5 h, followed by the addition of IM-95c (1.1 g, 2.28 mmol) in DCM (7 mL) and stirring for 30 min. DIPEA (1.47 g, 11.37 mmol) in DCM (2 mL) was then added and stirred for 15-30 min. The mixture was analyzed with acetonitrile and analyzed by LCMS. After completion of the reaction, water (20 mL) was added and the mixture was extracted with DCM (30 mL x 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the desired product. 1 g of product was obtained with a yield of 93.46%. LCMS (ESI) m / z: [M+1] = 476.49.

[0336] Synthesis of intermediates IM-100 to IM-109: The preparation methods of intermediates IM-100 to IM-109 were similar to that of intermediate IM-99, as shown in Table 8.

[0337] Table 8 Compound numbers and structures

[0338] Synthesis of intermediate IM-110

[0339] Step 1: Synthesis of IM-110a

[0340] 5-Bromo-4-fluoro-2-nitrobenzaldehyde (35.6 g, 143.43 mmol) and morpholine (50.1 g, 575.06 mmol) were dissolved in 445 mL of DMSO and the reaction mixture was allowed to react at 80°C for 1 h. After completion, the reaction was diluted with water (890 mL) and extracted with EA (900 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 4) to obtain the desired product (35 g, 77.6% yield). LCMS (ESI) m / z: [M+1] = 316.12.

[0341] Step 2: Synthesis of IM-110b

[0342] IM-110a (7 g, 22.22 mmol) was dissolved in 231 mL of isopropanol, followed by the addition of tert-butyl 4-aminopiperidine-1-carboxylate (5.34 g, 26.66 mmol). The mixture was reacted at 80°C under nitrogen for four hours, then cooled to 25°C. Tributylphosphine (13.48 g, 66.63 mmol) was then added and the mixture was reacted at 80°C under nitrogen for 16 hours. After completion of the reaction, the organic solvent was removed by vortexing, the mixture was diluted with water (200 mL), and extracted with EA (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 10:1 to PE / EA = 5 / 1) afforded 10 g of the product in a 96.7% yield. LCMS (ESI) m / z: [M+1] = 467.29.

[0343] Step 3: Synthesis of IM-110

[0344] IM-110b (2 g, 4.30 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.77 g, 4.75 mmol), Cs2CO3 (3.36 g, 10.31 mmol), and Xantphos (0.50 g, 0.864 mmol) were dissolved in 20 mL of 1,4-dioxane. Pd2(dba)3 (0.39 g, 0.426 mmol) was quickly added. The atmosphere was purged with nitrogen five times, and the reaction mixture was stirred at 100°C for 16 h. After completion, the reaction was filtered through celite, dried, and purified by column chromatography (DCM / MeOH = 100:1 to DCM / MeOH = 40:1) to obtain 156 mg of the product in a 6.8% yield. LCMS (ESI) m / z: [M+1] = 547.63.

[0345] Synthesis of intermediates IM-111 to IM-114: The preparation methods of intermediates IM-111 to 114 were similar to the preparation of intermediate IM-105, as shown in Table 9.

[0346] Table 9 Compound numbers and structures

[0347] Synthesis of intermediate IM-115

[0348] Step 1: Synthesis of intermediate IM-115b

[0349] A solution of 5-chloro-2-methyl-4-nitroaniline (10 g, 53.6 mmol) in 3M sulfuric acid (100 mL) was placed in an ice bath at 0°C. A solution of sodium nitrite (3.70 g, 53.6 mmol) in water (10 mL) was slowly added dropwise (approximately 1 hour). After the addition was complete, the mixture was stirred in an ice bath for 10 minutes. A solution of potassium iodide (10.7 g, 64.3 mmol) in water was then added. The reaction temperature was maintained at 0°C in an ice bath for 1 hour, then slowly raised to room temperature (25°C). Stirring was continued at 25°C for 1 hour. TLC confirmed the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:0 to 100:1) to yield 1-chloro-5-iodo-4-methyl-2-nitrobenzene (11.6 g, 72% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d) δ8.24(s,1H),8.04(s,1H),2.43(s,3H).

[0350] Step 2: Synthesis of intermediate IM-115c

[0351] 1-Chloro-5-iodo-4-methyl-2-nitrobenzene (11.6 g, 39.2 mmol) was dissolved in DMF (80 mL). Tetrakistriphenylphosphine palladium (4.53 g, 3.92 mmol) and sodium carbonate (8.31 g, 78.4 mmol) were added, followed by solid zinc cyanide (2.76 g, 23.5 mmol). The mixture was evacuated and the atmosphere was exchanged with nitrogen three times. Stirring was continued at 50°C under nitrogen for 24 hours. TLC confirmed the reaction completion. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (3 x 300 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:0 to 80:1) to yield 5-chloro-2-methyl-4-nitrobenzonitrile (5.99 g, 78% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.82-7.79 (m, 2H), 2.64 (s, 3H).

[0352] Step 3: Synthesis of intermediate IM-115d

[0353] Dissolve 5-chloro-2-methyl-4-nitrobenzonitrile (1g, 5mmol) in glacial acetic acid (10mL). Add water (10mL) and concentrated sulfuric acid (10mL). Heat to 120°C and react overnight. Monitor the reaction by TLC until complete. After cooling the reaction mixture to room temperature, dilute with water (100mL) to precipitate a solid. Filter and dry to obtain an off-white solid, 5-chloro-2-methyl-4-nitrobenzoic acid (0.86g, 80% yield). 1 H NMR (400MHz, CDCl3) δ8.22(1H),7.76(s,1H),2.70(s,3H).

[0354] Step 4: Synthesis of intermediate IM-115e

[0355] 5-Chloro-2-methyl-4-nitrobenzoic acid (0.90 g, 4.15 mmol) was dissolved in methanol (10 mL). Thionyl chloride (0.3 mL, 4.15 mmol) was slowly added dropwise (approximately 1 hour). The mixture was heated to 80°C and refluxed overnight. The reaction was stopped after completion of the reaction as monitored by TLC. The reaction mixture was distilled under reduced pressure, and the solvent was evaporated to dryness. Dichloromethane (10 mL) and saturated sodium bicarbonate solution (20 mL) were added, and the mixture was extracted three times with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded methyl 5-chloro-2-methyl-4-nitrobenzoate (0.84 g, 87% yield) as a pale white solid. 1 H NMR (400MHz, CDCI3): δ8.08(s,1H),7.73(s,1H),3.95(s,3H),2.64(s,3H).

[0356] Step 5: Synthesis of intermediate IM-115f

[0357] Methyl 5-chloro-2-methyl-4-nitrobenzoate (3.1 g, 13.5 mmol) was dissolved in acetonitrile (60 mL). NBS (2.88 g, 16.2 mmol) and AIBN (0.11 g, 0.68 mmol) were added. The mixture was heated to 70°C under a nitrogen atmosphere and refluxed for 16 hours. The reaction was stopped after completion of the reaction as monitored by TLC. The reaction mixture was distilled under reduced pressure to dryness, followed by addition of ethyl acetate (100 mL) and water (100 mL). The mixture was extracted three times with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded methyl 2-bromomethyl-5-chloro-4-nitrobenzoate (3.80 g, 91% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ8.15(s,1H),7.99(s,1H),4.92(s,2H),4.01(s,3H).

