Aromatic compounds, pharmaceutical compositions containing the same, and their use

Abstract

Aromatic compounds, pharmaceutical compositions containing them, and their uses are disclosed in this invention. The aromatic compounds are compounds having formula (I) and can effectively degrade IRAK4 or otherwise inhibit IRAK4 activity. The compounds and pharmaceutical compositions of this invention have good prospects for application in IRAK4-mediated diseases, including immune diseases, tumors, Alzheimer's disease, and fibrotic diseases, and provide new options for clinical screening and / or drug preparation for diseases related to IRAK4 activity. [Formula 1] JPEG2026529049000277.jpg36109

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to the Chinese patent application filed with the China National Intellectual Property Administration on 13 July 2023, entitled “AROMATIC COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING SAME, AND USE THEREOF” (application number 202310859092.8), the entirety of which is incorporated herein by reference.

[0002] This invention belongs to the field of pharmaceutical synthesis, and more particularly to aromatic compounds, pharmaceutical compositions containing them, and their use. [Background technology]

[0003] Proteolysis 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 bound to terminal lysine residues by E3 ubiquitin ligases, thereby labeling proteins for degradation into small peptides by the proteasome, which are ultimately digested into their constituent amino acids, which are then used as building blocks for new proteins. The UPP plays a central role in multiple cellular processes, and when defective or imbalanced, it can lead to the pathogenesis of various diseases. The UPP is central to the regulation of almost all cellular processes, including antigen presentation, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, nerve and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors and ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection. Deficiencies in proteasome degradation are associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0004] Proteolytic chimeras (PROTACs) are an effective means of degrading pathogenic proteins. A small molecule capable of binding to a target protein is linked to another small molecule capable of binding to an E3 ligase, such as CRBN, VHL, MDM2, and DRAF, forming a heterobifunctional molecule. This simulates the ubiquitin-proteasome pathway (UPP), thereby ubiquitinating the target protein and allowing it to be degraded by the proteasome. A potential advantage of proteolytic chimeras compared to small molecule inhibitors is their ability to neutralize all functions of pathogenic proteins.

[0005] Currently, more than 600 E3 ubiquitin ligases have been found to promote the in vivo ubiquitination of different proteins, and these can be classified 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. As a 442-amino acid protein, Cereblon belongs to the Cullin RING E3 ubiquitin ligase family and forms the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex, interacting with adapter protein-damaged DNA-binding protein 1 (DDB1). In the CRL4 complex, CRBN acts as a substrate-specific receptor. Known CRBN ligands include thalidomide and other immunomodulatory imide drugs. After CRBN binds to a ligand, its E3 ubiquitin ligase activity is reregulated, thereby increasing the recruitment of transcription factors Ikaros and Aiolos, and subsequently inducing ubiquitination and proteasomal degradation. Currently, CRBN has been successfully used as an E3 ligase for PROTACs to target over 30 different proteins, including proteins involved in various cancers (Sun X. et al., 2019), proteins involved in immune dysfunction (Bassi et al., 2018), proteins involved in neurodegenerative diseases (Silva et al., 2019), and hepatitis C virus proteins (de Wispelaere et al., 2019). Most CRBN-targeted PROTACs use pomalidomide, 4-hydroxythalidomide, alkyl-linked thalidomide derivatives, or lenalidomide derivatives. However, it is possible to develop better CRBN ligands. These new CRBN ligands offer more options for the development of PROTAC technologies.

[0006] IRAK4 belongs to the serine / threonine kinase family and is a key protein in mediating Toll-like receptor (TLR) signaling and pathogen recognition of the interleukin-1 (IL-1) receptor family (IL-1, IL-18, and IL-33 receptors). Studies have shown that when foreign pathogens and inflammatory stress are recognized, under the action of extracellular ligands, the interleukin-1 receptor or TLR receptor recruits the adapter protein myelo-differentiation primary response protein (Myd88), which then forms a complex with IRAK4, thereby activating NF-κB light chain enhancer and activating protein 1 (AP-1), leading to the production of various inflammatory factors such as tumor necrosis factor α (TNFα) and IL-6 by cells, as well as inducing various immune diseases such as psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, and systemic lupus erythematosus. Furthermore, IRAK4 has been identified as being involved in lymphocytic leukemia and lymphoma, Alzheimer's disease, and fibrosis. Therefore, IRAK4 is an attractive target for drug development.

[0007] Currently, leading pharmaceutical companies, including Pfizer, Gilead, Bayer, and Curis, are continuously promoting the entry of IRAK4 small molecule inhibitors into clinical trials for conditions such as hematological malignancies, psoriasis, rheumatoid arthritis, colitis, and systemic lupus erythematosus. The IRAK4 inhibitor PF-06650833, studied by Pfizer, has entered Phase II clinical trials. Early clinical results indicate that PF-06650833 has good safety, and its efficacy suggests that PF-06650833 can inhibit the IRAK4-mediated inflammatory pathway. Such clinical data fully demonstrate that IRAK4 is a clinically proven drug target with the potential to treat a variety of diseases.

[0008] Recent studies have shown that not only does IRAK4 kinase activity mediate inflammatory signaling pathways, but the IRAK4 protein skeleton can also activate several inflammatory signaling pathways. In human dermal fibroblasts, inhibition of IRAK4 with ATP-competitive small molecule inhibitors fails to effectively inhibit the release of IL-6 and TNF-α stimulated by IL-1β. Furthermore, IRAK4 knockout can effectively eliminate inflammatory responses mediated by IL-1, IL-8, and TLR ligands. Therefore, ATP-competitive small molecule inhibitors cannot completely eliminate inflammatory signaling pathways mediated by the IRAK4 protein. This indicates that targeting IRAK4 with small molecule inhibitors has therapeutic limitations.

[0009] Proteolytically targeted chimeras (PROTACs) are an effective means of degrading pathogenic proteins. A small molecule capable of binding to a target protein is linked to another small molecule capable of binding to an E3 ligase, such as CRBN, VHL, MDM2, and DRAF, forming a heterobifunctional molecule. This simulates the ubiquitin-proteasome pathway (UPP), thereby ubiquitinating the target protein and allowing it to be degraded by the proteasome. A potential advantage of proteolytically targeted chimeras compared to small molecule inhibitors is their ability to disable all functions of pathogenic proteins. Furthermore, GSK scientists demonstrated that the IRAK4 protein can be degraded by forming a proteolytically targeted chimera (PROTAC) by linking the IRAK4 small molecule inhibitor to the E3 ligases CRBN and VHL via ligands and linker fragments. Simultaneously, Kymera and Avinas designed PROTACs corresponding to IRAK4. These emerging technologies offer novel therapeutic options for targeting IRAK4. [Overview of the project]

[0010] The objective of this invention is to overcome the shortcomings of the prior art and provide an IRAK4-targeted protac drug.

[0011] Provided is a compound represented by formula I, or an enantiomer, diastereomer, racemate, mixture containing them, deuterated compound thereof, or pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0012] In some embodiments of the present invention, ring D is [ka] Selected from.

[0013] In some embodiments of the present invention, the compound of formula I is as shown in formula Ia: [ka] (In the formula, Ring D is, [ka] Selected from, U is selected from N, and W is C or CR. W Selected from, T is C or CR T Selected from, Alternatively, W is selected from N, and U is C or CR. U Selected from, T is C or CR T Selected from, At most one of X, Y, and Z is N. R 1 The substituent is selected from hydrogen, deuterium, halogen, cyano, or substituted or unsubstituted C1-C6 linear or branched alkyl groups, and the substituent is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkoxy, or 3-10 membered cycloalkoxy, and the number of substituents is 1, 2, or 3, for example, R 1 This is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, or cyclopropoxymethyl. [ka] teeth, [ka] And, R U , R W , R T , R X , R Y , R Z and R e Each of these elements is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, or substituted or unsubstituted C1-C6 linear or branched alkoxy, for example, H, F, or methyl. Ring A is the following ring: [ka] Selected independently from, R 7 teeth, [ka] (Selected from).

[0014] In some preferred embodiments of the present invention, Ring D is, [ka] Selected from, *Each terminal is connected to ring C, [ka] teeth, [ka] And, Ring A is, [ka] Selected from, R e It is either hydrogen or methyl.

[0015] Furthermore, the compounds represented by formula Ia are as follows: [ka] (In the formula, R 7 teeth, [ka] Selected from, R C (Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, or C1-C6 linear or branched alkylamino).

[0016] In some specific embodiments of the present invention, the compound is selected from the following structures. [Table 1-1] [Table 1-2]

[0017] In some preferred embodiments of the present invention, the compound of formula I is as shown in formula Ib or formula Ic: [ka] or [ka] (In the formula, Ring D is, [ka] Selected from, Q is CR 2a Or selected from N, U is selected from N, and W is C or CR. W Selected from, T is C or CR T Selected from, Alternatively, W is selected from N, and U is C or CR. U Selected from, T is C or CR T Selected from, At most one of X, Y, and Z is N. V' is selected from N or C, and U' is CR. 2 or NR 2 Selected from, W' is CR 3 Or selected from N. X' is CR 4 Alternatively, it is selected from N, and Y' is CR 5 Alternatively, it is selected from N, and Z' is C, CR 6 , or selected from N, where at most one of X', Y', and Z' is N, R 1’ The substituent is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, or substituted or unsubstituted C1-C6 linear or branched alkylamino; where the substituent is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)- or 3-10 membered cycloalkyl-C(=O)-, and the number of substituents is 1, 2, or 3. For example, R 1’This is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, or cyclopropoxymethyl, and in another example, R 1’ teeth, [ka] 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 and R e Each 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, or substituted or unsubstituted 3-10 membered cycloalkyl, for example, selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy, or methyl. Ring A is the following ring: [ka] Selected independently from, R 7The substituent is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, or substituted or unsubstituted C1-C6 linear or branched alkylamino; where the substituent is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)- or 3-10 membered cycloalkyl-C(=O)-, and the number of substituents is 1, 2, or 3. For example, R 7 This is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, or cyclopropoxymethyl, and in another example, R 7 teeth, [ka] Selected from.

[0018] In some preferred embodiments, ring D is [ka] Selected from.

[0019] In some preferred embodiments of the present invention, Ring D is, [ka] Selected from, *Each terminal is connected to ring C, R 2 , R 4 , R5 and R 6 Each 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, or substituted or unsubstituted 3-10 membered cycloalkyl, preferably R 2 , R 4 , R 5 and R 6 Each of these is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy, or methyl. Ring A is, [ka] Selected from.

[0020] Furthermore, the compounds represented by formula Ib are as follows: [ka] [ka] [ka] [ka] (In the formula, R 2 , R 4 , R 5 and R 6 Each of these is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy, or methyl. R 1’Hydrogen, deuterium, methyl, ethyl, propyl, hydroxymethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, amino, monomethylamino, dimethylamino, deuterated monomethylamino, deuterated dimethylamino, [ka] Selected from, R 7 These include hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, [ka] (Selected from).

[0021] In some preferred embodiments of the present invention, the compound is selected from the following compounds: [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0022] The present invention further provides the use of the above-mentioned compound, or its enantiomer, its diastereomer, its racemic mixture, a mixture containing the same, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical product, wherein the pharmaceutical product is a pharmaceutical product for the treatment and prevention of one or more diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signaling pathway, the interleukin-6 (IL-6) receptor, and tumor necrosis factor α (TNFα), or the pharmaceutical product is a pharmaceutical product for the treatment and / or prevention of autoimmune diseases and / or cancer or proliferative disorders.

[0023] Furthermore, in the above use, the disease includes cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, organ transplant-related diseases, immunodeficiency diseases, osteocellular diseases, proliferative disorders, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, and cardiovascular diseases. Cancer or proliferative disorders include 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, epidermal carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin lymphoma or non-Hodgkin lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma, ABC DLBCL, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, perisplenic zone lymphoma, plasmacytoma, or intravascular large B-cell lymphoma; may be selected from epidermal hyperproliferative disorders, psoriasis, benign prostatic hyperplasia, IL-1-driven disorders, and MyD88-driven disorders. MyD88-driven diseases may be selected from ABC DLBCL, Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia. Neurodegenerative diseases 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. Inflammatory diseases include ocular allergies, conjunctivitis, keratoconjunctivitis sicca, phlebitis-conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, or acne; or other inflammatory diseases caused by an autoimmune response, such as systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease, or other autoimmune inflammatory bowel diseases. Irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Graves' disease, sarcoidosis, alveolar catarrh, 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 reaction, anaphylaxis C, sinusitis, chronic obstructive pulmonary disease, lung disease, cystic fibrosis, appendicitis, atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, conjunctivitis, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, epididymitis, fasciitis, fibrous tissue inflammation, gastritis, gastroenteritis, allergic purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis The following conditions may be selected: otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, enteritis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, herpetiform dermatitis, subcutaneous dermatitis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, or osteoarthritis.

[0024] The compounds and derivatives provided in this invention may be named according to the nomenclature of IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, CoLumbus, OH).

[0025] Definitions of terms used in this invention: Unless otherwise specified, the first definition provided for a base or term in this specification is applicable throughout this specification, and for terms not specifically defined herein, the meaning that a person skilled in the art could assign to them should be provided based on this disclosure and context.

[0026] "Substitution" refers to replacing a hydrogen atom in a molecule with another different atom or molecule.

[0027] "Further substitution is possible" means that substitution may or may not occur, including both occurrence and non-occurrence.

[0028] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, prefix C a~b Alkyl refers to any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1~4 "Alkyl" refers to alkyl groups containing 1 to 4 carbon atoms.

[0029] In this invention, "alkyl" refers to a saturated hydrocarbon chain having a specific number of member atoms. For example, C 1~6Alkyl refers to an alkyl radical having 1 to 6 member atoms, for example, 1 to 4 member atoms. Alkyl radicals may be linear or branched. Typical branched alkyl radicals have one, two, or three branched chains. Alkyl radicals may be optionally substituted with one or more substituents as defined herein. Examples of alkyls include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl radicals may also be the portion of an additional radical, which may be, for example, C 1~6 It is an alkoxy.

[0030] In this invention, "alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specific number of carbon atoms. a~b "Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight hydrocarbon groups. For example, "C 1~6 "Alkylene" is intended to include, for example, methylene, ethylidene, propyridene, 2-methylpropyridene, dimethylethylidene, and pentylidene. Therefore, the term "propyridene" can have structures such as those shown below: [ka] Similarly, the term "dimethylbutylidene" can refer to any one of the following structures: [ka] .

[0031] As used in this invention, "alkenyl" refers to a linear or branched hydrocarbon group having a specific number of carbon atoms and at least one unsaturated ethenyl moiety (>C=C<). For example, C a~bThe term "alkenyl" refers to an alkenyl radical having a to b carbon atoms, and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0032] As used in this invention, "alkynyl" refers to a linear monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is further intended to include hydrocarbon groups each having one triple bond and one double bond. For example, C 2~6 Alkinyl is intended to include, for example, ethinyl and propynyl.

[0033] The term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0034] In this invention, "haloalkyl" or "alkyl halogen" means that the hydrogen atoms in the alkyl group may be substituted with one or more halogen atoms. For example, C 1~4 Haloalkyl refers to an alkyl group having one or more hydrogen atoms substituted with halogen atoms and containing 1 to 4 carbon atoms, and further includes, for example, trifluoromethyl and difluoromethyl.

[0035] In this invention, substituents such as "=O" or "=S" refer to a double bond formed by the substitution of two hydrogen atoms or lone pairs of electrons with oxygen or sulfur atoms.

[0036] In this invention, "-OR," "-NRR," etc., refer to a radical R that is bonded to an oxygen atom or a nitrogen atom by a single bond.

[0037] In the "-C(O)R", "-S(O)2R", "-P(O)RR", etc. mentioned in the present invention, the oxygen atom is double-bonded to a carbon atom, sulfur atom, or phosphorus atom, and R is single-bonded to a carbon atom or sulfur atom. In the "-C(O)NRR", "-S(O)2NRR", etc. mentioned in the present invention, the oxygen atom is double-bonded to a carbon atom or sulfur atom, the nitrogen atom is single-bonded to a carbon atom or sulfur atom, and R is single-bonded to a nitrogen atom. In the "-NRC(O)R", "-NRS(O)2R", etc. mentioned in the present invention, R is single-bonded to a nitrogen atom, other Rs are single-bonded to a carbon atom or sulfur atom, nitrogen atoms are single-bonded to a carbon atom or sulfur atom, and oxygen atoms are double-bonded to a carbon atom or sulfur atom.