[0358] Step 6: Synthesis of intermediate IM-115g

[0359] Methyl 2-bromomethyl-5-chloro-4-nitrobenzoate (3.1 g, 13.5 mmol) was dissolved in methanol (40 mL). (4-Aminocyclohexyl)methanol (2.01 g, 15.6 mmol) was added, followed by triethylamine (3.61 mL, 25.9 mmol) under nitrogen. The mixture was heated to 80°C and refluxed for 16 hours. The reaction was terminated after completion of the reaction as monitored by TLC. The reaction mixture was distilled under reduced pressure, the solvent evaporated, and then purified by silica gel column chromatography to yield a yellow solid (2.40 g, 57% yield). 1 H NMR (400MHz, CDCl3) δ8.01(s,1H),7.91(s,1H),4.44(s,2H),4.25(tt,J=3.6,12.1Hz,1H),3.53(d,J= 6.2Hz,2H),2.01-1.93(m,4H),1.62-1.55(m,2H),1.55-1.49(m,1H),1.46(s,1H),1.28-1.17(m,2H).

[0360] Step 7: Synthesis of intermediate IM-115

[0361] Dissolve IM-115g (4.5g) and diisopropylethylamine (7.2mL) in 45mL of DMSO. Add morpholine (2.42mL) to the reaction mixture, heat to 90°C, and react for 12 hours. Add 150mL of water to the reaction mixture, extract with ethyl acetate, collect the organic layer, wash with water, then with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (PE / EA = 1 / 1) to yield 3.3g. LCMS (ESI) m / z: [M+1] = 376.2.

[0362] Synthesis of intermediates IM-116 to IM-122: The preparation method of intermediates IM-116 to 122 is similar to that of intermediate IM-115, as shown in Table 10.

[0363] Table 10 Compound numbers and structures

[0364] Synthesis of intermediate IM-123

[0365] Step 1: Synthesis of intermediate IM-123a

[0366] IM-115 (5 g) was dissolved in 50 mL of MeOH / H2O (4 / 1), and iron powder (7.4 g) and ammonium chloride (7.1 g) were added successively. The mixture was heated at 70°C and refluxed for 4 hours. LC-MS confirmed the completion of the reaction. The reaction solution was filtered through celite, the filter cake was washed with DCM / MeOH (10 / 1) solution, the filtrate was collected, concentrated under reduced pressure, and the residue was extracted with DCM. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 4 g of crude product. The product was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 346.2.

[0367] Step 2: Synthesis of intermediate IM-123b

[0368] IM-99b (2.36 g) was dissolved in 30 mL of acetonitrile, and nitrogen-methylimidazole (3.57 g) was added. The mixture was cooled to 0°C, and TCFH (4.26 g) was added. After stirring for 10 minutes, IM-123a (5.00 g) was added. After the addition, the reaction was allowed to proceed at room temperature for 2 hours and quenched with water. The organic solvent was evaporated and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound IM-123b (700 mg). LCMS (ESI) m / z: [M+1] = 491.24.

[0369] Step 3: Synthesis of intermediate IM-123

[0370] The preparation method of IM-123 is similar to step 3 of the preparation of intermediate IM-99. LCMS (ESI) m / z: [M+1]=489.24.

[0371] Synthesis of intermediates IM-124 to IM-126: The preparation methods of intermediates IM-124 to 126 were similar to the preparation of intermediate IM-123, as shown in Table 11.

[0372] Table 11 Compound numbers and structures

[0373] Synthesis of intermediate IM-127

[0374] Step 1: Synthesis of intermediate 127a

[0375] IM-119 (3.5 g) was dissolved in 50 mL of MeOH / H2O (4 / 1), and iron powder (4.4 g) and ammonium chloride (4.2 g) were added successively. The mixture was heated at 70°C and refluxed overnight. LC-MS confirmed the completion of the reaction. The reaction mixture was filtered through celite, the filter cake was washed with DCM / MeOH (10 / 1) solution, the filtrate was collected, concentrated under reduced pressure, and the residue was extracted with DCM. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2.68 g of crude product. The product was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 417.2.

[0376] Step 2: Synthesis of intermediate 127b

[0377] IM-99b (1.1 g) was dissolved in 30 mL of acetonitrile, and nitrogen-methylimidazole (2.04 g) was added. The mixture was cooled to 0°C, and TCFH (2.27 g) was added. After stirring for 10 minutes, IM-127a (2.6 g) was added. After addition, the reaction was incubated at 40°C for 2 hours, filtered, and the filter cake was washed with water and acetonitrile, and dried to yield 2.6 g of the product. LCMS (ESI) m / z: [M+1] = 562.2.

[0378] Step 3: Synthesis of Intermediate 127

[0379] IM-127b (200 mg) was dissolved in 4 mL of DCM, cooled to 0°C, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 hours. LC-MS confirmed the reaction was complete. The residue was concentrated and used directly in the next step. LCMS (ESI) m / z: [M+1] = 462.2.

[0380] Synthesis of intermediates IM-128 to IM-130: The preparation methods of intermediates IM-128 to 130 were similar to the preparation of intermediate IM-127, as shown in Table 12.

[0381] Table 12 Compound numbers and structures

[0382] Synthesis of intermediate IM-131

[0383] Step 1: Synthesis of intermediate IM-131b

[0384] IM-131a (3 g) and 4-hydroxymethylpiperidine (3.3 g) were dissolved in NMP (30 mL). KCO (5.3 g) was added at room temperature and the reaction was carried out at 120°C for 16 h. Water (100 mL) was added and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried and filtered, and the crude product was spin-dried and purified with normal phase (PE to EA:PE = 3:1) to afford IM-130b (3.8 g). LCMS (ESI) m / z: [M+1] = 252.1.

[0385] Step 2: Intermediate IM-131c

[0386] IM-131b (1 g) was dissolved in ethylene glycol (10 mL), and hydrazine hydrate (1 mL, 20.615 mmol) was added. The mixture was microwaved at 220°C for 2 h. LCMS indicated the reaction was complete. Water (50 mL) was added, and extraction with ethyl acetate (60 mL x 3) was performed. The combined organic phases were dried, filtered, and then purified by reverse phase purification (mobile phase: TFA (0.05% in water) / MeCN, yielding approximately 60% product) to afford IM-131c. LCMS (ESI) m / z: [M+1] = 246.1.

[0387] Step 3: Synthesis of intermediate IM-131d

[0388] IM-131c (780 mg) was dissolved in pyridine (10 mL), and DMTr-Cl (1.12 g) was added under ice. The mixture was slowly warmed to room temperature and allowed to react for 1 h. LCMS indicated the reaction was complete. The solvent was then dried and purified by normal phase purification (PE to PE:EA = 5:1) to afford 1 g of the title compound. LCMS (ESI) m / z: [M+1] = 548.2.

[0389] Step 4: Synthesis of intermediate IM-131e

[0390] IM-131d was dissolved in THF (10 mL) and DMSO (10 mL). NaH (208.14 mg) was added under ice-cooling and allowed to react for 0.5 h. KI (230.35 mg, 1.388 mmol) and 3-bromopiperidine-2,6-dione (832.62 mg, 4.336 mmol) were then added. The mixture was slowly warmed to room temperature and allowed to react for 2 h. LCMS indicated completion of the reaction. Ice water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined, dried, filtered, and spin-dried to afford the desired product, which was used directly in the next step. LCMS (ESI) m / z: [M+1] = 659.3.

[0391] Step 5: Synthesis of intermediate IM-131f

[0392] IM-131e (1.1 g, 1.670 mmol) was dissolved in DCM (6 mL). TFA (2 mL, 26.118 mmol) was added at room temperature and stirred for 2 h. LCMS indicated the reaction was complete. The solvent was then dried and purified by reverse phase chromatography to yield 130 mg (mobile phase: TFA (0.05% in water) / MeCN, yield approximately 55%). LCMS (ESI) m / z: [M+1] = 357.1.

[0393] Step 6: Synthesis of intermediate IM-131

[0394] IM-131f (50 mg, 0.140 mmol) was dissolved in MeCN (3 mL), and IBX 2-iodoacetylbenzoic acid (50.96 mg, 0.182 mmol) was added. The mixture was heated to 65°C and allowed to react for 2 h. LCMS indicated the reaction was complete. The mixture was filtered and the filtrate was dried to give the crude product (50 mg, 0.085 mmol, 60.34%), which was used directly in the next step. LCMS (ESI) m / z: [M+1] = 355.2.

[0395] Synthesis of intermediates IM-132 to IM-139: The preparation methods of intermediates IM-132 to 139 were similar to the preparation of intermediate IM-131, as shown in Table 13.

[0396] Table 13 Compound numbers and structures

[0397] Synthesis of intermediate IM-140

[0398] Step 1: Synthesis of intermediate IM-140b

[0399] Compound IM-140a (5 g) was dissolved in DMSO / THF (v / v = 25 mL / 25 mL). NaH (3.77 g) was added portionwise at 0°C under nitrogen. The mixture was stirred for 30 min, followed by KI (3 g). A solution of 3-bromopiperidine-2,6-dione (9 g) dissolved in 20 mL of DMSO and tetrahydrofuran (20 mL) was then added dropwise. The mixture was gradually warmed to room temperature and stirred for 1 hour. After completion of the reaction, the temperature was lowered to 0-10°C, and 2M HCI was added to adjust the pH to 6-7. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. 3 g of the desired product was obtained by column chromatography. LCMS (ESI) m / z: [M+1] = 323.0.

[0400] Step 2: Synthesis of intermediate IM-140c

[0401] IM-140b (3 g) was dissolved in 40 mL of DMF and cooled in an ice-water bath. DBU (4.7 g) and SEMCl (2.3 g) were added sequentially. After addition, the mixture was heated to 40°C and allowed to react overnight. Extraction was performed with ethyl acetate, and the organic layer was washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Column chromatography yielded 2.8 g of the desired product. LCMS (ESI-MS): 453.1 [M+H]. +

[0402] Step 3: Synthesis of intermediate IM-140d

[0403] IM-140c (1.5 g), Cs2CO3 (2.2 g), and Ruphos (300 mg) were dispersed in 20 mL of dioxane. Under nitrogen, Pd2(dba)3 (300 mg) was added. The air in the reaction system was replaced with nitrogen, and the mixture was allowed to react at 100°C for 18 hours. 20 mL of dioxane was added to the reaction solution, and after ultrasonic dispersion, the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by column chromatography to yield 800 mg of the desired product. LCMS (ESI) m / z: [M+1] = 559.2.

[0404] Step 4: Synthesis of intermediate IM-140

[0405] IM-140d (100 mg) was dissolved in 2 mL of dichloromethane, and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 4 h. 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] = 329.2.

[0406] Synthesis of intermediates IM-141 to IM-145: The preparation methods of intermediates IM-141 to 145 were similar to the preparation of intermediate IM-140, as shown in Table 14.

[0407] Table 14 Compound numbers and structures

[0408] Synthesis of intermediate IM-146

[0409] Step 1: Synthesis of intermediate IM-146b

[0410] IM-146a (2 g, prepared according to WO2020 / 264499) was dissolved in 20 mL of MeOH, 20 mL of THF, and 10 mL of water. LiOH (375 mg) was added and allowed to react overnight. The organic solvent was evaporated and the aqueous phase was adjusted to pH 4. A yellow solid was separated, filtered, and dried to obtain 1.5 g of the desired product. LCMS (ESI) m / z: [M+1] = 340.3.

[0411] Step 2: Synthesis of intermediate IM-146c

[0412] IM-146b (1.49 g) and NMM (470 mg) were dissolved in 20 mL of THF. Under nitrogen protection, isobutyl chloroformate (643 mg) was added dropwise at 0°C. After addition, the mixture was stirred for 30 minutes, filtered, and washed with THF. The filtrate was collected and an aqueous solution of NaBH4 (335 mg) was added dropwise at 0°C. The reaction was allowed to react for 1 hour, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography yielded 1.35 g of the desired product. LCMS (ESI-MS): 326.2 [M+H]. +

[0413] Step 3: Synthesis of intermediate IM-146d

[0414] Compound IM-146c (1.35 g) was added with 20 mL of methanol, triethylamine (629 mg), and (Boc)2O (2.72 g). The mixture was stirred at room temperature for 10 min, and 0.05 eq of palladium on carbon was added. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was filtered and concentrated, and the residue was purified by column chromatography to obtain 1.64 g of the desired product. LCMS (ESI-MS): 396.2 [M+H] +

[0415] Step 4: Synthesis of intermediate IM-146

[0416] Compound IM-146d (100 mg) was dissolved in 3 mL of DCM, and DMP (135 mg) was added under ice-water bath and stirred for 3 h. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was filtered, separated, dried over anhydrous sodium sulfate, concentrated, and filtered through a chromatography column to obtain compound IM-146 (78 mg). LCMS (ESI) m / z: [M+1] = 394.2.

[0417] Synthesis of intermediate IM-147

[0418] Step 1: Synthesis of intermediate IM-147a

[0419] IM-59 (500 mg) was dissolved in DMF / THF (1.0 mL / 10.0 mL). The reaction mixture was cooled to -10°C, and IM-146 (600 mg) and TEA (300 mg) were added. The mixture was stirred under argon for 0.5 h. HOAc (262 mg) and NaBH(OAc)3 (928 mg) 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 (DCM / MeOH = 100 / 1 to 20 / 1) to yield 568 mg of the title compound. LCMS (ESI) m / z: [M+1] = 704.3.

[0420] Step 2: Synthesis of intermediate IM-144

[0421] IM-147a (500 mg) was dissolved in 8 mL of dichloromethane, and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 4 h. 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] = 604.4.

[0422] Synthesis of intermediates IM-148 to IM-160: The preparation methods of intermediates IM-148 to IM-160 were similar to the preparation of intermediate IM-147, as shown in Table 15.