[0038] As used in this invention, "cycloalkyl" refers to a saturated or partially saturated cyclic radical having multiple carbon atoms, without a ring heteroatom, and being monocyclic or polycyclic (including condensed, crosslinked, spiro, and adamantane systems). In the case of polycyclic systems having aromatic and non-aromatic rings without a ring heteroatom, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) is applicable when the bond site is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl radicals such as cyclohexenyl. Examples of cycloalkyls include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyls including polybicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, and bicyclooctyl. Two such polybicycloalkyl structures are shown and named below: [ka] Bicyclohexyl and [ka] Bicyclohexyl. Adamantyl includes, but is not limited to, the following structures: [ka] Specific examples of the crosslinked ring (crosslinked cycloalkyl) of the present invention include, for example, [ka] Examples include: [ka] These are some examples.

[0039] As used in this invention, "heterocyclic" refers to a saturated or unsaturated non-aromatic ring containing at least one heteroatom, where the heteroatom refers to, for example, a nitrogen atom, an oxygen atom, and a sulfur atom. Typically, this refers to a monovalent saturated or partially unsaturated monocyclic or dicyclic ring system having multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or dicyclic ring system having 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, and the remaining carbocyclic atoms. A dicyclic ring consists of two rings sharing two ring atoms, i.e., the bridging separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocyclyls include oxetanil, azetidinil, pyrrolidinil, 2-oxo-pyrrolidinil-3-yl, tetrahydrofuranil, tetrahydrothienyl, pyrazolidinil, imidazolidinil, thiazolidinil, piperidinil, tetrahydropyranil, tetrahydrothiopyranil, piperazinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholin-4-yl, azepanil, diazepanil, homopiperazinil, or oxazepanil. Examples of dicyclic saturated heterocycloalkyls include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and 9-aza-bicyclo[3.3.1]nonyl, while examples of partially unsaturated heterocycloalkyls include dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl. Some other examples, but not limited to, include: [ka] (for example, [ka] (for example, [ka] ), [ka] (for example, [ka] ), [ka] (for example, [ka] ), [ka] (for example, [ka] ), [ka] (for example, [ka] ), [ka] (for example, [ka] ). Another example of a bicyclic example is octahydrocyclopentane[C]pyrrolyl (for example, [ka] ), octahydropyrrolo[3,4-C]pyrrolyl (for example, [ka] ) and 3-azabicyclo[3.1.0]hexyl (for example, [ka] ) are examples.

[0040] As used in this invention, “heterospirocyclyl” or “heterospiro ring” refers to a group comprising at least one heteroatom, the one carbon atom of which is shared by two rings. Heterospirocyclyls comprise 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; this includes saturated or partially unsaturated non-aromatic heterospirocyclyls. For example, 4 to 10-membered heterospirocyclyls include 2-azaspiro[3.3]heptyl (e.g., [ka] ), 7-azaspiro[3.5]nonyl (for example, [ka] ), 2-azaspiro[3.5]nonyl (for example, [ka] ), 2,7-diazaspiro[3.5]nonyl (for example, [ka] ), 6-azaspiro[3.4]octyl (for example, [ka] ), 4-oxa-7-azaspiro[2.5]octyl (for example, [ka] ), 5-oxa-8-azaspiro[3.5]nonyl (for example, [ka] ), 2-oxa-6-azaspiro[3.3]heptyl (for example, [ka] ), 2-oxa-6-azaspiro[3.4]octyl (for example, [ka] ), or 4,7-diazaspiro[2.5]octyl (for example, [ka] ) is also acceptable.

[0041] As used in this invention, “crosslinked heterocyclyl” or “crosslinked heterocycle” refers to a radical comprising at least one heteroatom, in which two non-adjacent carbon atoms or heteroatoms are shared by two rings. A crosslinked heterocyclyl is a saturated or partially unsaturated non-aromatic crosslinked heterocyclyl comprising 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, e.g., 2-oxa-5-azabicyclo[2.2.1]heptyl (e.g., [ka] ) or 8-oxa-3-azabicyclo[3.2.1]octyl (for example, [ka] ) includes.

[0042] As used herein, “aromatic ring” or “aryl” refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryls generally include monocyclic, dicyclic, or tricyclic aryls. Furthermore, as used herein, the term “aryl” refers to an aromatic substituent that may be a monoaromatic ring or a condensed polyaromatic ring. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0043] In this invention, "heteroaromatic ring" or "heteroaryl" refers to an unsaturated aromatic ring containing at least one heteroatom, where the heteroatom is, for example, a nitrogen atom, an oxygen atom, or a sulfur atom, and generally includes aromatic monocyclic or dicyclic hydrocarbons containing multiple ring atoms, of which one or more ring atoms are selected from O, N, and S, preferably 1 to 3 heteroatoms. Representative heteroaryls include, for example, pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl. Some other examples, though not limited to, include: [ka] These are some examples.

[0044] "Stereoisomers" include enantiomers and diastereomers. The term "pharmaceutically acceptable" means that the carrier, vehicle, diluent, adjuvant, and / or the salt formed is generally chemically or physically compatible with the other components that make up the pharmaceutical dosage form and physiologically compatible with the receptor.

[0045] The terms “salt” and “pharmaceutically acceptable salt” refer to acidic and / or basic salts or stereoisomers of the above compounds formed with inorganic and / or organic acids and bases, further comprising zwitterionic salts (internal salts) and further comprising quaternary ammonium salts such as alkylammonium salts. These salts may be obtained directly from the final isolation and purification of the compounds, or may be obtained by appropriately mixing the above compounds or their stereoisomers with a certain amount (e.g., equivalent) of acid or base. These salts may be obtained by precipitation in solution and recovery by filtration, or by recycling after solvent evaporation, or by reaction in an aqueous medium and subsequent freeze-drying. The salts referred to in this invention may be hydrochloride, sulfate, citrate, besylate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate of the compounds.

[0046] In some embodiments, one or more compounds of the present invention may be used in combination with each other. The compounds of the present invention may optionally be used in combination with any other activators for producing pharmaceuticals or pharmaceutical compositions for modulating cellular function or treating diseases. When the group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0047] Clearly, based on the above-described content of the present invention, various other forms of modifications, substitutions, or changes can be made in accordance with common technical knowledge and conventional means in the art, without departing from the above-described basic technical idea of ​​the present invention.

[0048] The beneficial effects of this invention are as follows: The present invention discloses a compound of formula I that can effectively degrade IRAK4 or inhibit IRAK4 activity by other means and has very good potential for application in the treatment of IRAK4-mediated diseases, including, for example, immune diseases (psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, alcoholic liver disease, autoimmune liver disease, acne, etc.), tumors (multiple myeloma, lymphocytic leukemia, lymphoma, etc.), Alzheimer's disease, and fibrosis.

[0049] Compared to the positive compound (International Publication No. 2020113233 of the Patents of Kymera Therapeutics, Inc.), the compounds of the present invention have advantages in the following aspects: inhibitory effect on R848-induced IL-6 secretion levels in PBMC cells, inhibitory effect on LPS+IL-1β-induced IL-6 secretion levels in PBMC cells, effect on IRAK4 proteolysis in THP1 cells, stability in hepatic microsomes, therapeutic effect on IMQ-induced psoriatic skin and ear thickening, and oral bioavailability. Accordingly, the compounds disclosed in the present invention provide a new option for the clinical selection and / or preparation of pharmaceuticals for treating diseases associated with IRAK4 activity. [Brief explanation of the drawing]

[0050] [Figure 1] Figure 1 shows the therapeutic effect of the compound of the present invention on IMQ-induced psoriatic skin thickening. [Figure 2] Figure 2 shows the significant therapeutic effect of the compound of the present invention on IMQ-induced psoriasis-like ear thickening. [Modes for carrying out the invention]

[0051] The present invention is further introduced below with reference to embodiments, but is not limited to the scope of those embodiments. Experimental methods of the following embodiments, which do not explicitly state specific conditions, are performed based on conventional methods and conditions or selected based on product specifications.

[0052] All raw materials and apparatus used in specific embodiments of the present invention are known products and can be obtained by purchasing commercially available products.

[0053] Unless otherwise specified in the embodiments, the reaction temperature is room temperature, which refers to 20-25°C. All temperatures are expressed in degrees Celsius (°C).

[0054] One night is 14 ± 1 hours.

[0055] High-performance liquid chromatography (HPLC) conditions: Waters high-performance liquid chromatograph (e2695 / e2487). Analytical high-performance liquid chromatography conditions: C18 column (3.5 μm, 4.6 × 75 mm), UV detection wavelength bands: 220 nm and 254 nm, elution conditions: gradient elution for 10 minutes with 5-95% acetonitrile (containing 0.1% V / V TFA or 10 mmol NH4CO3).

[0056] For reverse-phase purification, a GiLson GX-281 reverse-phase preparative chromatograph or a Biotage IsoLera One flash purification system is used.

[0057] The Bruker Avance III 400 or 600 NMR spectrometer is 10 -6 It is used for NMR measurements using NMR shift (δ) given in units of ppm. The solvents are, for example, deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCL3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0058] The known starting materials, reagents, and solvents of the present invention can be synthesized using or in accordance with methods known in the art, or can be purchased, for example, from Chengdu Jinshan Chemical Reagent Co., Ltd., Shanghai Bide Technology Co., Ltd., and Shanghai Titan Technology Co., Ltd.

[0059] The known starting materials, reagents, and solvents of the present invention can be synthesized using or in accordance with methods known in the art, or can be purchased, for example, from Chengdu Jinshan Chemical Reagent Co., Ltd., Shanghai Bide Technology Co., Ltd., and Shanghai Titan Technology Co., Ltd.

[0060] In the above description and the following embodiments, the following abbreviations have the meanings set forth below. Unless otherwise defined, abbreviations have the generally accepted meanings. MPLC stands for preparative medium-pressure liquid chromatography; TLC stands for thin-layer chromatography; MeOH stands for methanol; EtOH stands for ethanol; DMAP stands for 4-dimethylaminopyridine; DMF stands for N,N-dimethylformamide; DMA stands for N,N-dimethylacetamide; EA stands for ethyl acetate; THF stands for tetrahydrofuran; DMSO stands for dimethyl sulfoxide; DCM stands for dichloromethane; DCE stands for dichloroethane; MTBE stands for methyl tert-butyl ether; Boc2O stands for ditert-butyl dicarbonate; Boc stands for tert-butyloxycarbonyl; SEMCl stands for 2-(trimethylsilyl)ethoxymethyl chloride; SEM stands for 2-(trimethylsilyl)ethoxymethyl; CbzCl stands for benzyloxyformyl chloride; Cbz stands for benzyloxyformyl; FmocCl stands for 9-fluorenylmethylchloroformate; Fmoc stands for 9-fluorenyl τmethoxyformyl; MsCl is methanesulfonyl chloride; Ms is methanesulfonyl; TBSCl is tert-butyldimethylchlorosilane; TBS is tert-butyldimethylchlorosilyl; TBDPSCl is tert-butyldiphenylchlorosilane; TBDPS is tert-butyldiphenylsilyl; TBAF is tetrabutylammonium fluoride; NBS is N-bromosuccinimide; TFA is trifluoroacetic acid; DBU is 1,8-diazabicycloundec-7-ene; DIPEA is N,N-diisopropylethylamine; TEA is triethylamine; HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HBTU is 2-(benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; and NMM is N-methylmorpholine. [Examples]

[0061] Synthesis of intermediate IM-1 [ka]

[0062] Step 1: Synthesis of intermediate 1b Compound 1a (850 g, 3.47 mmol) was added to methanol, and 1 / 200 concentrated sulfuric acid was added. The mixture was refluxed at 65°C for 12 hours for reaction. After the reaction was complete, saturated sodium carbonate solution was added. The mixture was adjusted to pH 7, filtered, and concentrated. 2,000 mL of EA was added. The mixture was extracted three times with saturated brine (400 mL x 3 times), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1b (900 g), which was added directly to the next step.

[0063] Step 2: Synthesis of intermediate 1c Compound 1b (900 g) was added to THF (6,000 mL), and 150 g of lithium aluminum hydride was added in batches at -20°C. After the reaction was complete, the reaction was quenched by sequentially adding equivalent amounts of water, equivalent amounts of 15% sodium hydroxide aqueous solution, and 3× aqueous solution, using lithium aluminum hydride as the reference. The mixture was filtered and concentrated to obtain compound 1c (410 g).

[0064] Step 3: Synthesis of intermediate 1d Compound 1c (400 g) was added to DCM (6,000 mL) in an ice bath, and a solution of 521 g of TBSCl in DCM was added dropwise to compound 4 (251 g). The mixture was maintained at room temperature for 12 hours for the reaction. After the reaction was complete, the mixture was concentrated and washed three times with water (2,000 mL). The aqueous phase was washed twice with DCM. The organic phase was extracted once with 1,000 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1d (737 g).

[0065] Step 4: Synthesis of intermediate 1e Compound 1d (720 g, 2.95 mol) was dissolved in DCM (10 L), and a solution of 940 g of TsCl in dichloromethane (2 equivalents) was rapidly added dropwise. Then, a solution of DMAP in DCM was slowly added dropwise, and the mixture was reacted at 30°C for 12 hours. 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, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound 6 (760 g).

[0066] Step 5: Synthesis of intermediate 1f 73.64 g of 3-(difluoromethyl)-4-nitro-1H-pyrazole was added to 1 L of DMF and 1.4 equivalents of cesium carbonate, and the mixture was held for 10 minutes for reaction. 180 g of compound 1e was added, and the mixture was held at 60°C for 12 hours for reaction. After adding 2,500 mL of water, the mixture was extracted three times with 500 mL of petroleum ether and washed twice with 500 mL of water. The petroleum ether was washed once with 500 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and then passed through a chromatography column to obtain 52.6 g of compound 1f.

[0067] Step 6: Synthesis of 1 g of intermediate Compound 8 (52.6 g) was added to 500 mL of methanol, 1 equivalent of triethylamine, and (Boc)2O (3 equivalents). The mixture was stirred at room temperature for 10 minutes, and 0.05 equivalents of palladium carbon were added. After three hydrogenation cycles, the mixture was allowed to react overnight at room temperature. After the reaction was complete, the mixture was filtered and concentrated to obtain compound 9 (62 g).

[0068] Step 7: Synthesis of intermediate 1h 1 g (62 g) of the compound was added to 300 mL of THF, and HF.py (2 equivalents) was added dropwise in an ice bath. The mixture was allowed to warm naturally and stirred for 12 hours. 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, then once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a chromatography column to obtain the compound (39.6 g). ESI-LCMS: m / z 346 [M+1], 1.45 min.

[0069] Step 8: Synthesis of intermediate IM-1 Compound 1h (39.6g) was added to 250mL of DCM, and DMP (1.3 equivalents) was added batch by batch in an ice bath. The mixture was stirred for 3 hours. After the reaction was complete, the mixture was adjusted to pH 7 with saturated sodium bicarbonate, filtered, the layers were separated, dried over anhydrous sodium sulfate, concentrated, and passed through a chromatography column to obtain compound 1 (31g). ESI-LCMS: m / z 344 [M+1], 1.55 min.

[0070] Synthesis of intermediate IM-2 [ka]

[0071] Step 1: Synthesis of intermediate 2b Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.25 g, 10 mmol) was dissolved in 10 mL of acetonitrile, then morpholine (1.31 g, 15 mmol) and DIPEA (2.58 g, 20 mmol) were added, and the mixture was heated under reflux for 2 hours. After the reaction was complete, 10 mL of water was added to precipitate the solid. After cooling, the mixture was filtered, and the filter cake was rinsed with water. The solid was collected and dried to obtain 2.55 g of ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate. LCMS(ESI) m / z:[M+1]=277.

[0072] Step 2: Synthesis of intermediate IM-2 Ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (2.55 g, 9.2 mmol) was dissolved in 20 ml of methanol, then a solution of sodium hydroxide (800 mg) in water (10 ml) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, 1 M dilute hydrochloric acid was added to the mixture to adjust the pH to approximately 5-6, and the solid was precipitated. After removing the organic solvent under reduced pressure, the mixture was filtered. The solid was washed with water, recovered, and dried to obtain 2.01 g of 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid. LC-MS(ESI) m / z:[M+1]=249.