[0423] Table 15 Compound numbers and structures

[0424] Synthesis of intermediate IM-161

[0425] Step 1: Synthesis of intermediate IM-161b

[0426] IM-161a (1 g) was dissolved in THF / DMSO (10 mL) at a ratio of 1:1. NaH (0.94 g) was added at 0-10°C and stirred for half an hour. A solution of KI (0.63 g, 3.773 mmol) and 3-bromopiperidine-2,6-dione (1.81 g) in THF / DMSO (10 mL) was then added. LCMS analysis confirmed that after the reaction of IM-161a was complete, the reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was collected, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to yield 1.45 g of the product. LCMS (ESI) m / z: [M+1] = 322.9.

[0427] Step 2: Synthesis of intermediate IM-161c

[0428] IM-161b (1.45 g) was dissolved in DMF (15 mL), and DBU (1.006 mL, 6.731 mmol) and SEMCl (0.953 mL, 5.384 mmol) were added. After addition, the reaction was stirred at 40°C for 4 hours. LCMS showed that the starting material was consumed. The mixture was diluted fivefold with water and extracted three times with ethyl acetate. The organic phase was collected and washed twice with water and then twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE / EA = 1:1) to yield 845 mg of the product. LCMS (ESI) m / z: [M+1] = 452.70.

[0429] Step 3: Synthesis of intermediate IM-161d

[0430] IM-161c (470 mg), 4-(dimethoxymethyl)-piperidine (248.13 mg), Cs2CO3 (846.20 mg), and RuPhos (96.96 mg) were dissolved in anhydrous 1.4-dioxane (10 mL). The atmosphere was switched with nitrogen three times. Finally, under nitrogen protection, Pd2(dba)3 (95.13 mg, 0.104 mmol) was added and replaced three times. The mixture was heated to reflux at 100°C and stirred for 4 h. The mixture was extracted with EA, washed with NaCl, concentrated, and purified by column chromatography (PE / EA = 1 / 1-EA) to obtain 100 mg of the product as an oil. LCMS (ESI) m / z: [M+1] = 532.66.

[0431] Step 3: Synthesis of intermediate IM-161

[0432] To a 25 mL eggplant-shaped flask, add reactant IM-161d (100 mg, 0.188 mmol), dissolve in DCM (1.5 mL), add 0.5 mL of TFA at 0°C, and stir overnight. Concentrate, add dichloromethane and water, separate the layers, and wash the organic phase with saturated sodium bicarbonate solution and NaCl solution, dry over sodium sulfate, and concentrate to obtain the product. LCMS (ESI) m / z: [M+1] = 356.2.

[0433] The following is the synthesis of the compound of the present invention.

[0434] Example 1: Synthesis of TM-1

[0435] Compound IM-2 (80 mg) was added to acetonitrile (2 mL), followed by NMI (82 mg) and TCFH (115 mg). The mixture was stirred at room temperature for 15 minutes, followed by the addition of compound 5 (160 mg) dissolved in DMF, and stirred at room temperature overnight. LCMS monitoring was performed, and the mixture was concentrated. Water was added to precipitate a solid, which was filtered and purified by high-pressure reverse phase chromatography to yield compound TM-1 (32.9 mg). LCMS (ESI) m / z: [M+1] = 851.4.

[0436] Synthesis of Examples 2 to 24: The preparation methods of Examples TM-2 to TM-24 are similar to the preparation of intermediate TM-1, as shown in Table 16.

[0437] Table 16 Compound numbers and structures

[0438] Example 25: Synthesis of TM-25

[0439] IM-59 (23 mg) was dissolved in DMF / THF (0.25 mL / 1 mL). The reaction mixture was cooled to -10°C, and TM-24a (30 mg, method derived from WO2020 / 264499) and TEA (10 mg) were added. Under argon, the mixture was stirred for 0.5 h. NaBH(OAc)3 (21 mg) was 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 layers were then dried over anhydrous sodium sulfate, concentrated, and subjected to reverse phase purification to yield 15 mg of the target compound. LCMS (ESI) m / z: [M+1] = 757.34. 1 H NMR(400MHz, Methanol-d4)δ8.77(s,1H),8.47(d,J=7.9Hz,1H),8.31(t,J=7.7Hz,1H), 8.20(s,1H),8.05(d,J=7.9Hz,1H),7.46-7.33(d,J=9.9Hz,2H),7.13-7.03(m,2H),5.6 5(dd,J=11.2,4.8Hz,1H),4.51-4.37(m,1H),4.06(s,3H),3.84-3.61(m,3H),3.38-3.3 3(m,2H),3.22-3.08(m,2H),2.98–2.69(m,7H),2.41–1.98(m,10H),1.67–1.04(m,4H).

[0440] Example 26: Synthesis of TM-26

[0441] The preparation method of TM-26 is similar to that of TM-25. LCMS (ESI) m / z: [M+1]=784.5.

[0442] Example 27: Synthesis of TM-27

[0443] The preparation method of TM-27 is similar to that of TM-25. LCMS (ESI) m / z: [M+1]=814.6.

[0444] Example 28: Synthesis of TM-28

[0445] The preparation method of TM-28 is similar to that of TM-25. LCMS (ESI) m / z: [M+1]=815.5.

[0446] Synthesis of Examples 29 to 114: The preparation methods of Examples TM-29 to TM-114 are similar to those of TM-25, as shown in Table 17.

[0447] Table 17 Compound numbers and structures

[0448] Example 115: Synthesis of TM-115

[0449] The preparation method of TM-115 is similar to that of TM-1. LCMS (ESI) m / z: [M+1]=834.4.

[0450] Synthesis of Examples 116 to 126: The preparation methods of Examples TM-116 to TM-126 are similar to those of TM-25, as shown in Table 18.

[0451] Table 18 Compound numbers and structures

[0452] The following test examples illustrate the beneficial effects of the compounds of the present invention.

[0453] The positive compound used in the invention is from Kymera Therapeutics, Inc. patent number WO2020113233, which was synthesized by the applicant himself and has the following structure:

[0454] Test Example 1: Inhibitory effect of the compounds of the present invention on TNFα secretion level in human THP-1 cells. This experiment was carried out in RPMI 1640 medium containing 10% FBS / 1% penicillin / streptomycin, and the initial assay concentration of the compound was 1 uM.

[0455] Dissolve the compound in DMSO to form a stock solution, dilute it with culture medium to a 3X working concentration, and add it to a 96-well plate, 100 μL per well; count THP1 cells in the logarithmic growth phase and dilute them to 2x 10 6 / mL concentration, added to the above compound-containing 96-well plate, 100μL per well, mixed, and incubated at 37°C, 5% CO2 incubator for 1 hour. Then, LPS was added to a final concentration of 1ng / mL, and incubated at 37°C, 5% CO2 incubator for another 5 hours. Then, centrifuged at 1000rpm for 1min, and 16uL of the supernatant was collected and tested using the TNFα ELISA kit. The OD450 value was read and converted to TNFα concentration based on the standard curve. The EC was calculated by fitting the dose-effect curve using GraphPad 5.0. 50 value.

[0456] Test Example 2: Inhibitory effect of the compound of the present invention on IL-6 secretion level in human peripheral blood mononuclear cells (PBMC) under R848 stimulation

[0457] (1) Experimental methods:

[0458] This experiment was performed in RPMI 1640 medium containing 10% FBS / 1% penicillin-streptomycin. The initial concentration of the compound was 1 μM. The compound was dissolved in DMSO to form a stock solution, and then diluted 4-fold with culture medium to a 4× working solution concentration. 50 μL was added to each well of a 96-well plate. PBMC (lot number: HPP20062307, Sichuan Houpu Biotechnology Co., Ltd.) was counted and diluted to 2×10 6 / mL concentration, added to the above-mentioned 96-well plate containing the compound, 150μL per well, mixed, and incubated at 37°C, 5% CO2 incubator for 20h. Then, R848 was added to a final concentration of 2.5μg / mL, and incubated at 37°C, 5% CO2 incubator for another 24h. Then, centrifuged at 2000rpm for 4min, the supernatant was diluted 110×, and tested using the IL-6 ELISA kit. The OD450 value was read and converted to IL-6 concentration based on the standard curve. The IC was calculated by fitting the dose-effect curve using GraphPad 5.0. 50 value.

[0459] (2) Experimental results

[0460] The experimental results are shown in Table 19 below.

[0461] Table 19 Inhibitory effect of compounds on R848-induced IL-6 secretion levels in PBMC cells

[0462] The half-inhibitory concentration, or half-inhibitory rate, or IC50, is a very important data in the indirect competitive ELISA standard curve. Generally, the smaller the IC50 value, the stronger the specificity of the antibody.

[0463] The results in Table 19 show that the compounds of the present invention have obvious advantages in inhibiting the IL-6 secretion level of PBMC cells induced by R848.

[0464] Test Example 3: Inhibitory effect of the compound of the present invention on IL-6 secretion level in human peripheral blood mononuclear cells (PBMC) under LPS+IL-1β stimulation

[0465] This experiment was performed in RPMI 1640 medium containing 10% FBS / 1% penicillin-streptomycin. The initial concentration of the compound was 1 μM. The compound was dissolved in DMSO to form a stock solution, and then diluted 5-fold with culture medium to a 4× working solution concentration. 50 μL was added to each well of a 96-well plate. PBMC (lot number: HPP20062307, Sichuan Houpu Biotechnology Co., Ltd.) was counted and diluted to 2×10 6 / mL concentration, added to the above-mentioned 96-well plate containing the compound, 150μL per well, mixed, and incubated at 37°C, 5% CO2 incubator for 24h. Then, LPS and IL-1β were added to the final concentrations of 10ng / mL and 20ng / mL, and incubated at 37°C, 5% CO2 incubator for 20h. Then, centrifuged at 2000rpm for 4min, the supernatant was diluted 110×, and tested using the IL-6 ELISA kit. The OD450 value was read and converted to IL-6 concentration according to the standard curve. The IC was calculated by fitting the dose-effect curve using GraphPad 5.0. 50 The results are shown in Table 20.

[0466] Table 20 Inhibitory effect of compounds on LPS+IL-1β-induced IL-6 secretion levels in PBMC cells

[0467] The half-inhibitory concentration, or half-inhibitory rate, or IC50, is a very important data in the indirect competitive ELISA standard curve. Generally, the smaller the IC50 value, the stronger the specificity of the antibody.

[0468] The results in Table 20 show that the compound of the present invention has a significant advantage in inhibiting the IL-6 secretion level of PBMC cells induced by LPS+IL-1β.

[0469] Test Example 4: Study on the Effect of the Compounds of the Invention on the Degradation Level of IRAK4 in Human Peripheral Blood Mononuclear Cells (PBMCs) This experiment was carried out in RPMI 1640 medium containing 10% FBS / 1% penicillin / streptomycin, and the initial assay concentration of the compound was 1 uM.

[0470] Thaw frozen human PBMCs into culture medium. At least 2.5 × 10 6 c / mL. PBMCs were cultured at 37°C / 5% CO2 and allowed to stand overnight. After overnight recovery, cell count / viability assessment was performed by trypan blue exclusion. The cell density was adjusted to 2.5×10 6 / mL. Then add 90 μL per well to a 96-well plate. Dissolve the compound in DMSO to a stock solution and dilute it with culture medium to a 3X working concentration. Add 10 μL per well of the 96-well plate. Incubate in a 37°C, 5% CO2 incubator for 20 hours. At the end of treatment, harvest the cells and centrifuge at 1800 rpm for 5 minutes. Wash with 1× PBS and centrifuge at 1800 rpm for 5 minutes. Frozen cell pellets were stored at -80°C until further processing. Lysates were generated by resuspending in lysis buffer. Protein quantification was performed using a BCA kit. 20 μg of protein was loaded per lane and run on a 26-well 4-12% Bis-Tris SDS-PAGE gel. Transfer to a PVDF membrane using the BioRad Mixed MW turbo program for 7 minutes. Block the membrane on a shaker for one hour at room temperature. Incubate the primary antibody overnight at 4°C on a shaker. Wash the membrane 3× with TBST for 5 minutes each. Secondary antibody was added and incubated for one hour at room temperature on a shaker. The membrane was washed 3× with TBST for 5 minutes each and rinsed extensively with deionized H 2 O. The membrane was scanned using a Lyco Odyssey CLx, and the bands were quantified using Image Studio Lite version 5.2 software.

[0471] Test Example 5: Effect of Compounds on IRAK4 Protein Degradation in THP1 Cells

[0472] THP-1 cells were seeded into 96-well cell culture plates at 5 × 10 cells per well. 4Cells, 100 μL medium. Incubate the cell culture plate in a 37°C, 5% CO2 incubator overnight. Add 100 nL of prepared compound stock solution and compound-free DMSO stock solution to each well of cells. Incubate the cell culture plate in a 37°C, 5% CO2 incubator for 24 hours. Add one protease inhibitor tablet and one phosphatase inhibitor tablet to 20 mL of cell lysis buffer and mix gently until completely dissolved. Add DTT to a final concentration of 200 mM to the 4x sample preparation buffer to prepare a 4x sample preparation working solution. Dilute the 20x running buffer to 1x with ultrapure water. Dilute the 20x transfer buffer to 1x with ultrapure water and add 20% methanol. Dilute the 10x running buffer to 1x with ultrapure water. IRAK4 primary antibody working solution: Add 20 μL of IRAK4 antibody to 20 mL of blocking buffer. β-Actin primary antibody working solution: Add 2 μL of beta-actin (13E5) rabbit mAb to 20 mL of blocking buffer. IRAK4 secondary antibody working solution: Donkey Anti-Goat IgG H&L (HRP) diluted 1 / 5000 in blocking buffer. β-Actin secondary antibody working solution: Anti-rabbit IgG, HRP-linked antibody diluted 1 / 10000 in blocking buffer. Centrifuge the cell culture plate at 3000 rpm for 3 minutes. Carefully aspirate most of the medium, invert the plate, and centrifuge at 300 rpm for 30 seconds. Add 45 μL of lysis buffer to each well and shake at 300 rpm for 30 seconds. Incubate on ice for 30 minutes, pipetting 30 times every 20 minutes. Prepare the sample by adding 6 μL of 4x sample preparation solution to 18 μL of protein supernatant and heating at 70°C for 10 minutes. The remaining protein samples were stored at -80°C. In the precast gel, 8 μl was loaded into each well and electrophoresis was performed at a constant voltage of 120V for about 60 minutes. The membrane was transferred using a PVDF membrane with a constant current of 300 mA for 1 hour. After transfer, the membrane was blocked with blocking solution at room temperature for 1 hour. The primary antibody working solution was incubated overnight at 4°C. The membrane was washed with 1×TBST buffer for 3×10 minutes. The secondary antibody working solution was incubated at room temperature for 1 hour. The membrane was washed with 1×TBST buffer for 3×10 minutes and exposed to color with a color developing solution. The grayscale value of each band was calculated using ImagJ software, semi-quantitative analysis was performed, and DC was calculated using GraphPad Prism8.0. 50 The results are shown in Table 21.