[0073] Synthesis of intermediates IM-3 to IM-13: The preparation method for intermediates IM-3 to IM-13 is the same as that for intermediate IM-2, as shown in Table 1. [Table 8]

[0074] Synthesis of intermediate IM-15 [ka]

[0075] Step 1: Synthesis of intermediate IM-15b IM-15a (15g), triphenylphosphine (31g), and phthalimide (12.9g) were dissolved in 200mL of THF, and diisopropyl azodicarboxylate (23.5mL) was slowly added at 0°C. After the addition was complete, the mixture was allowed to react overnight at room temperature, concentrated, and subjected to column chromatography to obtain a yellow solid (20g). LCMS(ESI) m / z:[M+1]=316.9.

[0076] Step 2: Synthesis of intermediate IM-15c IM-15b (20g) was dissolved in 200mL of ethanol, and 10mL of hydrazine hydrate was added. The mixture was heated, refluxed for 5 hours, cooled to room temperature, and filtered. The filtrate was concentrated and extracted with EA. The organic layer was successively 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 separation or purification. LCMS(ESI)m / z:[M+1]=186.9.

[0077] Step 3: Synthesis of intermediate IM-15d IM-15c (10 g) was dissolved in 100 mL of dichloromethane, 11 mL of triethylamine was added, the mixture was cooled, and 6 mL of acetic anhydride was added dropwise at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane. The organic layer was recovered, continuously washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8 g of crude product, which was used directly in the next step without separation or purification. LC-MS (ESI) m / z: [M+1] = 228.9.

[0078] Step 4: Synthesis of intermediate IM-15e IM-15d (8g) was dissolved in 60mL of phosphorus oxychloride and refluxed overnight. The reaction mixture was concentrated, and an ice block was added to the residue. The mixture was neutralized with saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was subjected to column chromatography to obtain 5g of the product. LC-MS (ESI) m / z: [M+1] = 210.9.

[0079] Step 5: Synthesis of intermediate IM-15f IM-15e (5g) was dissolved in 50mL of concentrated sulfuric acid, and 1.8mL of concentrated nitric acid was added dropwise under an ice bath. The mixture was reacted overnight. Ice blocks were slowly added to the reaction mixture to precipitate a yellow solid. After suction filtration, the yellow solid was washed with water, and the filtration cake was collected by suction filtration. This was dried under vacuum or reduced pressure to obtain the target product. LCMS(ESI) m / z:[M+1]=255.9.

[0080] Step 6: Synthesis of intermediate IM-15g IM-15f (2g) was dissolved in 20mL of trifluoroacetic acid, and 2.7mL of anhydrous trifluoroacetic acid and 2.55g of zinc powder were added sequentially. The mixture was allowed to react at room temperature. After the reaction was complete, the reaction mixture was concentrated, and the residue was extracted with EA. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was subjected to column chromatography to obtain 1.8g of the target product. LC-MS (ESI) m / z: [M+1] = 321.9.

[0081] Step 7: Synthesis of intermediate IM-15h IM-15g (1.5g) was dissolved in 20mL of methanol, 1.3g of potassium carbonate was added, and the mixture was heated under reflux until the reaction was complete. After suction filtration, the filtrate was concentrated to obtain the target product, which was used in the next step without purification. LC-MS (ESI) m / z: [M+1] = 225.9.

[0082] Step 8: Synthesis of intermediate IM-15i IM-15h (1 g) was dissolved in 10 mL of ethanol, and 2 mL of trifluoromethanesulfonic acid and 4.8 mL of ethyl acrylate were added sequentially. The mixture was heated under reflux. After the reaction was complete, the mixture was concentrated and extracted with EA. The organic layer was sequentially washed with saturated sodium carbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was subjected to column chromatography to obtain 900 mg of the target product. LC-MS (ESI) m / z: [M+1] = 327.2.

[0083] Step 9: Synthesis of intermediate 15j IM-15i (900 mg) was dissolved in 6 mL of MeOH / THF / H2O (V / V / V=4 / 1 / 1), 165 mg of sodium hydroxide was added, and the reaction was allowed to proceed at room temperature. After the reaction was complete, the mixture was concentrated and evaporated to remove the organic solvent, the aqueous phase was adjusted to pH 4 to precipitate a white solid, the mixture was filtered by suction to collect the filter cake, and this was dried to obtain 800 mg of a white solid. LCMS(ESI)m / z:[M+1]=298.0.

[0084] Step 10: Synthesis of intermediate IM-15k IM-15j (800 mg) was dispersed in 10 mL of dioxane, and 255 mg of ammonium bicarbonate, 0.33 mL of pyridine, and 703 mg of anhydrous Boc were added sequentially. After the addition was complete, the mixture was heated to 60°C and reacted for 3 hours, then concentrated. Water was added to precipitate a white solid. The mixture was filtered by suction and dried to obtain 750 mg of the target product. LC-MS (ESI) m / z: [M+1] = 297.0.

[0085] Step 11: Synthesis of intermediate IM-15 IM-15k (500 mg), 1.36 g of carbonyldiimidazole, and 1.64 g of cesium carbonate were dispersed in 5 mL of acetonitrile. The mixture was refluxed, and after the reaction was complete, it was concentrated and extracted with dichloromethane. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 360 mg of the target product. LC-MS (ESI) m / z: [M+1] = 323.1.

[0086] Synthesis of intermediate IM-16 [ka] The method for preparing intermediate IM-16 is the same as the method for preparing intermediate IM-15.

[0087] Synthesis of intermediate IM-17 [ka]

[0088] Step 1: Synthesis of intermediate IM-17b IM-17a (5g) was dissolved in 30mL of DME, and 3.1g of dichloroacetaldehyde was added. The mixture was heated and reacted for 6 hours, and the solid was collected by suction filtration to obtain 5.2g of a yellow solid. LCMS (ESI-MS): 178 [M+H] +

[0089] Step 2: Synthesis of intermediate IM-17c IM-17b was dissolved in 50 mL of DMF, and 4.98 g of NBS was added in batches. The mixture was maintained at room temperature for 2 hours for reaction, and 4.8 g of yellow solid was obtained by suction filtration. LCMS (ESI-MS): 256 [M+H] + .

[0090] Step 3: Synthesis of intermediate IM-17d IM-17c (4.8g) was dissolved in MeOH / H2O (V / V=3 / 1), and 10g of ammonium chloride and 10.5g of iron powder were added. The mixture was reacted at 80°C for 2 hours under nitrogen protection and filtered by suction. The filtrate was concentrated, and the residue was extracted with EA. The organic layers were combined, continuously washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurryed with dichloromethane to obtain a white solid. LCMS (ESI-MS): 226 [M+H] + ;1HNMR(400 MHz,CD3OD)δ 7.44(s,1H),6.48(d,J=7.6 Hz,1H),6.40(d,J=7.5 Hz,1H),2.94(s,3H).

[0091] Steps 4-7: Synthesis of intermediate IM-17 Steps 4-7 are the same as steps 8-11 in the preparation of IM-15. LCMS (ESI-MS): 323.0 [M+H] + .

[0092] Synthesis of intermediate IM-18 [ka] The preparation method for intermediate IM-18 is the same as that for intermediate IM-17.

[0093] Synthesis of intermediate IM-19 [ka]

[0094] Step 1: Synthesis of intermediate IM-19b IM-17a (5g) was dissolved in 30mL of DME, and 5.9g of 1-bromopropan-2-one was added. The mixture was heated and reacted for 6 hours, and the solid was collected by suction filtration to obtain 5.2g of a yellow solid.

[0095] Step 2: Synthesis of intermediate IM-19c IM-19b (4g) was dissolved in 40mL of DMF, 4.8g of NBS was added in batches, and the mixture was allowed to react at room temperature for 2 hours. 500mL of water was added to the reaction mixture, and the mixture was filtered by suction to obtain 5g of a yellow solid.

[0096] Step 3: Synthesis of intermediate IM-19d IM-19c (5g) was dissolved in 100mL of MeOH / H2O (V / V=3 / 1), and 11g of ammonium chloride and 12g of iron powder were added. The mixture was reacted under nitrogen protection at 80°C for 2 hours and then filtered by suction. 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 subjected to column chromatography to obtain the target product. LCMS (ESI-MS): 226 [M+H] + ; 1 HNMR(400 MHz,DMSO)δ 7.48(d,J=6.6 Hz,1H),6.77(t,J=7.0 Hz,1H),6.31(d,J=7.4 Hz,1H),5.71(s,2H),2.32(s,3H).

[0097] Steps 4-7: Synthesis of intermediate IM-19 Steps 4-7 are the same as steps 8-11 in the preparation of IM-15. LCMS (ESI-MS): 323.0 [M+H] +

[0098] Synthesis of intermediate IM-20 [ka] The preparation method for intermediate IM-20 is the same as that for intermediate IM-19. LCMS (ESI-MS): 323.0 [M+H] +

[0099] Synthesis of intermediate IM-21 [ka] The preparation method for intermediate IM-21 is the same as that for intermediate IM-19. LCMS (ESI-MS): 323.0 [M+H] +

[0100] Synthesis of intermediate IM-22 [ka]

[0101] Step 1: Synthesis of intermediate IM-22b Compound MSH (31.00 g) was added to DCM (150 mL), and compound IM-22a (15 g) was slowly added. The reaction mixture was stirred overnight, monitored by LC-MS, and concentrated to obtain crude compound IM-22b.

[0102] Step 2: Synthesis of intermediate IM-22c The crude product from the final step was added to DMF (150 mL), and potassium carbonate (26 g) and methylbuta-2-inoate (18 g) were added in an ice bath. The mixture was stirred overnight at room temperature, monitored by LC-MS, concentrated, and subjected to column chromatography to obtain compound IM-22c (5 g). ESI-LCMS: m / z 268.9 [M+H] + .

[0103] Step 3: Synthesis of intermediate IM-22d IM-22c (5g) was dissolved in 25mL of acetic acid, and 10mg of hydrobromic acid aqueous solution (48%) was added. The mixture was heated overnight at 100°C. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was subjected to column chromatography to obtain 3.5g of the target product. ESI-LCMS: m / z 210.9 [M+H] + .

[0104] Steps 4-9: Synthesis of intermediate IM-22 Steps 4-9 for the preparation of intermediate IM-22 are the same as steps 2-7 for the preparation of intermediate IM-20. ESI-LCMS: m / z 323.0 [M+H] + .

[0105] Synthesis of intermediate IM-23 [ka]

[0106] Step 1: Synthesis of intermediate IM-23a IM-22d (1.5 g) was dissolved in 10 mL of methanol, and triethylamine (1.1 mL) and palladium carbon were added. After three purgings with a hydrogen balloon, the mixture was reacted overnight at room temperature and then filtered by suction. The filtrate was concentrated and subjected to column chromatography to obtain the target product (600 mg).

[0107] Step 2: Synthesis of intermediate IM-23b IM-23a (600 mg) was dissolved in 6 mL of anhydrous tetrahydrofuran, the mixture was cooled to -78°C, and 4.3 mL (1.6 M) of n-butyllithium was added dropwise. After the addition was complete, the mixture was held for 30 minutes to react, 2.2 g of 1,2-dibromotetrachloroethane was added, and the reaction was continued for another 30 minutes. The mixture was slowly heated to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 700 mg of the target product. ESI-LCMS: m / z 210.9 [M+H] + .

[0108] Steps 3-8: Synthesis of intermediate IM-23 Steps 3-8 for the preparation of intermediate IM-23 are the same as steps 2-7 for the preparation of intermediate IM-20. ESI-LCMS: m / z 323.0 [M+H] + .

[0109] Synthesis of intermediate IM-24 [ka]

[0110] Step 1: Synthesis of intermediate IM-24c IM-24a (4g) was dissolved in 30mL of DME, and 3.7g of IM-24b was added. The mixture was heated and reacted for 6 hours, and the solid was collected by suction filtration and redissolved in 30mL of methanol. The mixture was heated to 80°C and reacted overnight, and concentrated to obtain the target compound. LCMS (ESI-MS): 285 [M+H] +

[0111] Step 2: Synthesis of intermediate IM-24d IM-24c (4.9 g) was dissolved in 30 mL of tetrahydrofuran, 15 mL of methanol, and 7.5 mL of water. 1.3 g of lithium hydroxide was added. The mixture was kept at room temperature for 3 hours for the reaction, concentrated, evaporated to remove the organic solvent, and the pH was adjusted to 4-5 to precipitate the solid. This was then filtered by suction to collect the filter cake, yielding 2.9 g of a white solid. LCMS (ESI-MS): 255 [M+H] + .

[0112] Step 3: Synthesis of intermediate IM-24e IM-24d was dissolved in 30 mL of tert-butanol, and 4.4 g of DIEA and 6.1 g of DPPA were added. The mixture was heated to 80°C under nitrogen and reacted overnight. 50 mL of water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was subjected to column chromatography to obtain 950 mg of the target product as a white solid. LCMS (ESI-MS): 326 [M+H] + , 1 HNMR(400 MHz,CD3OD)δ 8.11(d,J=7.2 Hz,1H),7.67(d,J=1.4 Hz,1H),7.11(dd,J=7.2,2.0 Hz,1H),2.40(s,3H),1.54(s,9H).

[0113] Steps 4-7: Synthesis of intermediate IM-24 Steps 4-7 are the same as steps 8-11 in the preparation of IM-15. LCMS (ESI-MS): 323.0 [M+H] +

[0114] Synthesis of intermediate IM-25 [ka] The preparation method for intermediate IM-25 is the same as that for intermediate IM-24. LCMS (ESI-MS): 323.0 [M+H] +

[0115] Synthesis of intermediate IM-26 [ka]

[0116] Step 1: Synthesis of intermediate IM-26b 15 mL of acetonitrile was added to 200 mL of anhydrous tetrahydrofuran, the mixture was cooled to -78°C, and n-butyllithium (178 mL, 1.6 M) was added. The reaction mixture was maintained at -78°C and reacted for 45 minutes, and IM-26a (20 g) was slowly added. After the addition was complete, the reaction mixture was heated to -30°C and reacted 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 sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 16 g of the target product. LCMS (ESI-MS): 196.9 [M+H] +

[0117] Step 2: Synthesis of intermediate IM-26c Dissolve 16 g in 100 mL of DMF, add NaH (6.5 g, 60%) in batches under nitrogen protection in an ice bath, stir the mixture for 15 minutes, and add 15.4 mL of dimethyl sulfate. After the addition is complete, heat the reaction mixture to room temperature and allow to react overnight, then add water to quench the reaction. Extract the mixture with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 14 g of the target product. LCMS (ESI-MS): 210.9 [M+H] +

[0118] Step 3: Synthesis of intermediate IM-26d The synthesis in step 3 is the same as in step 1 for the preparation of intermediate IM-22.

[0119] Step 4: Synthesis of intermediate IM-26e IM-26d (20 g) was dissolved in 100 mL of methanol, and K2CO3 (13 g) was added. The mixture was stirred overnight at room temperature and concentrated. Water was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 9.7 g of the target product. LCMS (ESI-MS): 225.9 [M+H] +

[0120] Steps 5-8: Synthesis of intermediate IM-26 Steps 5-8 are the same as steps 8-11 in the preparation of IM-15. LCMS (ESI-MS): 323.0 [M+H] +

[0121] Synthesis of intermediate IM-27 [ka] The preparation method for intermediate IM-27 is the same as that for intermediate IM-26. LCMS (ESI-MS): 323.0 [M+H] +

[0122] Synthesis of intermediate IM-28 [ka]

[0123] Step 1: Synthesis of intermediate IM-28b IM-15 (500 mg), IM-28a (876 mg), and K3PO4 (985 mg) were dispersed in 5 mL of dioxane and 1 mL of water. Pd(PPh3)4 (89.4 mg) was added under nitrogen protection. After three nitrogen purging cycles, the mixture was heated at 90°C for 18 hours and concentrated. The residue was subjected to column chromatography to obtain the target product (420 mg). LCMS (ESI-MS): 494.2 [M+H] +

[0124] Step 2: Synthesis of intermediate IM-28 IM-28b was added to a 4M dioxane hydrochloride solution. After the starting material had disappeared, the solvent was removed using a rotary evaporator to obtain IM-28, which was then used directly in the next reaction without purification. LC-MS(ESI) m / z:[M+1]=394.2.