[0473] Table 21 Effects of compounds on IRAK4 protein degradation in THP1 cells

[0474] DC50 (nM) is an indicator to measure the degradation activity of a compound. The lower the value, the stronger the degradation activity.

[0475] The above results indicate that the compound of the present invention has a better degradation effect in THP1 cells.

[0476] Test Example 6: The following is a pharmacodynamic experiment of the compound of the present invention on the Lewis rat model of arthritis induced by complete Freund's adjuvant (CFA).

[0477] Experimental methods:

[0478] (1) Establishment of animal model: Male Lewis rats (about 100-125 g) were divided into groups, with 8 rats in each group. They were randomly divided into 6 groups, namely normal control group, model control group, three groups of test compound at low, medium and high doses (10 mg / kg, 30 mg / kg, 100 mg / kg) and positive drug control group (PF06650883, 30 mg / kg). Except for the normal group, rat AA model was established in each experimental group on day 0. The method was to inject 0.08 ml of complete Freund's adjuvant containing inactivated Mycobacterium tuberculosis (H37RA, 10 mg / ml) into the left hind paw of the rat to create a rat adjuvant arthritis model. From the 10th day of modeling, treatment with different doses of test substances was carried out by oral administration. This was continued for 10 consecutive days. On the 8th, 11th, 14th, 17th, 20th, 23rd and 26th days after modeling, joint scores were scored and the diameters of the left and right hind paws were measured to observe the effects of drugs on rat adjuvant arthritis.

[0479] The arthritis evaluation indicators are as follows:

[0480] A. Joint scoring of the limbs: Scored on a 0-4 scale: no erythema or swelling (0); slight erythema or swelling, with erythema or swelling in one of the anterior / posterior toe joints (1); erythema or swelling in more than one toe (2); swelling of the paw below the ankle or wrist joint (3); swelling of all paws including the ankle joint (4). All four paws of the rat were scored separately, with the highest score being 16. Joint scoring was performed on days 8, 11, 17, 14, 17, 20, 23, and 26 after modeling, and the results were recorded.

[0481] B. Measure ankle diameter

[0482] The diameters of the left and right ankles from medial to lateral sides and the thickness of the ankles were measured with a vernier caliper before modeling and on days 8, 11, 17, 14, 17, 20, 23, and 26 after modeling. The results were recorded. The mean ± SD was used to express the data. Comparisons between the treatment groups and the control group were performed using SPSS 11.0 software.

[0483] Test Example 7: Metabolic Stability Test

[0484] Preheat empty incubation plates T60 and NCF60 for 10 minutes; dilute liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer, transfer 445 μL of microsome working solution (0.56 mg / mL) to the preheated "incubation" plates T60 and NCF60, and then preincubate the incubation plates T60 and NCF60 at 37°C with constant shaking for 10 minutes. Transfer 54 μL of liver microsomes to the blank plate, then add 6 μL of NAPDH cofactor to the blank plate, and then add 180 μL of quenching solution to the blank plate; add 5 μL of compound working solution (100 μM) to the incubation plates containing microsomes (T60 and NCF60) and mix thoroughly three times; for the NCF60 plate, add 50 μL of buffer and mix thoroughly three times. Start the timer; the plate will be incubated at 37°C with shaking for 60 minutes; in the quench plate T0, add 180 μL of quench solution and 6 μL of NAPDH cofactor. Make sure the plate is cooled to prevent evaporation. For the T60 plate, mix thoroughly 3 times and immediately transfer 54 μL of the mixture to the quench plate at the 0 minute time point. Then add 44 μL of NAPDH cofactor to the incubation plate (T60). Start the timer; the plate will be incubated at 37°C with shaking for 60 minutes. At 5, 15, 30, 45, and 60 minutes, add 180 μL of quench solution to the quench plate, mix once, and then continuously transfer 60 μL of sample from the T60 plate to the quench plate for each time point.

[0485] For NCF60, the plates were mixed once, and at the 60-minute time point, 60 μL of sample was transferred from the NCF60 incubation to a quenching plate containing the quenching solution. All sample plates were shaken for 10 minutes, then centrifuged at 4000 rpm for 20 minutes at 4°C. 80 μL of the supernatant was transferred to 240 μL of HPLC water and mixed on a plate shaker for 10 minutes. Prior to LC-MS / MS analysis, each bioassay plate was sealed and shaken for 10 minutes. Results are shown in Table 22.

[0486] Table 22 Metabolic stability of test substances in liver microsomes

[0487] The results showed that the compounds of the present invention were more stable in liver microsomes than the positive compounds (positive drugs).

[0488] Test Example 8: Therapeutic Effects of the Compounds of the Invention on Psoriasis Models

[0489] Male BALB / c mice, 6-8 weeks old, were randomly divided into 15 or 6 groups after 1 week of adaptive feeding: a control group, an imiquimod model group (i.e., the Model group), a clobetasol propionate group (i.e., the CLO group), and the compounds of this invention, TM-57 ICL-004192 (3 mg / kg, 10 mg / kg, and 30 mg / kg), TM-109 ICL-004240 (3 mg / kg, 10 mg / kg, 30 mg / kg, and 60 mg / kg), and TM-101 ICL-004250 (3 mg / kg, 10 mg / kg, 30 mg / kg, and 60 mg / kg), with 5 mice per group. The mice were then randomly divided into control, imiquimod model, and clobetasol propionate groups (i.e., the CLO group). On day 0, the backs of the mice were depilated with a depilatory cream, with the depilatory area covering 2.5 cm × 1.5 cm. On the first day, IMQ cream was used to make the model, and the corresponding drug treatment was gavage. The compound of the present invention was gavaged twice a day, morning and evening, with an interval of 8 hours between gavages. IMQ cream was applied to the depilatory part of the back of the mouse and the left ear 2 hours after the first gavage on the same day. The dosage of IMQ cream for the depilatory part of the back of the mouse and the left ear was 62.5 mg and 7.5 mg respectively. The CLO group was smeared with clobetasol propionate cream 5 hours after applying IMQ cream to the depilatory part of the back of the mouse and the left ear, once a day. The blank group and the IMQ group were gavaged with the solvent twice a day, morning and evening, with an interval of 8 hours between gavages. Vaseline and IMQ cream were applied to the depilatory part of the back of the mouse and the ear 2 hours after the first gavage on the same day, and the drug was continuously administered for 5 days.

[0490] Refer to the Psoriasis Area and Severity Index (PASI) scoring criteria. Starting from the first day of modeling, the dorsal skin lesions were scored daily on a scale of 0 to 4 for psoriasis, erythema, and thickness. The scoring criteria are shown in Table 1. The three scores were summed to obtain the total PASI score. Starting from the first day, the thickness of the left ear of the mice was measured three times daily in the morning using a digital vernier caliper. The average of these measurements was used.