[0125] Synthesis of intermediates IM-29 to IM-42: The preparation method for intermediates IM-29 to IM-42 is the same as that for intermediate IM-28, as shown in Table 2. [Table 9]

[0126] Synthesis of intermediate IM-43 [ka]

[0127] Step 1: Synthesis of intermediate 43b IM-15 (150 mg) was dissolved in 5 ml of DMF, and then N-Boc-4-propargyloxypiperidine (124 mg), bis(triphenylphosphine)palladium(II) chloride (33 mg), and cesium carbonate (306 mg) were added. The reaction system was then protected under nitrogen and stirred overnight at 100°C. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was recovered, washed once with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed using a rotary evaporator. The residue was purified by column chromatography to obtain the target compound. LC-MS (ESI) m / z: [M+1] = 482.2.

[0128] Step 2: Synthesis of intermediate IM-43 IM-43b was dissolved in dioxane, and then a 4M dioxane hydrochloride solution was added. After the starting material had disappeared, the solvent was removed using a rotary evaporator to obtain IM-43 hydrochloride, which was used in the next step of the reaction without purification. LC-MS(ESI) m / z:[M+1]=382.2.

[0129] Synthesis of intermediate IM-44 [ka]

[0130] Step 1: Synthesis of intermediate IM-44a IM-1 (700 mg) was dissolved in DMF / THF (1.0 mL / 15.0 mL). The reaction mixture was cooled to -10°C, IM-28 (776 mg) and TEA (412 mg) were added, and the mixture was stirred under argon protection for 0.5 hours. Then, HOAc (367 mg) and NaBH(OAc)3 (1.3 g) were added to the reaction mixture. The reaction mixture was stirred for 3 hours, quenched with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column (DCM / MeOH = 100 / 1 to 20 / 1) to obtain a white solid in 77% yield. LC-MS (ESI) m / z: [M+1] = 721.4.

[0131] Step 2: Synthesis of intermediate IM-44 IM-44a (1 g) was dissolved in 10 mL of dioxane, and hydrochloric acid solution (4 M) was added to the dioxane. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the target product, which was used directly in the next step without purification. LC-MS (ESI) m / z: [M+1] = 621.3.

[0132] Synthesis of intermediates IM-45 to IM-58b: The preparation method for intermediates IM-45 to IM-58b is the same as that for intermediate IM-44, as shown in Table 3. [Table 10]

[0133] Synthesis of intermediate IM-59 [ka]

[0134] Step 1: Synthesis of intermediate IM-59b IM-59a (2g), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.5g), and K2CO3 (1.72g) were dispersed in 20 mL of dioxane and 5 mL of water. Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (725 mg) was added. The air in the reaction system was replaced with nitrogen, and the mixture was reacted under nitrogen protection at 90°C for 18 hours. 20 mL of dioxane was added to the reaction mixture. After complete sonication, the mixture was filtered by suction through Celite, and the filtrate was concentrated. The residue was dispersed in 20 mL of acetonitrile, CDI (5g) was added, and the mixture was refluxed at 80°C. After the reaction was complete, the mixture was concentrated and subjected to column chromatography to obtain 900 mg of the target product. LCMS(ESI) m / z:[M+1]=425.3.

[0135] Step 2: Synthesis of intermediate IM-59c 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 and reacted for 18 hours, then filtered by suction through Celite. The filtrate was concentrated to obtain 700 mg of the target product, which was used directly in the next step without separation or purification. LC-MS (ESI) m / z: [M+1] = 427.2.

[0136] Step 3: Synthesis of intermediate IM-59 IM-59c (500 mg) was dissolved in 5 mL of dioxane, and hydrochloric acid solution (4 M) was added to the dioxane. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the target product, which was used directly in the next step without purification. LC-MS (ESI) m / z: [M+1] = 327.2.

[0137] Synthesis of intermediates IM-60 to IM-72: The preparation method for intermediates IM-60 to IM-72 is the same as that for intermediate IM-59, as shown in Table 4. [Table 11]

[0138] Synthesis of intermediate IM-73 [ka]

[0139] Step 1: Synthesis of intermediate IM-73a IM-59a (5 g) was dissolved in 50 mL of tetrahydrofuran, the mixture was cooled in an ice bath, sodium hydride (931 mg) was slowly added, and the mixture was stirred in an ice bath for 10 minutes, after which SEM-Cl (3 g) was added. After the addition was complete, the mixture was warmed to room temperature and reacted overnight. The reaction product was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 5.6 g of the target product. LCMS (ESI-MS): 452.1 [M+H] +

[0140] Step 2: Synthesis of intermediate IM-73b IM-73a (3g), Cs2CO3 (4.3g), and Ruphos (609mg) were dispersed in 30mL of dioxane. Pd2(dba)3 (607mg) was added under nitrogen protection, the air in the reaction system was replaced with nitrogen, and the mixture was reacted at 100°C for 18 hours under nitrogen protection. 20mL of dioxane was added to the reaction mixture. After complete sonication, the reaction mixture was filtered by suction through Celite, the filtrate was concentrated, and the residue was subjected to column chromatography to obtain 1.8g of the target product. LCMS(ESI) m / z:[M+1]=558.7.

[0141] Step 3: Synthesis of intermediate IM-73 IM-73b (500 mg) was dissolved in 8 mL of dichloromethane, TFA (2 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the target product, which was used directly in the next step without purification. LC-MS (ESI) m / z: [M+1] = 328.2.

[0142] Synthesis of intermediate IM-74 [ka]

[0143] The preparation method for the synthesis of intermediate IM-74 is the same as that for the synthesis of IM-73. LCMS(ESI)m / z:[M+1]=354.2.

[0144] Synthesis of intermediates IM-75 to IM-81: The preparation method for intermediates IM-75 to IM-81 is the same as that for intermediate IM-73, as shown in Table 5. [Table 12]

[0145] Synthesis of intermediate IM-82 [ka]

[0146] Step 1: Synthesis of IM-82b 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 the reaction was complete, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain the target product in 77% yield. LC-MS (ESI) m / z: [M+1] = 149.2.

[0147] Step 2: Synthesis of IM-82c 3-Methyl-1H-indazole-4-ol (4.2 g, 28.37 mmol) was dissolved in 42 mL of tetrahydrofuran. 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. After the additions were complete, the reaction mixture was refluxed overnight and filtered by suction. The filtrate was concentrated and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain 4.5 g of product in 48% yield. LCMS(ESI) m / z:[M+1]=332.19.

[0148] Step 3: Synthesis of IM-82d 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 batch by batch under nitrogen protection at 0°C, and the mixture was stirred for 30 minutes. Then, a solution of KI (1.8 g, 10.86 mmol) in DMSO (20 mL) and a solution of 3-bromopiperidine-2,6-dione (5.19 g, 27.18 mmol) in tetrahydrofuran (20 mL) were added. The mixture was gradually warmed to room temperature and stirred for 1 hour. After the reaction was complete, the temperature was lowered to 0-10°C. The mixture was adjusted to pH 6-7 with 2 M HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE / EA = 3 / 1) to obtain 2.5 g of the target product in 42% yield. LC-MS (ESI) m / z:[M+1] = 443.22.

[0149] Step 4: Synthesis of IM-82 IM-82d (100 mg) was dissolved in 4 mL of dichloromethane, TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the target product, which was used directly in the next step without purification. LC-MS (ESI) m / z: [M+1] = 343.17.

[0150] Synthesis of intermediate IM-83 [ka]

[0151] Step 1: Synthesis of intermediate IM-83a IM-2 (2g), pyridine (1.3g), and ammonium bicarbonate (1.3g) were dispersed in 15mL of dioxane, and Boc2O (2.6g) was added. After the addition was complete, the reaction mixture was heated to 60°C and reacted for 3 hours. The mixture was diluted with 45mL of water and filtered by suction. The filtered cake was washed with a small amount of dioxane to collect the solid, which was then dried to obtain 1.85g of a white solid. LCMS(ESI) m / z:[M+1]=248.1.

[0152] Step 2: Synthesis of intermediate IM-83c IM-83b (1.56 g, preparation method from International Publication No. 2020 / 264499), IM-83a (1.25 g), Cs2CO3 (3.60 g), and xanthophos (532 mg) were dispersed in 20 mL of dioxane. Under nitrogen protection, Pd2(dba)3 (421 mg) was added, the air in the reaction system was replaced with nitrogen, and the mixture was reacted at 80°C for 72 hours under nitrogen protection. 20 mL of dioxane was added to the reaction mixture. After complete sonication, the reaction mixture was filtered by suction through Celite, the filtrate was concentrated, and the residue was subjected to column chromatography to obtain 320 mg of the target product. LCMS(ESI) m / z:[M+1]=506.2.

[0153] Step 3: Synthesis of intermediate IM-83 Compound IM-83c (100 mg) was dissolved in 3 mL of DCM, and DMP (1.3 equivalents) was added in an ice bath. The mixture was stirred for 3 hours. After the reaction was complete, the mixture was adjusted to pH 7 with saturated sodium bicarbonate, filtered, the layers were separated, dried over anhydrous sodium sulfate, concentrated, and then passed through a chromatography column to obtain compound IM-80 (80 mg). LC-MS (ESI) m / z: [M+1] = 504.2.

[0154] Synthesis of intermediates IM-84 to IM-87: The preparation method for intermediates IM-84 to IM-87 is the same as that for intermediate IM-83, as shown in Table 6. [Table 13]

[0155] Synthesis of intermediate IM-88 [ka]

[0156] Step 1: Synthesis of IM-88b 5-Bromo-4-fluoro-2-nitrobenzaldehyde (15 g) and dimethylamine hydrochloride (9.86 g) were dissolved in 150 mL of DMSO, and diisopropylethylamine (15.63 g) was added. The reaction mixture was maintained at 90°C and allowed to react overnight. After the reaction was complete, the mixture was diluted with water (600 mL) and extracted with EA (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, dried, and purified by column chromatography (PE / DCM = 5 / 1) to obtain 7.53 g of the target product. LCMS (ESI) m / z:[M+1] = 272.98.

[0157] Step 2: Synthesis of IM-88 IM-88b (2.5g) was dissolved in 30mL of isopropanol, and then IM-85c (1.43g) was added. The mixture was reacted at 80°C for 4 hours under nitrogen protection, and then allowed to cool naturally to 25°C. Tributylphosphine (5.56g) was then added to the reaction mixture, and the mixture was reacted at 80°C for 16 hours under nitrogen protection. After the reaction was complete, the organic solvent was evaporated by rotation. The residue was diluted with water (100mL) and extracted with EA (50mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA=1:1) to obtain 4.5g of product. LCMS(ESI) m / z:[M+1]=352.1.

[0158] Synthesis of intermediates IM-89 to IM-98: The preparation method for intermediates IM-89 to IM-98 is the same as that for intermediate IM-88, as shown in Table 7. [Table 14]

[0159] Synthesis of intermediate IM-99 [ka]

[0160] Step 1: Synthesis of IM-99b Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.5 g, 9.20 mmol) was dissolved in 15 mL of 1,4-dioxane and stirred until the mixture became clear. Pyridine (0.727 g, 9.19 mmol), BOC anhydrous (3.01 g, 13.79 mmol), and NH4HCO3 (1.45 g, 18.34 mmol) were added. The reaction mixture was stirred in a water bath at room temperature for 12 hours. After the reaction was complete, the mixture was filtered through Celite, washed with water, washed with 1,4-dioxane, and dried to constant weight in a vacuum drying oven to obtain the target product in 67% yield. LCMS(ESI) m / z:[M+1]=163.19.

[0161] Step 2: Synthesis of IM-99c IM-99b (1 g, 6.17 mmol), IM-86 (2.21 g, 5.60 mmol), CS2CO3 (4.38 g, 13.44 mmol), and xanthophos (0.649 g, 1.12 mmol) were dissolved in 19 mL of 1,4-dioxane. Finally, Pd2(dba)3 (0.513 g, 0.56 mmol) was rapidly added. After five nitrogen purgings, the mixture was held at 100°C for 16 hours to react. After the reaction was complete, the mixture was filtered through Celite, spin-dried under vacuum, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to obtain 1.168 g of the target product in 61.47% yield. LCMS(ESI) m / z:[M+1]=476.49.

[0162] Step 3: Synthesis of IM-99 Oxalyl chloride (0.434 g, 3.42 mmol) was added to DCM (18 mL). In a dry ice / ethanol bath at -70°C, DMSO (0.544 g, 6.96 mmol) / DCM (1 mL) solution was added dropwise, and the mixture was stirred for 0.5 hours. IM-95c (1.1 g, 2.28 mmol) / DCM (7 mL) solution was added, and the mixture was stirred for 30 minutes. DIPEA (1.47 g, 11.37 mmol) / DCM (2 mL) was added. The mixture was stirred for 15-30 minutes and analyzed by acetonitrile using LC-MS. After the reaction was complete, 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 1 g of the target product in 93.46% yield. LCMS(ESI)m / z:[M+1]=476.49.

[0163] Synthesis of intermediates IM-100 to IM-109: The preparation method for intermediates IM-100 to IM-109 is the same as that for intermediate IM-99, as shown in Table 8. [Table 15]

[0164] Synthesis of intermediate IM-110 [ka]

[0165] Step 1: Synthesis of IM-110a 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 held at 80°C for 1 hour. After the reaction was complete, the mixture 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, dried, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 4) to obtain 35 g of product in 77.6% yield. LCMS(ESI) m / z:[M+1]=316.12.

[0166] Step 2: Synthesis of IM-110b IM-110a (7 g, 22.22 mmol) was dissolved in 231 mL of isopropanol, and then tert-butyl 4-aminopiperidine-1-carboxylate (5.34 g, 26.66 mmol) was added. The mixture was reacted at 80°C for 4 hours under nitrogen protection, and then allowed to cool naturally to 25°C. Tributylphosphine (13.48 g, 66.63 mmol) was then added to the reaction mixture, and the mixture was reacted at 80°C for 16 hours under nitrogen protection. After the reaction was complete, the organic solvent was evaporated by rotation. The residue 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, concentrated, and purified by column chromatography (PE / EA = 10:1 to PE / EA = 5 / 1) to obtain 10 g of product in 96.7% yield. LCMS(ESI)m / z:[M+1]=467.29.

[0167] Step 3: Synthesis of IM-110 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 xanthophos (0.50 g, 0.864 mmol) were dissolved in 20 mL of 1,4-dioxane. Finally, Pd2(dba)3 (0.39 g, 0.426 mmol) was rapidly added, followed by five nitrogen purging cycles, and the reaction mixture was held at 100°C for 16 hours. After the reaction was complete, the mixture was filtered through Celite, spin-dried, and purified by column chromatography (DCM / MeOH = 100:1 to DCM / MeOH = 40:1) to obtain 156 mg of product in a yield of 6.8%. LCMS(ESI)m / z:[M+1]=547.63.

[0168] Synthesis of intermediates IM-111 to IM-114: The preparation method for intermediates IM-111 to IM-114 is the same as that for intermediate IM-105, as shown in Table 9. [Table 16]

[0169] Synthesis of intermediate IM-115 [ka]

[0170] Step 1: Synthesis of intermediate IM-115b A solution of 5-chloro-2-methyl-4-nitroaniline (10 g, 53.6 mmol) in sulfuric acid (3 M, 100 mL) was placed in an ice bath at 0°C, and a solution of sodium nitrite (3.70 g, 53.6 mmol) in water (10 mL) was slowly added dropwise (over approximately 1 hour). After the addition was complete, the mixture was stirred in the ice bath for 10 minutes, and then aqueous potassium iodide solution (10.7 g, 64.3 mmol) was added. The mixture was maintained in the ice bath at a reaction temperature of 0°C and stirred for 1 hour, then slowly warmed to room temperature of 25°C, and further stirred at room temperature of 25°C for another hour. TLC detection indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (3 × 200 mL). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 100:1) to obtain 1-chloro-5-iodo-4-methyl-2-nitrobenzene (11.6 g, yield 72%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d)δ 8.24(s,1H),8.04(s,1H),2.43(s,3H).

[0171] Step 2: Synthesis of intermediate IM-115c 1-Chloro-5-iodo-4-methyl-2-nitrobenzene (11.6 g, 39.2 mmol) was dissolved in DMF solution (80 mL), and tetrakis(triphenylphosphine)palladium (4.53 g, 3.92 mmol) and sodium carbonate (8.31 g, 78.4 mmol) were added, followed by zinc cyanide solid (2.76 g, 23.5 mmol). The mixture was vacuumed, nitrogen purged three times, and then stirred at 50°C for 24 hours under nitrogen protection. TLC monitoring indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 80:1) to obtain 5-chloro-2-methyl-4-nitrobenzonitrile (5.99 g, yield 78%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.82-7.79(m,2H),2.64(s,3H).

[0172] Step 3: Synthesis of intermediate IM-115d 5-chloro-2-methyl-4-nitrobenzonitrile (1 g, 5 mmol) was dissolved in glacial acetic acid solution (10 mL), water (10 mL) and concentrated sulfuric acid (10 mL) were added, and the mixture was heated to 120°C and reacted overnight. After TLC monitoring indicated that the reaction was complete, the reaction was stopped. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) to precipitate the solid, which was then filtered by suction and dried to obtain 5-chloro-2-methyl-4-nitrobenzoic acid (0.86 g, yield 80%) as a grayish-white solid. 1 H NMR(400MHz,CDCl3)δ 8.22(1H),7.76(s,1H),2.70(s,3H).

[0173] Step 4: Synthesis of intermediate IM-115e 5-chloro-2-methyl-4-nitrobenzoic acid (0.90 g, 4.15 mmol) was dissolved in methanol solution (10 mL), and thionyl chloride solution (0.3 mL, 4.15 mmol) was slowly added dropwise (over approximately 1 hour). The mixture was then heated to 80°C and refluxed overnight. After TLC monitoring indicated that the reaction was complete, the reaction was stopped. The reaction mixture was removed under reduced pressure until the solvent evaporated to dryness, then dichloromethane (10 mL) and saturated sodium bicarbonate solution (20 mL) were added, and the mixture was extracted three times with dichloromethane (50 mL x 3 times). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain methyl 5-chloro-2-methyl-4-nitrobenzoate (0.84 g, yield 87%) as a pale white solid. 1 H NMR (400 MHz, CDCI3): δ 8.08(s,1H),7.73(s,1H),3.95(s,3H),2.64(s,3H).

[0174] Step 5: Synthesis of intermediate IM-115f Methyl 5-chloro-2-methyl-4-nitrobenzoate (3.1 g, 13.5 mmol) was dissolved in acetonitrile solution (60 mL), and NBS (2.88 g, 16.2 mmol) and AIBN (0.11 g, 0.68 mmol) were added. The mixture was then heated to 70°C under nitrogen protection and refluxed for 16 hours. After TLC monitoring indicated that the reaction was complete, the reaction was stopped. The reaction mixture was removed under reduced pressure until the solvent evaporated to dryness, and ethyl acetate (100 mL) and water (100 mL) were added. The mixture was extracted three times with ethyl acetate (100 mL x 3 times). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain methyl 2-bromomethyl-5-chloro-4-nitrobenzoate (3.80 g, 91% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.15(s,1H),7.99(s,1H),4.92(s,2H),4.01(s,3H).

[0175] Step 6: Synthesis of intermediate IM-115g Methyl 2-bromomethyl-5-chloro-4-nitrobenzoate (3.1 g, 13.5 mmol) was dissolved in methanol solution (40 mL), and (4-aminocyclohexyl)carbinol (2.01 g, 15.6 mmol) was added, followed by triethylamine solution (3.61 mL, 25.9 mmol). The mixture was heated to 80°C under nitrogen protection and refluxed for 16 hours. After TLC monitoring indicated completion of the reaction, the reaction was stopped. The reaction mixture was distilled under reduced pressure until the solvent evaporated to dryness, and the residue was purified by silica gel column chromatography to obtain a yellow solid (2.40 g, 57% yield). 1 H NMR(400 MHz,CDCl3)δ 8.01(s,1H),7.91(s,1H),4.44(s,2H),4.25(tt,J=3.6,12.1 Hz,1H),3.53(d,J=6.2 Hz,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).

[0176] Step 7: Synthesis of intermediate IM-115 IM-115g (4.5g) and diisopropylethylamine (7.2mL) were dissolved in 45mL of DMSO, and morpholine (2.42mL) was added to the reaction mixture. The mixture was heated to 90°C and reacted for 12 hours. The reaction mixture was diluted with 150mL of water and extracted with ethyl acetate. The organic layer was recovered, washed sequentially with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to column chromatography (PE / EA=1 / 1) to obtain 3.3g. LCMS(ESI) m / z:[M+1]=376.2.

[0177] Synthesis of intermediates IM-116 to IM-122: The preparation method for intermediates IM-116 to IM-122 is the same as that for intermediate IM-115, as shown in Table 10. [Table 17]

[0178] Synthesis of intermediate IM-123 [ka]

[0179] Step 1: Synthesis of intermediate IM-123a IM-115 (5g) was dissolved in 50mL of MeOH / H2O(4 / 1), and iron powder (7.4g) and ammonium chloride (7.1g) were added sequentially. The mixture was heated under reflux at 70°C for 4 hours to allow the reaction to proceed. LC-MS detection indicated that the reaction of the starting materials was complete. The reaction mixture was filtered through Celite, and the filtered cake was washed with DCM / MeOH(10 / 1) solution. The filtrate was collected and concentrated under reduced pressure. 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 obtain 4g of crude product, which was used directly in the next step without purification. LC-MS(ESI)m / z:[M+1]=346.2.

[0180] Step 2: Synthesis of intermediate IM-123b IM-99b (2.36 g) was dissolved in 30 mL of acetonitrile, N-methylimidazole (3.57 g) was added, the mixture was cooled to 0°C, TCFH (4.26 g) was added, the mixture was stirred for 10 minutes, and IM-123a (5.00 g) was added. After the addition was complete, the mixture was reacted at room temperature for 2 hours, and the reaction was quenched by adding water. The mixture was evaporated to remove the organic solvent and extracted with ethyl acetate. The organic layer was recovered, 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). LC-MS (ESI) m / z: [M+1] = 491.24.

[0181] Step 3: Synthesis of intermediate IM-123 The preparation method for IM-123 is the same as step 3 of the preparation of intermediate IM-99. LCMS(ESI)m / z:[M+1]=489.24.

[0182] Synthesis of intermediates IM-124 to IM-126: The preparation method for intermediates IM-124 to IM-126 is the same as that for intermediate IM-123, as shown in Table 11. [Table 18]

[0183] Synthesis of intermediate IM-127 [ka]

[0184] Step 1: Synthesis of intermediate 127a IM-119 (3.5g) was dissolved in 50 mL of MeOH / H2O(4 / 1), and iron powder (4.4g) and ammonium chloride (4.2g) were added sequentially. The mixture was heated under reflux at 70°C and reacted overnight. LC-MS detection indicated that the reaction of the starting materials was complete. The reaction mixture was filtered through Celite, and the filtered cake was washed with DCM / MeOH(10 / 1) solution. The filtrate was collected and concentrated under reduced pressure. 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 obtain 2.68 g of crude product, which was used directly in the next step without purification. LC-MS(ESI) m / z:[M+1]=417.2.

[0185] Step 2: Synthesis of intermediate 127b IM-99b (1.1g) was dissolved in 30 mL of acetonitrile, N-methylimidazole (2.04g) was added, the mixture was cooled to 0°C, TCFH (2.27g) was added, the mixture was stirred for 10 minutes, and IM-127a (2.6g) was added. After the addition was complete, the mixture was reacted at 40°C for 2 hours and filtered by suction. The filtered cake was continuously washed with water, washed with acetonitrile, and dried to obtain 2.6 g of product. LCMS(ESI)m / z:[M+1]=562.2.

[0186] Step 3: Synthesis of intermediate 127 IM-127b (200 mg) was dissolved in 4 mL of DCM, the mixture was cooled to 0°C, and 1 mL of TFA was added. The mixture was heated and stirred for 2 hours. LC-MS detection indicated that the reaction was complete. The mixture was concentrated, and the residue was used directly in the next step. LC-MS (ESI) m / z: [M+1] = 462.2.

[0187] Synthesis of intermediates IM-128 to IM-130: The preparation method for intermediates IM-128 to IM-130 is the same as that for intermediate IM-127, as shown in Table 12. [Table 19]

[0188] Synthesis of intermediate IM-131 [ka]

[0189] Step 1: Synthesis of intermediate IM-131b IM-131a (3g) and 4-hydroxymethylpiperidine (3.3g) were dissolved in NMP (30mL), and K2CO3 (5.3g) was added at room temperature. The mixture was reacted at 120°C for 16 hours. Water (100mL) was added, and the mixture was extracted with ethyl acetate (50mL x 3). The organic phases were combined, washed with saturated brine (100mL), dried, and filtered. The resulting crude product was spin-dried and purified by normal-phase HPLC (PE to EA:PE = 3:1) to obtain IM-130b (3.8g). LC-MS (ESI) m / z:[M+1] = 252.1.

[0190] Step 2: Intermediate IM-131c IM-131b (1 g) was dissolved in ethylene glycol (10 mL), hydrazine hydrate (1 mL, 20.615 mmol) was added, and the mixture was microwaved at 220°C for 2 hours to allow the reaction to proceed. LC-MS indicated that the reaction was complete. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried, filtered, spin-dried, and purified by reverse-phase HPLC (mobile phase: TFA (0.05% in water) / MeCN, product yield approximately 60%) to obtain IM-131c. LC-MS (ESI) m / z: [M+1] = 246.1.

[0191] Step 3: Synthesis of intermediate IM-131d IM-131c (780 mg) was dissolved in pyridine (10 mL), and DMTr-Cl (1.12 g) was added in an ice bath. The mixture was slowly heated to room temperature and reacted for 1 hour. LC-MS indicated that the reaction was complete. The mixture was spin-dried to remove the solvent, and purified by normal-phase HPLC (PE~PE:EA = 5:1) to obtain 1 g of the target compound. LC-MS (ESI) m / z:[M+1] = 548.2.

[0192] Step 4: Synthesis of intermediate IM-131e IM-131d was dissolved in THF (10 mL) and DMSO (10 mL), and NaH (208.14 mg) was added to an ice bath. The mixture was kept in the ice bath for 0.5 hours to react, and then KI (230.35 mg, 1.388 mmol) and 3-bromopiperidine-2,6-dione (832.62 mg, 4.336 mmol) were added. The mixture was slowly heated to room temperature and maintained at room temperature for 2 hours for the reaction. LC-MS indicated that the reaction was complete. The reaction was quenched with ice water and extracted with ethyl acetate. The organic phases were combined, dried, filtered, and spin-dried to obtain the target product, which was used directly in the reaction in the next step. LC-MS(ESI) m / z:[M+1]=659.3.

[0193] Step 5: Synthesis of intermediate IM-131f IM-131e (1.1 g, 1.670 mmol) was dissolved in DCM (6 mL), and TFA (2 mL, 26.118 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The solvent was spin-dried, and the solution was purified by reverse-phase HPLC (mobile phase: TFA (0.05% in water) / MeCN, product yield approximately 55%) to obtain 130 mg. LC-MS (ESI) m / z: [M+1] = 357.1.

[0194] Step 6: Synthesis of intermediate IM-131 IM-131f (50 mg, 0.140 mmol) was dissolved in MeCN (3 mL), and IBX2-iodoxybenzoic acid (50.96 mg, 0.182 mmol) was added. The mixture was heated at 65°C for 2 hours for the reaction. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was spin-dried to obtain the crude product (50 mg, 0.085 mmol, 60.34%), which was used directly in the next step of the reaction. LC-MS(ESI) m / z:[M+1]=355.2.

[0195] Synthesis of intermediates IM-132 to IM-139: The preparation method for intermediates IM-132 to IM-139 is the same as that for intermediate IM-131, as shown in Table 13. [Table 20]

[0196] Synthesis of intermediate IM-140 [ka]

[0197] Step 1: Synthesis of intermediate IM-140b Compound IM-140a (5 g) was dissolved in DMSO / THF (v / v = 25 mL / 25 mL), and NaH (3.77 g) was added batch by batch under nitrogen protection at 0°C. The mixture was stirred for 30 minutes. Then, KI (3 g) was added, and a solution of 3-bromopiperidine-2,6-dione (9 g) in 20 mL of DMSO and a solution of tetrahydrofuran (20 mL) were added dropwise. The mixture was gradually warmed to room temperature and stirred for 1 hour. After the reaction was complete, the temperature was lowered to 0-10°C. The mixture was adjusted to pH = 6-7 with 2 M HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain 3 g of the target product. LC-MS (ESI) m / z: [M+1] = 323.0.

[0198] Step 2: Synthesis of intermediate IM-140c IM-140b (3 g) was dissolved in 40 mL of DMF, cooled in an ice bath, and DBU (4.7 g) and SEMCl (2.3 g) were added sequentially. After the addition was complete, the mixture was heated to 40°C and reacted overnight. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 2.8 g of the target product. LCMS (ESI-MS): 453.1 [M+H] +

[0199] Step 3: Synthesis of intermediate IM-140d IM-140c (1.5g), Cs2CO3 (2.2g), and Ruphos (300mg) were dispersed in 20mL of dioxane. Pd2(dba)3 (300mg) was added under nitrogen protection, the air in the reaction system was replaced with nitrogen, and the mixture was reacted at 100°C for 18 hours under nitrogen protection. 20mL of dioxane was added to the reaction mixture. After complete sonication, the reaction mixture was filtered by suction through Celite, the filtrate was concentrated, and the residue was subjected to column chromatography to obtain 800mg of the target product. LCMS(ESI) m / z:[M+1]=559.2.

[0200] Step 4: Synthesis of intermediate IM-140 IM-140d (100 mg) was dissolved in 2 mL of dichloromethane, TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the target product, which was used directly in the next step without purification. LC-MS (ESI) m / z: [M+1] = 329.2.

[0201] Synthesis of intermediates IM-141 to IM-145: The preparation method for intermediates IM-141 to IM-145 is the same as that for intermediate IM-140, as shown in Table 14. [Table 21]

[0202] Synthesis of intermediate IM-146 [ka]

[0203] Step 1: Synthesis of intermediate IM-146b IM-146a (2 g, preparation method from International Publication No. 2020 / 264499) was dissolved in 20 mL of MeOH, 20 mL of THF, and 10 mL of water. LiOH (375 mg) was added and the mixture was reacted overnight. The mixture was concentrated and evaporated to remove the organic solvent. The aqueous phase was adjusted to pH 4 to precipitate a yellow solid, which was then filtered by suction and dried to obtain 1.5 g of the target product. LC-MS (ESI) m / z: [M+1] = 340.3.

[0204] Step 2: Synthesis of intermediate IM-146c IM-146b (1.49 g) and NMM (470 mg) were dissolved in 20 mL of THF, and isobutyl chloroformate (643 mg) was added dropwise at 0°C under nitrogen protection. After the addition was complete, the mixture was stirred for 30 minutes, filtered by suction, and washed with THF. The filtrate was collected. Aqueous NaBH4 solution (335 mg) was added dropwise at 0°C. The mixture was held for 1 hour for reaction and extracted with ethyl acetate. The organic layer was sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain 1.35 g of the target product. LCMS (ESI-MS): 326.2 [M+H] +

[0205] Step 3: Synthesis of intermediate IM-146d Compound IM-146c (1.35 g) was mixed with 20 mL of methanol, triethylamine (629 mg), and (Boc)2O (2.72 g). The mixture was stirred at room temperature for 10 minutes, and 0.05 equivalents of palladium-carbon were added. After three hydrogenation cycles, the mixture was allowed to react overnight at room temperature. After the reaction was complete, the mixture was filtered and concentrated, and the residue was subjected to column chromatography to obtain 1.64 g of the target product. LCMS (ESI-MS): 396.2 [M+H] +

[0206] Step 4: Synthesis of intermediate IM-146 Compound IM-146d (100 mg) was dissolved in 3 mL of DCM, and DMP (135 mg) was added in an ice bath. The mixture was stirred for 3 hours. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate, the mixture was filtered, the layers were separated, dried over anhydrous sodium sulfate, concentrated, and then passed through a chromatography column to obtain compound IM-146 (78 mg). LC-MS (ESI) m / z: [M+1] = 394.2.

[0207] Synthesis of intermediate IM-147 [ka]

[0208] Step 1: Synthesis of intermediate IM-147a 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 protection for 0.5 hours. Then, HOAc (262 mg) and NaBH(OAc)3 (928 mg) were added to the reaction mixture. The reaction mixture was stirred for 3 hours, quenched with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column (DCM / MeOH = 100 / 1 to 20 / 1) to obtain 568 mg of the target compound. LC-MS (ESI) m / z:[M+1] = 704.3.