[0491] Table 23 Psoriasis Area and Severity Index (PASI) scoring criteria

[0492] FIG1 shows the therapeutic effect of the compound of the present invention on IMQ-induced psoriatic skin thickening; FIG2 shows the therapeutic effect of the compound of the present invention on IMQ-induced psoriatic ear thickening.

[0493] The results showed that the compound of the present invention had a significant therapeutic effect on IMQ-induced psoriasis skin thickening and ear thickening.

[0494] Figure 1 shows the therapeutic effect of compounds on IMQ-induced psoriatic skin thickening. Compared with the Model group, TM-57 (30 mg / kg, BID) had a P<0.01.

[0495] Figure 2 shows the therapeutic effects of the compounds on IMQ-induced psoriatic ear thickening. Compared with the Model group, TM-57 (10 mg / kg, BID) had a P value < 0.05, TM-57 (30 mg / kg, BID) had a P value < 0.0001, TM-109 (60 mg / kg, BID) had a P value < 0.01, and TM-101 (60 mg / kg, BID) had a P value < 0.05.

[0496] Test Example 9: In vivo drug metabolism test of the present invention

[0497] Pharmacokinetics in ICR Mice: This study employed two administration routes: oral gavage and tail vein injection. The oral dose was 5 mg / kg, using the compound of this invention. The dosing volume was 10 mL / kg. Prior to use, the compound was accurately weighed, and the appropriate amount of drug was first dissolved in dimethyl sulfoxide (DMSO). Solutol and HO were added in appropriate proportions, with sonication and vortexing mixing. A clear drug solution of 0.5 mg / mL was prepared. The intravenous dose was 1 mg / kg, using ICL004 (API). The dosing volume was 10 mL / kg. Prior to use, the appropriate amount of drug was accurately weighed, and a final volume of PEG 400 and 80% Saline was prepared. PEG 400 and Saline were added in appropriate proportions, with sonication and vortexing mixing mixing. A clear drug solution of 0.1 mg / mL was prepared. Twelve ICR mice weighing 28-32 g were randomly divided into two groups. After fasting overnight with free access to water, the first group was gavage-administered. Blood was collected via orbital orbit at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration (three mice from the same batch were used for 15 minutes, 1 hour, 4 hours, and 8 hours; three mice from the same batch were used for 30 minutes, 2 hours, 6 hours, and 24 hours). 100 μL of blood was collected into anticoagulant tubes at each time point. Blood samples were centrifuged at 10,000 rpm within one hour. The cells were centrifuged at 4°C for 20 minutes (stored on ice before centrifugation), and the supernatant, i.e., plasma, was collected and stored at -20°C for LC-MS / MS analysis. In the second group, the cells were intravenously administered, and 100 μL of blood was collected from the orbital cavity into an anticoagulant tube at each time point 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration (three mice from the same batch were used for 5 minutes, 30 minutes, 2 hours, and 8 hours; three mice from the same batch were used for 15 minutes, 1 hour, 4 hours, and 24 hours). The blood samples were centrifuged at 10,000 rpm for 20 minutes at 4°C within one hour (stored on ice before centrifugation), and the supernatant, i.e., plasma, was collected and stored at -20°C for LC-MS / MS analysis.

[0498] Pharmacokinetics in SD rats: This study used two administration routes: oral gavage and tail vein injection. The oral dose was 5 mg / kg, using the compound of this invention. The dosing volume was 10 mL / kg. Immediately prior to use, the compound was accurately weighed, and the appropriate amount of drug was first dissolved in dimethyl sulfoxide (DMSO). Solutol and HO were added in appropriate proportions to prepare a final volume of 5% DMSO, 10% Solutol, and 85% H₂O. Solutol and HO were then added in appropriate proportions, followed by sonication and vortexing. A clear drug solution of 0.5 mg / mL was prepared. The intravenous dose was 1 mg / kg, using ICL004-derived active pharmaceutical ingredient. The dosing volume was 10 mL / kg. Immediately prior to use, the appropriate amount of drug was accurately weighed, and a final volume of PEG 400 and 80% Saline was prepared. PEG 400 and Saline were added in appropriate proportions, followed by sonication and vortexing. Prepare a clear drug solution at 0.1 mg / mL.

[0499] Six SD rats, weighing 180-220 g, were randomly divided into two groups. After fasting overnight but with free access to water, the first group received oral administration. 200 μL of blood was collected from the eye socket at each time point 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. The blood samples were centrifuged at 10,000 rpm for 20 minutes at 4°C within one hour (preserved on ice before centrifugation). The supernatant, i.e., plasma, was collected and stored at −20°C for LC-MS / MS analysis. The second group received intravenous administration. 200 μL of blood was collected from the eye socket at each time point 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. The blood samples were centrifuged at 10,000 rpm for 20 minutes at 4°C within one hour (preserved on ice before centrifugation). The supernatant, i.e., plasma, was collected and stored at −20°C for LC-MS / MS analysis. The results are shown in Table 24.

[0500] Table 24 Pharmacokinetic data of the compounds of the present invention

[0501] The results are as follows: The compound of the present invention has excellent oral bioavailability in mice and rats.

[0502] In summary, the present invention discloses compounds of Formula I, which can effectively degrade IRAK4 or inhibit IRAK4 activity in other ways. These compounds have excellent application prospects in IRAK4-mediated diseases, including immune diseases (such as psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, alcoholic liver disease, autoimmune liver disease, acne, etc.), tumors (such as multiple myeloma, lymphocytic leukemia and lymphoma, etc.), Alzheimer's disease, and fibrotic diseases. These compounds provide a new option for clinical screening and / or preparation of drugs for diseases related to IRAK4 activity.