[0209] Step 2: Synthesis of intermediate IM-144 IM-147a (500 mg) was dissolved in 8 mL of dichloromethane, TFA (2 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the target product, which was used directly in the next step without purification. LC-MS (ESI) m / z: [M+1] = 604.4.

[0210] Synthesis of intermediates IM-148 to IM-160: The preparation method for intermediates IM-148 to IM-160 is the same as that for intermediate IM-147, as shown in Table 15. [Table 22]

[0211] Synthesis of intermediate IM-161 [ka]

[0212] Step 1: Synthesis of intermediate IM-161b IM-161a (1 g) was dissolved in THF / DMSO = 1:1 (10 mL), NaH (0.94 g) was added at 0-10°C, the mixture was stirred for 30 minutes, and then a solution of KI (0.63 g, 3.773 mmol) and 3-bromopiperidine-2,6-dione (1.81 g) in THF / DMSO = 1:1 (10 mL) was added.

[0213] After LC-MS detection indicated the completion of the IM-161a reaction, 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, concentrated, and weighed to obtain 1.45 g of product. LC-MS(ESI) m / z:[M+1]=322.9.

[0214] Step 2: Synthesis of intermediate IM-161c 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 the addition was complete, the reaction mixture was stirred at 40°C for 4 hours. LC-MS showed that the starting material had been consumed. The mixture was diluted with 5 × water and extracted three times with ethyl acetate. The organic phase was recovered, washed twice with water, then twice again with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (PE / EA = 1:1) to obtain 845 mg of product. LC-MS (ESI) m / z: [M+1] = 452.70.

[0215] Step 3: Synthesis of intermediate IM-161d 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). After three nitrogen purgings, Pd2(dba)3 (95.13 mg, 0.104 mmol) was added last under nitrogen protection. After three purgings, the mixture was heated under reflux at 100°C, stirred for 4 hours, extracted with EA, washed with NaCl, concentrated, and subjected to 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.

[0216] Step 3: Synthesis of intermediate IM-161 The reaction product IM-161d (100 mg, 0.188 mmol) was added to a 25 mL round-bottom flask and dissolved in DCM (1.5 mL). 0.5 mL of TFA was added at 0°C. The mixture was stirred overnight and concentrated. Dichloromethane and water were added, and the mixture layers were separated. The organic phase was washed with saturated sodium bicarbonate solution and NaCl solution, dried over sodium sulfate, and concentrated to obtain the product. LCMS(ESI) m / z:[M+1]=356.2.

[0217] The synthesis of the compound of the present invention is provided below.

[0218] Example 1: Synthesis of TM-1 [ka] Compound IM-2 (80 mg) was added to acetonitrile (2 mL), followed by the addition of NMI (82 mg) and TCFH (115 mg). The mixture was stirred at room temperature for 15 minutes, and then compound 5 (160 mg) dissolved in DMF was added. The mixture was stirred overnight at room temperature, monitored by LC-MS, concentrated, diluted with water to precipitate the solid, and filtered. The solid was subjected to preparative reverse-phase HPLC to obtain compound TM-1 (32.9 mg). LC-MS (ESI) m / z: [M+1] = 851.4.

[0219] Synthesis in Examples 2-24: The preparation method for TM-2 to TM-24 in the examples is the same as that for the preparation of intermediate TM-1, as shown in Table 16. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4]

[0220] Example 25: Synthesis of TM-25 [ka] 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 International Publication No. 2020 / 264499) and TEA (10 mg) were added. The mixture was stirred under argon protection for 0.5 hours. Then, NaBH(OAc)3 (21 mg) was added to the reaction mixture. The reaction mixture was stirred for 3 hours, quenched with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to reverse-phase preparative HPLC to obtain 15 mg of the target product. LC-MS (ESI) m / z: [M+1] = 757.34. 1H NMR(400 MHz,Methanol-d4)δ 8.77(s,1H),8.47(d,J=7.9 Hz,1H),8.31(t,J=7.7 Hz,1H),8.20(s,1H),8.05(d,J=7.9 Hz,1H),7.46-7.33(d,J=9.9 Hz,2H),7.13-7.03(m,2H),5.65(dd,J=11.2,4.8 Hz,1H),4.51-4.37(m,1H),4.06(s,3H),3.84-3.61(m,3H),3.38-3.33(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).

[0221] Example 26: Synthesis of TM-26 [ka] The preparation method for TM-26 is the same as for TM-25. LCMS(ESI)m / z:[M+1]=784.5.

[0222] Example 27: Synthesis of TM-27 [ka] The preparation method for TM-27 is the same as for TM-25. LCMS(ESI)m / z:[M+1]=814.6.

[0223] Example 28: Synthesis of TM-28 [ka] The preparation method for TM-28 is the same as for TM-25. LCMS(ESI)m / z:[M+1]=815.5.

[0224] Synthesis in Examples 29-114: The preparation method for TM-29-TM-114 in the examples is the same as that for TM-25, as shown in Table 17. [Table 24-1] Table 24-2 Table 24-3 Table 24-4 Table 24-5 Table 24-6 Table 24-7 Table 24-8 Table 24-9 Table 24-10 Table 24-11 Table 24-12 Table 24-13 Table 24-14 Table 24-15 Table 24-16 Table 24-17 Table 24-18 Table 24-19 Table 24-20 Table 24-21 Table 24-22 Table 24-23 Table 24-24 Table 24-25 Table 24-26 Table 24-27 Table 24-28 [Table 24-29] [Table 24-30] [Table 24-31] [Table 24-32]

[0225] Example 115: Synthesis of TM-115 [ka] The preparation method for TM-115 is the same as for TM-1. LCMS(ESI)m / z:[M+1]=834.4.

[0226] Synthesis in Examples 116-126: The preparation method for TM-116-TM-126 in the examples is the same as that for TM-25, as shown in Table 18. [Table 25-1] [Table 25-2]

[0227] The following test examples are used to illustrate the beneficial effects of the compounds of the present invention.

[0228] The positive compound used in this invention is derived from International Publication No. 2020113233, a patent of Kymera Therapeutics, Inc., synthesized by the applicant itself, and has the following structure. [ka]

[0229] Test Example 1: Inhibitory effect of the compound of the present invention on TNFα secretion levels in human THP-1 cells This experiment was conducted in RPMI 1640 medium containing 10% FBS / 1% penicillin / streptomycin, with each compound at an initial test concentration of 1 μM.

[0230] The compound DMSO was dissolved to form a stock solution, which was then diluted to a 3× working concentration with culture medium. The diluted solution was added to a 96-well plate at a rate of 100 μL / well. THP1 cells in the logarithmic growth phase were counted, and 2 × 10⁶ cells were identified. 6 The solution was diluted to a concentration of / mL. The diluted cells were added to a 96-well plate containing the compound at a concentration of 100 μL / well, thoroughly mixed, and incubated in a 5% CO2 incubator at 37°C for 1 hour. LPS was then added until the final concentration reached 1 ng / mL, and the cells were incubated in a 5% CO2 incubator at 37°C for a further 5 hours. After centrifugation at 1,000 rpm for 1 minute, 16 μL of the supernatant was detected using a TNFα ELISA kit. The OD450 value was read, converted to TNFα concentration based on a standard curve, and the EC50 value was calculated by fitting a dose-effect curve using GraphPad 5.0.

[0231] Test Example 2: Inhibitory effect of the compound of the present invention on IL-6 secretion levels in human peripheral blood mononuclear cells (PBMCs) in response to R848 stimulation. (1) Experimental method: This experiment was conducted in RPMI 1640 medium containing 10% FBS / 1% penicillin / streptomycin, with each compound at an initial test concentration of 1 μM. The compounds were dissolved in DMSO to form stock solutions, which were then diluted fourfold with culture medium to a 4× working solution concentration. The diluted solutions were added to 96-well plates at a rate of 50 μL / well. PBMC (batch number: HPP20062307, Sichuan Hope Bio-tech Co.,Ltd.) cells were counted, resulting in 2 × 10⁶ cells. 6The solution was diluted to a concentration of / mL. The diluted cells were added to a 96-well plate containing the compound at a rate of 150 μL / well, thoroughly mixed, and incubated in a 5% CO2 incubator at 37°C for 20 hours. R848 was then further added until the final concentration reached 2.5 μg / mL, and the cells were incubated in a 5% CO2 incubator at 37°C for a further 24 hours. After centrifugation at 2,000 rpm for 4 minutes, the supernatant was diluted 110-fold and detected using an IL-6 ELISA kit. The OD450 value was read, converted to IL-6 concentration based on a standard curve, and IC was obtained by fitting a dose-effect curve using GraphPad 5.0. 50 The value was calculated.

[0232] (2) Experimental results The experimental results are shown in Table 19 below. [Table 26]

[0233] The median inhibitory concentration, or median inhibition rate, known as IC50, is crucial data in standard curves for indirect competitive ELISA. Generally, a lower IC50 value indicates stronger antibody specificity.

[0234] The results in Table 19 demonstrate that the compounds of the present invention have a clear advantage in inhibiting the R848-induced secretion level of IL-6 in PBMC cells.

[0235] Test Example 3: Inhibitory effect of the compound of the present invention on IL-6 secretion by human peripheral blood mononuclear cells (PBMCs) in response to LPS + IL-1β stimulation. This experiment was conducted in RPMI 1640 medium containing 10% FBS / 1% penicillin / streptomycin, with each compound at an initial test concentration of 1 μM. The compounds were dissolved in DMSO to form stock solutions, which were then diluted fivefold with culture medium to a 4× working solution concentration. The diluted solutions were added to 96-well plates at a rate of 50 μL / well. PBMC (batch number: HPP20062307, Sichuan Hope Bio-tech Co.,Ltd.) cells were counted, resulting in 2 × 10⁶ cells. 6 The solution was diluted to a concentration of / mL. The diluted cells were added to a 96-well plate containing the compound at a concentration of 150 μL / well, thoroughly mixed, and incubated in a 5% CO2 incubator at 37°C for 24 hours. LPS and IL-1β were then added to final concentrations of 10 ng / mL and 20 ng / mL, respectively, and the cells were incubated further in a 5% CO2 incubator at 37°C for 20 hours. After centrifugation at 2,000 rpm for 4 minutes, the supernatant was diluted 110-fold and detected using an IL-6 ELISA kit. The OD450 value was read, converted to IL-6 concentration based on a standard curve, and IC was obtained by fitting a dose-effect curve using GraphPad 5.0. 50 The values ​​were calculated. The results are shown in Table 20. [Table 27-1] [Table 27-2]

[0236] The median inhibitory concentration, or median inhibition rate, known as IC50, is crucial data in standard curves for indirect competitive ELISA. Generally, a lower IC50 value indicates stronger antibody specificity.

[0237] The results in Table 20 demonstrate that the compounds of the present invention have a clear advantage in inhibiting the LPS+IL-1β-induced secretion level of IL-6 in PBMC cells.

[0238] Test Example 4: Investigation of IRAK4 degradation levels in human peripheral blood mononuclear cells (PBMCs) using the compound of the present invention. This experiment was conducted in RPMI 1640 medium containing 10% FBS / 1% penicillin / streptomycin, with each compound at an initial test concentration of 1 μM.

[0239] Frozen human PBMCs were thawed in culture medium. Cells were divided into at least 2.5 × 10⁶ cells. 6 The cells were cultured in c / mL. PBMCs were incubated at 37°C / 5% CO2 and left overnight. After harvesting overnight, cell count / viability was evaluated by trypan blue exclusion. The cells were 2.5 × 10⁶. 6 The concentrations were adjusted to 1 / mL and then added to 96-well plates at 90 μL / well. Each compound was dissolved in DMSO to form stock solutions, which were diluted to 3× working concentrations in culture medium. The diluted solutions were added to the 96-well plates at 10 μL / well. Cells were incubated in an incubator containing 5% CO2 at 37°C for 20 hours. At the end of processing, cells were collected, centrifuged at 1,800 rpm for 5 minutes, washed with 1× PBS, and centrifuged again at 1,800 rpm for 5 minutes. The cell pellet was frozen and stored at -80°C until further processing, and resuspended in lysis buffer to produce lysates. Protein quantification was performed using a BCA kit on 26-well 4-12% Bis-Tris SDS-page gels loaded with 20 μg of protein per lane. PVDF membranes were transferred for 7 minutes using the BioRad Mixed MW turbo program and blocked in a shaker at room temperature for 1 hour. Primary antibodies were incubated overnight on a shaker at 4°C. The membranes were washed with 3×TBST for 5 minutes each. Secondary antibodies were added and incubated on a shaker at room temperature for 1 hour. The membranes were washed with 3×TBST for 5 minutes each and rinsed thoroughly with deionized H2O. The membranes were scanned using LI-COR Odyssey CLx and the wavelength bands were quantified using Image Studio Lite version 5.2 software.

[0240] Test Example 5: Effect of a compound on IRAK4 protein degradation in THP1 cells Place THP-1 cells in a 96-well cell culture plate, 5 × 10 4Cells were inoculated with 100 μL of culture medium per well. Cell culture plates were incubated overnight at 37°C in a 5% CO2 incubator. 100 nl of well-prepared compound stock solution and 100 nl of compound-free DMSO stock solution were added to each well of cells. Cell culture plates were incubated at 37°C for 24 hours in a 5% CO2 incubator. Protease inhibitor tablets and phosphatase inhibitor tablets were added to 20 mL of cell lysis buffer and gently mixed until completely dissolved. A 4x sample preparation solution was prepared by adding 200 mM DTT to 4x sample preparation buffer. 20x electrophoresis buffer was diluted 1x with ultrapure water. 20x transfer buffer was diluted 1x with ultrapure water and 20% methanol was added. 10x electrophoresis buffer was diluted 1x with ultrapure water. IRAK4 protein primary antibody working solution: 20 μL of IRAK4 antibody added to 20 mL of blocking solution; β-actin primary antibody working solution: 2 μL of β-actin (13E5) rabbit mAb antibody added to 20 mL of blocking solution. IRAK4 protein secondary antibody working solution: Donkey anti-goat IgG H&L (HRP) diluted 1 / 5000 with blocking solution; β-actin secondary antibody working solution: Anti-rabbit IgG, HRP-conjugated antibody diluted 1 / 10000 with blocking solution. The cell culture plate was centrifuged at 3000 rpm for 3 minutes, and most of the culture medium was carefully pipetted away. The cell plate was inverted and centrifuged at 300 rpm for 30 seconds. 45 μL of lysis buffer was added to each well. The mixture was shaken at 300 rpm for 30 seconds, left on ice for 30 minutes, and pipetted 30 times over 20 minutes. 6 μL of 4x sample preparation working solution was added to 18 μL of sample preparation protein supernatant, and the mixture was heated at 70°C for 10 minutes. The remaining protein sample was stored at -80°C. In a precast gel, 8 μL of sample was loaded into each well for electrophoresis at a constant voltage of 120 V for approximately 60 minutes, transferred using a PVDF membrane at a constant current of 300 mA for 1 hour, then blocked with blocking solution at room temperature for 1 hour, and incubated overnight at 4°C in the primary antibody working solution. 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 the color-developing solution was used for exposure and color development. The gray value of each stripe was calculated using ImagJ software for semi-quantitative analysis and DC. 50 This was calculated using GraphPad Prism 8.0, and the results are shown in Table 21. [Table 28]

[0241] DC50(nM) is an index used to measure the decomposition activity of a compound; a lower value indicates stronger decomposition activity.

[0242] The above results indicate that the compound of the present invention has a better degradation effect in THP1 cells.

[0243] Study Example 6: The following provides pharmacodynamic experiments on a Lewis rat model of arthritis induced by total Freund's adjuvant (CFA). Experimental method: (1) Establishment of animal models: Male Lewis rats (approximately 100-125g) were divided into groups of 8 rats each. The rats were randomly divided into 6 groups: a normal control group, a model control group, three dose groups (low, medium, and high) of the test compound (10mg / kg, 30mg / kg, and 100mg / kg), and a positive control group (PF06650883, 30mg / kg). Except for the normal group, in each experimental group, on day 0, a rat AA model was established by injecting 0.08 ml of complete Freund's adjuvant containing inactivated Mycobacterium tuberculosis (H37RA, 10mg / ml) into the left hind limb, thereby establishing a rat adjuvant arthritis model. From day 10 of model establishment, the rats were treated with different doses of the test substance by oral administration for 10 consecutive days. The rat joints were scored and the diameters of the left and right hind limbs were detected on days 8, 11, 14, 17, 20, 23, and 26 after modeling, to observe the effect of the drug on adjuvant arthritis in rats.

[0244] The arthritis assessment indicators are as follows: A. Joint scoring Limbs: 5-point scale from 0 to 4: No erythema or redness (0); Mild erythema or swelling with erythema or swelling of one of the anterior / posterior digital joints (1); Erythema or swelling of two or more toes (2); Swelling below the ankle or wrist joint of the foot (3); Swelling of the entire foot, including the ankle joint (4). Each of the rat's four feet was scored, with a maximum score of 16. The joints were scored and the results recorded on days 8, 11, 17, 14, 17, 20, 23, and 26 after modeling.

[0245] B. Ankle diameter measurement Before modeling and on days 8, 11, 17, 14, 17, 20, 23, and 26 after modeling, the diameter from the medial to the lateral side of the rat's ankle and the limb thickness were measured and recorded using calipers. The measurement data from the test results were expressed as a mathematical mean ± standard deviation (mean ± SD), and the difference between each treatment group and the control group was tested using SPSS 11.0 software.

[0246] Test Example 7: Metabolic Stability Test Blank incubation plates T60 and NCF60 were preheated for 10 minutes; liver microsomes were diluted to 0.56 mg / mL with 100 mM phosphate buffer, and 445 μL of microsome working solution (0.56 mg / mL) was transferred to the preheated "incubation" plates T60 and NCF60, and then incubation plates T60 and NCF60 were pre-incubated at 37°C for 10 minutes with continuous shaking; 54 μL of liver microsomes were transferred to a blank plate, 6 μL of NAPDH cofactor was added to the blank plate, and then 180 μL of quenching solution was added to the blank plate; 5 μL of compound working solution (100 μM) was added to each incubation plate containing microsomes (T60 and NCF60), and the mixture was thoroughly mixed three times; 50 μL of buffer was added to the NCF60 plate, and the mixture was thoroughly mixed three times. Timing was initiated; the plate was incubated at 37°C for 60 minutes with shaking. 180 μL of quenching solution and 6 μL of NAPDH cofactor were added to quench plate T0. The plate was cooled to prevent evaporation. For plate T60, the mixture was thoroughly mixed three times, and at 0 minutes, 54 μL of the mixture was immediately transferred to the quenching plate. Then, 44 μL of NAPDH cofactor was added to the incubation plate (T60). Timing was initiated; the plate was incubated at 37°C for 60 minutes with shaking. At 5, 15, 30, 45, and 60 minutes, 180 μL of quenching solution was added to the quenching plate, mixed once, and then 60 μL of the sample was successively transferred from plate T60 to the quenching plate at each time point.

[0247] For NCF60, the mixture was mixed once, and at 60 minutes, 60 μL of the sample was transferred from the NCF60 incubator to a quenching plate containing the quenching solution. All sampling plates were shaken for 10 minutes, and then centrifuged at 4,000 rpm for 20 minutes at 4°C. 80 μL of the supernatant was transferred to 240 μL of HPLC water and mixed for 10 minutes using a plate shaker. Each bioanalysis plate was sealed and shaken for 10 minutes before LC-MS / MS analysis. The results are shown in Table 22. [Table 29]

[0248] The results indicate that the compound of the present invention has better stability in liver microsomes than the positive compound (positive drug).

[0249] Test Example 8: Therapeutic effect of the compound of the present invention on a psoriasis model Male BALB / c mice aged 6-8 weeks were randomly divided into 15 or 6 groups after one week of adaptive rearing: a control group, an imiquimod model group (i.e., a model group), a clobetasol propionate group (i.e., a CLO group), and the compounds of the present invention: TM-57ICL-004192 (3 mg / kg, 10 mg / kg, 30 mg / kg), TM-109ICL-004240 (3 mg / kg, 10 mg / kg, 30 mg / kg, 60 mg / kg), TM-101ICL-004250 (3 mg / kg, 10 mg / kg, 30 mg / kg, 60 mg / kg), with 5 mice in each group, comprising the control group, the imiquimod model group (i.e., a model group), and the clobetasol propionate group (i.e., a CLO group). On day 0, a 2.5 cm × 1.5 cm area on the back of each mouse was depilated using a depilatory cream. On day 1, IMQ cream was used as a model, and the corresponding drug was administered via gastric tube feeding for treatment. The compound of the present invention was administered via gastric tube feeding at the corresponding dose twice daily, in the morning and evening, with an 8-hour interval between the two doses. Two hours after the first gastric tube feeding on the same day, IMQ cream was applied to the depilatory areas on the back and left ear of each mouse, with doses of IMQ cream administered to the depilatory areas on the back and left ear being 62.5 mg and 7.5 mg, respectively. Five hours after applying IMQ cream to the depilatory areas on the back and left ear of each mouse in the CLO group, clobetasol propionate cream was applied once daily. The blank group and the IMQ group were administered the vehicle twice daily, in the morning and evening, with an 8-hour interval between the two doses. Two hours after the first dose on the same day, petrolatum and IMQ cream were applied to the hair loss areas on the backs and ears of each mouse, respectively, for five consecutive days of administration.

[0250] Referring to the Psoriasis Area and Severity Index (PASI) scoring criteria, the thickness of psoriasis, erythema, and dorsal skin lesions was scored daily from day 1 of modeling on a scale of 0 to 4, using the scoring criteria shown in Table 1. The three scores were summed to obtain the total score, i.e., the total PASI score. The ear thickness of the left ear of the mice was measured three times in the morning from day 1 using a digital caliper, and the average value was obtained. [Table 30]

[0251] Figure 1 shows the therapeutic effect of the compound of the present invention on IMQ-induced psoriatic skin thickening. Figure 2 shows the therapeutic effect of the compound of the present invention on IMQ-induced psoriatic ear thickening.

[0252] The results demonstrate that the compounds of the present invention have a significant therapeutic effect against IMQ-induced psoriatic skin thickening and ear thickening.

[0253] In the therapeutic effect of compounds on IMQ-induced psoriatic skin thickening shown in Figure 1, TM-57 (30 mg / kg, BID) showed P<0.01 compared to the model group.

[0254] In the therapeutic effects of the compounds on IMQ-induced psoriasis-like ear thickening shown in Figure 2, compared to the model group, TM-57 (10 mg / kg, BID) had a P<0.05, TM-57 (30 mg / kg, BID) had a P<0.0001, TM-109 (60 mg / kg, BID) had a P<0.01, and TM-101 (60 mg / kg, BID) had a P<0.05.

[0255] Test Example 9: In vivo metabolism study of the drug of the present invention Pharmacokinetic experiments in ICR mice: Two administration methods were selected for this experiment: oral intragastric administration and tail vein injection. The compounds of this patented invention were administered at an oral dose of 5 mg / kg and a dosage of 10 mL / kg. Immediately before use, the compounds were accurately weighed, and the appropriate amount of drug was accurately weighed and first dissolved in dimethyl sulfoxide (DMSO) to prepare the final volumes of 5% DMSO, 10% Solutol, and 85% H2O. The appropriate amounts of Solutol and H2O were added sequentially and proportionally, and thoroughly mixed by sonication using a vortex mixer to prepare a clear drug solution of 0.5 mg / mL. ICL004-protodrug was administered by intravenous injection at a dose of 1 mg / kg in a dosage of 10 mL / kg. Immediately before use, the appropriate amount of drug was accurately weighed and the final volumes of 20% PEG 400 and 80% physiological saline were prepared. Appropriate amounts of PEG 400 and physiological saline were added sequentially and proportionally, and the mixture was thoroughly mixed using vortexing and ultrasound to prepare a clear drug solution of 0.1 mg / mL.

[0256] Twelve ICR mice, each weighing 28–32 g, were randomly divided into two groups. After fasting, but with free access to water overnight, each mouse in the first group was administered by forced oral administration. At 15, 30, 1, 2, 4, 6, 8, and 24 hours post-administration, 100 μL of blood was collected from the orbit of each mouse into an anticoagulant tube (three mice from the same batch were used at 15, 1, 4, and 8 hours, and three mice from the same batch were used at 30, 2, 6, and 24 hours). Within one hour, each blood sample was centrifuged at 10,000 rpm at 4°C for 20 minutes (blood samples were stored in an icebox before centrifugation), and the supernatant, i.e., plasma, was stored in a refrigerator at -20°C for LC-MS / MS analysis. From the orbit of each mouse in Group 2, 100 μL of blood was collected in an anticoagulant tube at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after intravenous administration (three mice from the same batch were used at 5 minutes, 30 minutes, 2 hours, and 8 hours, and three mice from the same batch were used at 15 minutes, 1 hour, 4 hours, and 24 hours). Within 1 hour, each blood sample was centrifuged at 10,000 rpm for 20 minutes at 4°C (samples were stored in an icebox before centrifugation), and the supernatant (i.e., plasma) was stored in a refrigerator at -20°C for LC-MS / MS analysis.

[0257] Pharmacokinetic experiments in SD rats: Two administration methods were selected for this experiment: oral intragastric administration and tail vein injection. The compound of this patented invention was administered at an oral dose of 5 mg / kg and a dosage of 10 mL / kg. Immediately before use, the compound was accurately weighed, and the appropriate amount of drug was accurately weighed and first dissolved in dimethyl sulfoxide (DMSO) to prepare the final volumes of 5% DMSO, 10% Solutol, and 85% H2O. The appropriate amounts of Solutol and H2O were added sequentially and proportionally, and thoroughly mixed by sonication using a vortex mixer to prepare a clear drug solution of 0.5 mg / mL. ICL004-protodrug was administered by intravenous injection at a dose of 1 mg / kg in a dosage of 10 mL / kg. Immediately before use, the appropriate amount of drug was accurately weighed and the final volumes of 20% PEG 400 and 80% physiological saline were prepared. Appropriate amounts of PEG 400 and physiological saline were added sequentially and proportionally, and the mixture was thoroughly mixed using vortexing and ultrasound to prepare a clear drug solution of 0.1 mg / mL.

[0258] Six SD rats, each weighing 180–220 g, were randomly divided into two groups. After fasting, but with free access to water overnight, each mouse in group 1 was administered by forced oral administration. At 15, 30, 1, 2, 4, 6, 8, and 24 hours post-administration, 200 μL of blood was sampled from the eye socket into an anticoagulant tube. Within 1 hour, each blood sample was centrifuged at 10,000 rpm at 4°C for 20 minutes (samples were stored in an icebox before centrifugation), and the supernatant (i.e., plasma) was stored in a refrigerator at -20°C for LC-MS / MS analysis. At 5, 15, 30, 1, 2, 4, 8, and 24 hours after intravenous administration, 200 μL of blood was collected from the eye socket of each mouse in group 2 into an anticoagulant tube. Within one hour, each blood sample was centrifuged at 10,000 rpm at 4°C for 20 minutes (blood samples were stored in an icebox before centrifugation), and the supernatant, i.e., plasma, was stored in a refrigerator at -20°C for LC-MS / MS analysis. The results are shown in Table 24. [Table 31-1] [Table 31-2]

[0259] The results are as follows: The compounds of the present invention exhibit excellent oral bioavailability in mice and rats.

[0260] In summary, the present invention discloses a compound of formula I that can effectively degrade IRAK4 or inhibit IRAK4 activity by other means and has very good potential for application in the treatment of IRAK4-mediated diseases, including, for example, immune diseases (psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, alcoholic liver disease, autoimmune liver disease, acne, etc.), tumors (multiple myeloma, lymphocytic leukemia, lymphoma, etc.), Alzheimer's disease, and fibrosis, thus providing a new option for the clinical selection and / or preparation of pharmaceuticals for treating diseases related to IRAK4 activity.