Claims

1. A compound of formula I, or an enantiomer, diastereomer, racemate, a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: in, PTM is selected from D ring is selected from And when the D ring is selected from When PTM is not selected Q is selected from CR 2a , N; V' is selected from C, N; U' Selected from CR 2 NR 2 ; W' is selected from CR 3 , 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; U is selected from C, CR U , N; W is selected from C, CR W , N; T is selected from C, CR T , N; X is selected from C, CR X , N; Y is selected from C, CR Y , N; Z is selected from C, CR Z , N; represents a single bond or a double bond; V is selected from C and N; R 1 , R 1’ are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, 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 C1-C6 straight or branched alkylamino, 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; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, 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; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; 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 heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 2a , R 2 , R 3 , R 4 , R 5 , R 6 , R U , R W , R T , R X , R Y , R Z , R e , R 7 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amine, 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 heterocyclic ring, 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 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 deuterium, halogen, cyano, hydroxyl, amine, 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, 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, 3-10 membered cycloalkyl, C1-C6 straight or branched alkyl-C(=O)-, 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; L1 is selected from None, a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6; 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, 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 heterocyclic ring, 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 chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyloxy, substituted or unsubstituted C1-C6 straight chain or branched alkylamino, substituted or unsubstituted 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 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 heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring 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 group, C1-C6 straight chain or branched alkoxy group, 3-10 membered cycloalkoxy group, C1-C6 straight chain or branched alkylamino group, 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 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 , R 35 , R 36 , R 37 are independently selected from anhydrous, hydrogen, deuterium, halogen, cyano, hydroxyl, amine, 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 heterocyclic ring, 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 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 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 heterocyclic ring; wherein the heterocyclic group, heterobridged ring group, heterospirocyclic group, or aromatic heterocyclic ring contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen; L b’ , L c’ , L d’ , L i’ Independently selected from N, CR 38 ; 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, amine, 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 heterocyclic ring, 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, -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 S02R 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 heterocyclic ring; 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 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 of the groups can form a substituted or unsubstituted 3-12-membered ring through 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 31 -、-R 32 SO2NR 33 R 34 -、 R L121 , R L122 , R L123 , R L124 , R L125 , R L126 Any two of the 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, 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 31 -、-R 32 SO2NR 33 R 34 -、 R L127 , R L128 , R L129 , R L130 , R L131 , R L132 Any two groups can be connected by C, N, O, 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 31 -、-R 32 SO2NR 33 R 34 -、 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 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 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 heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; L2 is selected from None, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6; 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 ; 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 , R L230 , R L241 , R L242 , R L243 , R L244 , R L245 , R L246 R is independently selected from hydrogen, 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 heterocyclic ring, 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 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 3-10 membered cycloalkyloxy group, substituted or unsubstituted C1-C6 straight or branched alkylamino group, 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 heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring 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 S02R 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 of the groups can form a substituted or unsubstituted 3-12-membered ring through 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 31 -、-R 32 SO2NR 33 R 34 -、 R L221 , R L222 , R L223 , R L224 , R L225 , R L226 Any two of the 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, 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 31 -、-R 32 SO2NR 33 R 34 -、 R L227 , R L228 , R L229 , R L230 , R L231 , R L232 Any two of the 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, 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 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 S02R 24 -、 -R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 SO2R 31 -、-R 32 SO2NR 33 R 34 -、 The C ring is selected from the group consisting of no, 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 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic ring; the substituents are independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amine, C1-C6 a linear or branched alkyl group, a C2-C6 linear or branched unsaturated hydrocarbon group, a C1-C6 linear or branched alkoxy group, a halogen-substituted C1-C6 linear or branched alkyl group, a halogen-substituted C2-C6 linear or branched unsaturated hydrocarbon group, a halogen-substituted C1-C6 linear or branched alkoxy group, a 3-10-membered cycloalkyloxy group, a C1-C6 linear or branched alkylamino group, a 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 S02R 24 -、-R 25 OSO2R 26 -、-R 27 SO2OR 28 -、-R 29 NR 30 S02R 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 heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; in Selected from: Its single cis-trans isomers or mixtures thereof; For example Each of the halogens is independently fluorine, chlorine, bromine or iodine; The C1-C6 alkyl in each of the substituted or unsubstituted C1-C6 straight or branched alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl; the 3-10-membered cycloalkyl in each of the substituted or unsubstituted 3-10-membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, The 4-10 membered heterocyclic group in each of the substituted or unsubstituted 4-10 membered heterocyclic groups can be independently For example The C3-C10 heterospirocyclic group in each of the substituted or unsubstituted C3-C10 heterospirocyclic groups 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 The C5-C12 hetero-bridged ring group in each of the substituted or unsubstituted C5-C12 hetero-bridged ring groups is independently octahydrocyclopenta[C]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl; for example Each of the substituted or unsubstituted 5-10 membered aromatic heterocycles may be independently 2. The compound according to claim 1, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I is shown in formula Ia: in, D ring is selected from U is selected from N, W is selected from C, CR W , T is selected from C, CR T ; Or, W is selected from N, U is selected from C, CR U , T is selected from C, CR T ; At most one of X, Y and Z is N; R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl; 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; 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 R U , R W , R T , R X , R Y , R Z , R e Each of the following is independently selected from hydrogen, 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, F or methyl; Ring A is independently selected from the following rings: R 7 Selected from:

3. The compound according to claim 2, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: D ring is selected from: Among them, the * end is connected to the C ring; for Ring A is selected from: R e It is hydrogen or methyl.

4. The compound according to claim 2, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula Ia is shown below: in, R 7 Selected from R C Selected from hydrogen, deuterium, 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 cycloalkyloxy, C1-C6 straight chain or branched alkylamino.

5. The compound according to any one of claims 1 to 4, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

6. The compound according to claim 1, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I is shown in formula Ib or formula Ic: in, D ring is selected from Q is selected from CR 2a , N; U is selected from N, W is selected from C, CR W , T is selected from C, CR T ; Or, W is selected from N, and U is selected from C, CR U , T is selected from C, CR T ; At most one of X, Y and Z is N; V' is selected from N or C, U' is selected from CR 2 or NR 2 , W' is selected from CR 3 , N; 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; R 1’ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C1-C6 straight or branched alkylamino; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-; the number of the substitutions is 1, 2 or 3; 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, R 1’ Selected from: R 2a , R 2 , R 3 , R 4 , R 5 , R 6 , R U , R W , R T , R X , R Y , R Z , R e Each of the following is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl; for example, H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy or methyl; Ring A is independently selected from the following rings: R 7 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C1-C6 straight or branched alkylamino; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkyloxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-; the number of the substitutions is 1, 2 or 3; For example, R 7 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl; for example, R 7 Selected from:

7. The compound according to claim 6, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: D ring is selected from: Among them, the * end is connected to the C ring; among them, R 2 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl; preferably, R 2 , R 4 , R 5 , R 6 Each of the following is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy or methyl; Ring A is selected from:

8. The compound according to claim 6, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula Ib is shown below: in, R 2 , R 4 , R 5 , R 6 Each of the following is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy or methyl; R 1’ Selected from hydrogen, deuterium, methyl, ethyl, propyl, hydroxymethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, mono Fluoromethyl, methoxymethyl, amino, monomethylamino, dimethylamino, deuterated monomethylamino, deuterated dimethylamino, R 7 is selected from hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 9. The compound according to any one of claims 6 to 8, or its enantiomer, diastereomer, racemate, mixture containing the same, or deuterated compound thereof, or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following structures:

10. Use of the compound according to any one of claims 1 to 9, its enantiomer, diastereomer, racemate, mixture containing the same or a pharmaceutically acceptable salt thereof in the preparation of a medicament; the medicament is a medicament 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), or the medicament is a medicament for treating and / or preventing autoimmune diseases and / or cancer or proliferative diseases.

11. The use according to claim 10, characterized in that: The diseases 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 diseases, lesions caused by T cell activation, and cardiovascular diseases; The cancer or proliferative disease is selected from the group consisting of 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 carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's or non-Hodgkin's lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma, ABC DLBCL, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, or intravascular large B-cell lymphoma; epidermal hyperproliferative disorders, psoriasis, prostatic hyperplasia, IL-1-driven diseases, MyD88-driven diseases; The MyD88-driven disease is selected from ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia; 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; The inflammatory disease is selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, phlebitis conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red 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 syndrome , Celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Grave's 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, allergic reaction, 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, allergic purpura, hepatitis, suppurative hidradenitis, 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.

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