Claims

1. Compounds represented by formula I, their enantiomers, their diastereomers, their racemates, mixtures containing them, their deuterated compounds, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, PTM is, 【Chemistry 2】 Selected from, Ring D is, 【Transformation 3】 Selected from, ring D is 【Chemistry 4】 If selected from, PTM 【Transformation 5】 Not selected from, Q is CR ２ａ Or selected from N, V' is selected from C or N, U' is CR ２ or NR ２ Selected from, W' is CR ３ Or selected from N, X' is C, CR ４ , or selected from N, Y' is C, CR ５ , or selected from N, Z' is C, CR ６ , or selected from N, U is C, CR Ｕ , or selected from N, W is selected from C, CR Ｗ , or N, T is C, CR Ｔ , or selected from N, X is C, CR Ｘ Or selected from N, Y is C, CR Ｙ , or selected from N, Z is C, CR Ｚ Or selected from N, 【Transformation 6】 This represents a single bond or a double bond. V is selected from C or N, R １ and R １’ Each of these independently consists of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, or substituted Alternatively, the substituents are selected from unsubstituted C2-C6 linear or branched unsaturated hydrocarbon groups, the substituents being independently selected from deuterium, halogen, hydroxyl, cyano, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, or 4-10 membered heterocyclyl, the heterocyclyl comprising 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen. Ring A has 0 to 4 R ７ Substitution: Independently selected from 5-10 membered heteroaromatic rings or 5-6 membered heteroaromatic rings, wherein the heteroaryl comprises 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 , and R ７ Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 member heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 member aromatic ring, substituted or unsubstituted 5-10 member heteroaromatic ring, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted 3-10 member cycloalkyl, substituted or unsubstituted unsaturated 3-10 member 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 member cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 member cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, or substituted or unsubstituted 3-10 member cyanoalkylamino Selected from chloroalkanoyl groups, substituents include deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclyl. A heterocycline is independently selected from C5-C12 bridged heterocyclines, C3-C10 heterospirocyclines, 6-10 membered aromatic rings, 5-10 membered heteroaromatic rings, 3-10 membered cycloalkyls, and C1-C6 linear or branched alkyl-C(=O)- or 3-10 membered cycloalkyl-C(=O)-, where each heterocycline, bridged heterocycline, heterospirocycline, and heteroaromatic ring contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen. L1 is N.A. 【Transformation 7】 Selected from, a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are each independently selected from 0 to 6, and La, Lb, Lc, Ld, Le, L ａ’ , L ｅ’ , L ｆ’ , L ｇ’ , and L ｈ’ These are N.A., O, S, and -N(R) respectively, independently. ８ )-, -C(=O)-R ９ -, or -SO ２ R １０ - Selected from, R ８ This includes hydrogen, substituted or unsubstituted 4-10 member heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 member aromatic ring, substituted or unsubstituted 5-10 member heteroaromatic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 member cycloalkyl, substituted or unsubstituted unsaturated 3-10 member cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 member cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 member 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Transformation 8】 selected from, and the substituent is deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 member cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 member cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 member cycloalkanoyl, 4-10 member heterocyclyl, C5-C12 bridged heterocyclyl, C3-C10 heterospirocyclic, 6-10 member aromatic ring, or 5-10 member heteroaromatic ring, independently selected, and heterocyclyl, bridged heterocyclyl, heterospirocyclic, and heteroaromatic ring each contain 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, R ８ is R Ｌ１１１ R Ｌ１１２ R Ｌ１１３ R Ｌ１１４ R Ｌ１２３ R Ｌ１２４ R Ｌ１２５ R Ｌ１２６ R Ｌ１２７ R Ｌ１２８ R Ｌ１２９ R Ｌ１３０ and R １１ COR １２ -, -R<00000​​​​​​​​​​​​​​​​​​​​​​​​​​​​R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 9】 Selected independently from, 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 、およびR ３７ Each of these is independently N.A., hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 member heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 polyheterospirocyclyl, substituted or unsubstituted 6-10 member aromatic ring, substituted or unsubstituted 5-10 member heteroaromatic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 member cycloalkyl, substituted or unsubstituted unsaturated 3-10 member cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 member cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 member cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkyl Canoyl, or selected from substituted or unsubstituted 3-10 membered cycloalkanoyl groups, wherein the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon groups, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclyl, C5-C12 bridged heterocyclyl, C3-C10 heterospirocyclyl, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring, and each heterocyclyl, bridged heterocyclyl, heterospirocyclyl, and heteroaromatic ring contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen. L ｂ’ , L ｃ’ , L ｄ’ , and L ｉ’ These are, independently, N or CR ３８ Selected from, 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 , and R Ｌ１３２ Each of these is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 member heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 member aromatic ring, substituted or unsubstituted 5-10 member heteroaromatic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 member cycloalkyl, substituted or unsubstituted unsaturated 3-10 member cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 member cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 member 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 SO ２ R ２４ -、-R ２５ OSO ２ R ２６ -、-R ２７ SO ２ OR ２８ -、-R ２９ NR ３０ SO ２ R ３１ -、-R ３２ SO ２ NR ３３ R ３４ -、または 【Chemistry 10】 Selected from, The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclyl, C5-C12 bridged heterocyclyl, C3-C10 heterospirocyclyl, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring, where heterocyclyl, bridged heterocyclyl, heterospirocyclyl, and heteroaromatic ring each contain 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, respectively. ３８ R is transmitted via C, N, O or S. 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 , and R Ｌ１３２ It can form a substituted or unsubstituted 3- to 10-membered ring, and the substituents are deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -、-R ２５ OSO ２ R ２６ -、-R ２７ SO ２ OR ２８ -、-R ２９ NR ３０ SO ２ R ３１ -、-R ３２ SO ２ NR ３３ R ３４ -、または 【Chemistry 11】 Selected independently from, R Ｌ１１１ , R Ｌ１１２ , R Ｌ１１３ , R Ｌ１１４ , R Ｌ１１５ , R Ｌ１１６ , R Ｌ１１７ , R Ｌ１１８ , R Ｌ１１９ , and R Ｌ１２０ Any two of these groups can form a substituted or unsubstituted 3- to 12-membered ring via C, N, O, or S, and the substituents may be deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 12】 Selected independently from, R Ｌ１２１ , R Ｌ１２２ , R Ｌ１２３ , R Ｌ１２４ , R Ｌ１２５ , and R Ｌ１２６ Any two of these groups can form a substituted or unsubstituted 3- to 10-membered ring via C, N, O, or S, and the substituents may be deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 13】 Selected independently from, R Ｌ１２７ , R Ｌ１２８ , R Ｌ１２９ , R Ｌ１３０ , R Ｌ１３１ , and R Ｌ１３２ Any two of these groups can form a substituted or unsubstituted 3- to 10-membered ring via C, N, O, or S, and the substituents may be deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 14】 Selected independently from, Ring B is selected from N.A., substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, or substituted or unsubstituted 5-10 membered heteroaromatic ring, and the substituents are deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ - 【Chemistry 15】 A heterocyclyl is independently selected from a 4-10 membered heterocyclyl, a C5-C12 bridged heterocyclyl, a C3-C10 heterospirocyclyl, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, and each heterocyclyl, bridged heterocyclyl, heterospirocyclyl, and heteroaromatic ring contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen. L2 is N.A. 【Chemistry 16】 Selected from, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, and 2s are each independently selected from 0 to 6. L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L ２ａ’ , L ２ｅ’ , L ２ｆ’ , L ２ｇ’ , and L ２ｈ’ N.A., O, S, NR ３９ COR ４０ , or -SO ２ R ４１ Selected independently from, L ２ｂ’ , L ２ｃ’ , L ２ｄ’ , and L ２ｉ’ is N or CR ４４ Selected from, 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 , and R Ｌ２４６ Each of these is independently hydrogen, a substituted or unsubstituted 4-10 member heterocycline, a substituted or unsubstituted C5-C12 bridged heterocycline, a substituted or unsubstituted C3-C10 heterospirocycline, a substituted or unsubstituted 6-10 member aromatic ring, a substituted or unsubstituted 5-10 member heteroaromatic ring, a substituted or unsubstituted C1-C6 linear or branched alkyl group, a substituted or unsubstituted 3-10 member cycloalkyl group, a substituted or unsubstituted unsaturated 3-10 member cyclic hydrocarbon group, a substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, a substituted or unsubstituted C1-C6 linear or branched alkoxy group, a substituted or unsubstituted 3-10 member cycloalkoxy group, a substituted or unsubstituted C1-C6 linear or branched alkylamino group, a substituted or unsubstituted 3-10 member cycloalkylamino group, and -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 SO ２ R ２４ -、-R ２５ OSO ２ R ２６ -、-R ２７ SO ２ OR ２８ -、-R ２９ NR ３０ SO ２ R ３１ -、-R ３２ SO ２ NR ３３ R ３４ -、または 【Chemistry 17】 The substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclyl, C5-C12 bridged heterocyclyl, C3-C10 heterospirocyclyl, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring, and each heterocyclyl, bridged heterocyclyl, heterospirocyclyl, and heteroaromatic ring contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, respectively. ３９ These are R via C, N, O, and S respectively. 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 , and R Ｌ２３０ It can form a substituted or unsubstituted 3- to 10-membered ring, and the substituents are deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 10-membered cycloalkylamino, -R １１ COR １２ -, -R １３ OCOR １４ -, -R １５ COOR １６ -, -R １７ NR １８ 392 １９ -、-2 ２０ 3982 ２１ 2 ２２ -、-2 ２３ 39 ２ 2 ２４ -、-2 ２５ 939 ２ 2 ２６ -、-2 ２７ 39 ２ 92 ２８ -、-2 ２９ 82 ３０ 39 ２ 2 ３１ -、-2 ３２ 39 ２ 82 ３３ 2 ３４ -、または [Chemistry 18] Selected independently from, R Ｌ２１１ , R Ｌ２１２ , R Ｌ２１３ , R Ｌ２１４ , R Ｌ２１５ , R Ｌ２１６ , R Ｌ２１７ , R Ｌ２１８ , R Ｌ２１９ , and R Ｌ２２０ Any two of these groups can form a substituted or unsubstituted 3- to 12-membered ring via C, N, O, or S, and the substituents may be deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 19】 Selected independently from, R Ｌ２２１ , R Ｌ２２２ , R Ｌ２２３ , R Ｌ２２４ , R Ｌ２２５ , and R Ｌ２２６ Any two of these groups can form a substituted or unsubstituted 3- to 10-membered ring via C, N, O, or S, and the substituents may be deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 20】 Selected independently from, R Ｌ２２７ , R Ｌ２２８ , R Ｌ２２９ , R Ｌ２３０ , R Ｌ２３１ , and R Ｌ２３２ Any two of these groups can form a substituted or unsubstituted 3- to 10-membered ring via C, N, O, or S, and the substituents may be deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 21】 Selected independently of or R ４４ R is transmitted via C, N, O or S 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 , and R Ｌ２３２ It can form a substituted or unsubstituted 3- to 10-membered ring, and the substituents are deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- to 10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3- to 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ -,or 【Chemistry 22】 Selected independently from, Ring C is selected from N.A., substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, or substituted or unsubstituted 5-10 membered heteroaromatic ring, and the substituents are independently deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 linear or branched haloalkyl, C2-C6 linear or branched unsaturated halohydrocarbon group, C1-C6 linear or branched haloalkoxy, 3-10 membered cycloalkoxy, C1-C6 linear 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 SO ２ R ２４ -, -R ２５ OSO ２ R ２６ -, -R ２７ SO ２ OR ２８ -, -R ２９ NR ３０ SO ２ R ３１ -, -R ３２ SO ２ NR ３３ R ３４ - 【Chemistry 23】 Independently selected from 4-10 membered heterocyclyls, C5-C12 bridged heterocyclyls, C3-C10 heterospirocyclyls, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, each containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, the heterocyclyl, bridged heterocyclyl, heterospirocyclyl, and heteroaromatic ring each contain 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen. 【Chemistry 24】 Preferably, 【Chemistry 25-1】 【Chemistry 25-2】 , selected from a single cis-trans isomer or a mixture thereof, for example, 【Chemistry 26-1】 【Chemistry 26-2】 Selected from, Each halogen is independently fluorine, chlorine, bromine, or iodine. The C1-C6 alkyl groups in each of the substituted or unsubstituted C1-C6 linear or branched alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, and hexyl. Each of the substituted or unsubstituted 3- to 10-membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, 【Chemistry 27】 And, Each of the substituted or unsubstituted 4- to 10-membered heterocyclines is independently: 【Chemistry 28】 For example, 【Chemistry 29】 And, Each of the substituted or unsubstituted C3-C10 heterospirocyclils is independently 2-azaspirocyclo[3.3]heptyl, 7-azaspirocyclo[3.5]nonyl, 2-azaspirocyclo[3.5]nonyl, 2,7-diazaspirocyclo[3.5]nonyl, 6-azaspirocyclo[3.4]octyl, 4-oxa-7-azaspirocyclo[2.5]octyl, 5-oxa-8-azaspirocyclo[3.5]nonyl, 2-oxa-6-azaspirocyclo[3.3]heptyl, 2-oxa-6-azaspirocyclo[3.4]octyl, or 4,7-diazaspirocyclo[2.5]octyl, for example, 【Transformation 30】 And, The C5-C12 cross-linked heterocyclyl in each of the substituted or unsubstituted C5-C12 cross-linked heterocyclyls is independently octahydrocyclopenta[C]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, for example, 【Chemistry 31】 And, Each of the substituted or unsubstituted 5- to 10-membered heteroaromatic rings is independently: 【Chemistry 32】 (That is the case.)

2. The compound represented by formula I is, formula Ia: 【Transformation 33】 (In the formula, Ring D is, 【Transformation 34】 Selected from, U is selected from N, and W is C or CR Ｗ Selected from, T is C or CR Ｔ Selected from, or W is selected from N, and U is C or CR Ｕ Selected from, T is C or CR Ｔ Selected from, At most one of X, Y, and Z is N. R １ The substituent is selected from hydrogen, deuterium, halogen, cyano, or substituted or unsubstituted C1-C6 linear or branched alkyl groups, and the substituent is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkoxy, or 3-10 membered cycloalkoxy, and the number of substituents is 1, 2, or 3, for example, R １ This is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, or cyclopropoxymethyl. 【Chemistry 35】 teeth, 【Transformation 36】 And, R Ｕ , R Ｗ , R Ｔ , R Ｘ , R Ｙ , R Ｚ and R ｅ Each of these elements is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, or substituted or unsubstituted C1-C6 linear or branched alkoxy, for example, H, F, or methyl. Ring A is the following ring: 【Chemistry 37】 Selected independently from, R ７ teeth, 【Transformation 38】 (Selected from) The compound according to claim 1, or its enantiomer, its diastereomer, its racemate, a mixture containing the same, or its deuterated compound, or a pharmaceutically acceptable salt thereof, as shown in [reference].

3. The aforementioned ring D is 【Chemistry 39】 Selected from, with each *terminus connected to ring C, 【Chemistry 40】 but, 【Chemistry 41】 And, Ring A is 【Chemistry 42】 Selected from, R ｅ However, it is hydrogen or methyl. A compound according to claim 2, or its enantiomer, its diastereomer, its racemic mixture, a mixture containing the same, or its deuterated compound, or a pharmaceutically acceptable salt thereof.

4. The compound represented by the above formula Ia is as follows: 【Chemistry 43】 (In the formula, R ７ teeth, 【Chemistry 44】 Selected from, R Ｃ (Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, or C1-C6 linear or branched alkylamino) The compound according to claim 2, or its enantiomer, its diastereomer, its racemate, a mixture containing the same, or its deuterated compound, or a pharmaceutically acceptable salt thereof, as shown in [reference].

5. The compound is selected from the following compounds, one of the compounds described in any one of claims 1 to 4, or its enantiomer, its diastereomer, its racemic mixture, a mixture containing the same, its deuterated compound, or a pharmaceutically acceptable salt thereof: Table 1-1 Table 1-2 。

6. The compound represented by formula I is either formula Ib or Ic: 【Chemistry 45】 or 【Chemistry 46】 (In the formula, Ring D is, 【Chemistry 47】 Selected from, Q is CR ２ａ Or selected from N, U is selected from N, and W is C or CR Ｗ Selected from, T is C or CR Ｔ Selected from, Alternatively, W is selected from N, and U is C or CR Ｕ Selected from, T is C or CR Ｔ Selected from, At most one of X, Y, and Z is N. V' is selected from N or C, and U' is CR ２ or NR ２ Selected from, W' is CR ３ Or selected from N. X' is CR ４ Alternatively, selected from N, where Y' is CR ５ Or selected from N, where Z' is C, CR ６ , or selected from N, where at most one of X', Y', and Z' is N, R １’ The substituent is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, or substituted or unsubstituted C1-C6 linear or branched alkylamino, and the substituent is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)- or 3-10 membered cycloalkyl-C(=O)-, and the number of substituents is 1, 2, or 3. For example, R １’ R is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, or cyclopropoxymethyl, and in another example, R １’ teeth, 【Chemistry 48】 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 and R ｅ Each 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, or substituted or unsubstituted 3-10 membered cycloalkyl, for example, selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy, or methyl. Ring A is the following ring: 【Chemistry 49】 Selected independently from, R ７ The substituent is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 crosslinked heterocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, or substituted or unsubstituted C1-C6 linear or branched alkylamino, and the substituent is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)- or 3-10 membered cycloalkyl-C(=O)-, and the number of substituents is 1, 2, or 3. For example, R ７ R is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, or cyclopropoxymethyl, and in another example, R ７ teeth, [Transformation 50] (Selected from) The compound according to claim 1, or its enantiomer, its diastereomer, its racemate, a mixture containing the same, or its deuterated compound, or a pharmaceutically acceptable salt thereof, as shown in [reference].

7. The aforementioned ring D is 【Chemistry 51】 Selected from, *Each terminal is connected to ring C, R ２ , R ４ , R ５ and R ６ However, each 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, or substituted or unsubstituted 3-10 membered cycloalkyl, preferably R ２ , R ４ , R ５ and R ６ However, each is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy, or methyl. Ring A is 【Chemistry 52】 Selected from, A compound according to claim 6, or its enantiomer, its diastereomer, its racemic mixture, a mixture containing the same, or its deuterated compound, or a pharmaceutically acceptable salt thereof.

8. The compound represented by formula Ib has the following structure: 【Chemistry 53-1】 【Chemistry 53-2】 【Chemistry 53-3】 (In the formula, R ２ , R ４ , R ５ and R ６ Each of these is independently selected from H, F, Cl, cyclopropyl, cyclobutyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyano, methoxy, ethoxy, or methyl. R １’ Hydrogen, deuterium, methyl, ethyl, propyl, hydroxymethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, amino, monomethylamino, dimethylamino, deuterated monomethylamino, deuterated dimethylamino, 【Chemistry 54】 Selected from, R ７ This includes hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 【Transformation 55】 (Selected from) A compound according to claim 6, or its enantiomer, its diastereomer, its racemate, a mixture thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

9. The compound has the following structure: Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 A compound selected from any one of claims 6 to 8, or its enantiomer, its diastereomer, its racemate, a mixture containing the same, or its deuterated compound, or a pharmaceutically acceptable salt thereof.

10. Use of a compound according to any one of claims 1 to 9, or an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical product, wherein the pharmaceutical product is a pharmaceutical product for the treatment and prevention of one or more diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signaling pathway, the interleukin-6 (IL-6) receptor, and tumor necrosis factor α (TNFα), or the pharmaceutical product is a pharmaceutical product for the treatment and / or prevention of autoimmune diseases and / or cancer or proliferative disorders.

11. The aforementioned diseases include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, organ transplant-related diseases, immunodeficiency diseases, osteocellular diseases, proliferative disorders, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, and cardiovascular diseases; The aforementioned cancers or proliferative disorders include 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, epidermal carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin lymphoma or non-Hodgkin lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma, ABC Selected from DLBCL, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, perisplenic zone lymphoma, plasmacytoma, or intravascular large B-cell lymphoma; epidermal hyperproliferative disorder, psoriasis, benign prostatic hyperplasia, IL-1-driven disease, and MyD88-driven disease; The MyD88-driven diseases are selected from ABC DLBCL, Waldenström macroglobulinemia, Hodgkin 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 aforementioned inflammatory diseases include ocular allergies, conjunctivitis, keratoconjunctivitis sicca, phlebitis-conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, or acne; or another inflammatory disease caused by an autoimmune response, such as systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease, or other autoimmune inflammatory bowel diseases. Irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Graves' disease, sarcoidosis, alveolar catarrh, 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 reaction, anaphylaxis, sinuses Inflammation, chronic obstructive pulmonary disease, lung disease, cystic fibrosis, appendicitis, atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, conjunctivitis, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, epididymitis, fasciitis, fibrous tissue inflammation, gastritis, gastroenteritis, allergic purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis Use according to claim 10, selected from mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, enteritis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, herpetiform dermatitis, subcutaneous dermatitis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, or osteoarthritis.

Images