IRAK degrading agent and application thereof

Abstract

The invention relates to a compound as shown in a formula I and application of the compound in preparation of medicines. Relates to a novel compound with an IRAK4 degradation effect, which can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways. The compound has a very good application prospect in IRAK4-mediated diseases including immune diseases, tumors, Alzheimer's disease, fibrosis and the like, and a new choice is provided for clinical screening and / or preparation of drugs for diseases related to IRAK4 activity.

Description

IRAK degraders and uses thereof

[0001] This application claims priority to Chinese patent applications with application number 202311229384X, entitled IRAK4 degraders and uses thereof, filed with the Chinese Patent Office on September 21, 2023, and application number 202410504738.5, entitled IRAK degraders and uses thereof, filed with the Chinese Patent Office on April 24, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a class of compounds with IRAK degradation function and use thereof in preparing medicines. Background Art

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

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

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

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

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

[0008] Recent studies have shown that in addition to the inflammatory signaling pathways mediated by IRAK4's kinase activity, the IRAK4 protein skeleton can also activate certain inflammatory signaling pathways. In human skin fibroblasts, ATP-competitive small molecule inhibition of IRAK4 was unable to effectively inhibit the release of IL-6 and TNF-α stimulated by IL-1β. This means that although ATP-competitive inhibitors can inhibit the kinase activity of IRAK4, they may not be able to completely destroy its protein skeleton function, thereby affecting the inhibitory effect on the release of IL-6 and TNF-α. In addition, 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 the inflammatory signaling pathways mediated by the IRAK4 protein. Therefore, targeting IRAK4 with small molecule inhibitors has its therapeutic limitations.

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

[0010] Summary of the Invention

[0011] The present invention first provides a compound represented by Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0012] in,

[0013] V is selected from -C(O)NH- or -NHC(O)-;

[0014] T is selected from -NH- or a chemical bond;

[0015] represents a single bond or a double bond;

[0016] Y 2 、Y 3 are independently selected from C or N;

[0017] Y 1 、Y 4 Independently selected from CR Y , CR Y R Y 、N、NR Y , O, S, C(O), S(O) or S(O)2;

[0018] Y 5 Selected from C or N;

[0019] Y 6 、Y 7 Independently selected from CR 4 or N;

[0020] Each R Y Selected from hydrogen, deuterium, halogen, cyano, C1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl;

[0021] Q is selected from CR Q or N;

[0022] R Q Selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 1～6 Alkoxy, halogen-substituted C 1～6 Alkyl, halogen-substituted C 1～6 alkoxy;

[0023] Ring A is selected from a 5-10 membered aromatic heterocycle; wherein the aromatic heterocycle is optionally replaced by 1, 2 or 3 R A1 replace:

[0024] Each R A1 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR A2 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-3 to 10-membered carbocyclic group, -C 0～2 Alkylene-4- to 10-membered heterocyclic group;

[0025] R A2 、R A3 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl;

[0026] R 1 、R 4 are independently selected from hydrogen, deuterium, halogen, cyano, C1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR 11 、-C 0～2 Alkylene-NR 11 R 12 、-C 0～2 Alkylene-NR 11 C(O)R 12 、-C 0～2 Alkylene-C(O)R 11 、-C 0～2 Alkylene-C(O)NR 11 R 12 、-C 0～2 Alkylene-3 to 10-membered carbocyclic group, -C 0～2 Alkylene-4 to 10-membered heterocyclic group, -C 0～2 Alkylene-4 to 10-membered bridge ring, -C 0～2 Alkylene-4 to 10-membered bridged heterocycle, -C 0～2 Alkylene-5 to 12-membered spiro ring, -C 0～2 Alkylene-5- to 12-membered spiroheterocycle, -C 0～2 Alkylene-6 to 10-membered aromatic ring, -C 0～2 Alkylene-5 to 10 membered aromatic heterocycle; wherein the carbocyclic group, heterocyclic group, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle, aromatic ring, aromatic heterocycle are optionally substituted by 1, 2 or 3 R 13 replace:

[0027] R 11 、R 12 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl;

[0028] Each R 13 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR 14 、-C 0～2 Alkylene-NR 14 R 15 、-C 0～2 Alkylene-NR 14 C(O)R 15 、-C 0～2 Alkylene-C(O)R 14 、-C 0～2 Alkylene-C(O)NR 14 R 15 ;

[0029] R 14 、R 15 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl;

[0030] Ring D is selected from The cc end is connected to L, and the dd end is connected to Q;

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

[0032] X 2 、X 3 are independently selected from C or N;

[0033] X 1 、X 4 Independently selected from CR X , CR X R X 、N、NR X , O, S, C(O), S(O) or S(O)2;

[0034] X 5 Selected from C or N;

[0035] X 6 、X 7 Independently selected from CR 2 or N;

[0036] X 8 、X 9Independently selected from C, CR 2 or N;

[0037] Each R X Selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl;

[0038] Each R 2 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR 21 、-C 0～2 Alkylene-NR 21 R 22 、-C 0～2 Alkylene-3 to 10-membered carbocyclic group, -C 0～2 Alkylene-4- to 10-membered heterocyclic group;

[0039] R 21 、R 22 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl;

[0040] L is The B ring and R 1 The terminal aromatic heterocyclic nitrogen atoms are connected, and the C ring is connected to the D ring;

[0041] Ring B is selected from 3-10 membered carbocyclic group, 4-10 membered heterocyclic group, 4-10 membered bridged ring, 4-10 membered bridged heterocyclic ring, 5-12 membered spirocyclic ring, 5-12 membered spiro heterocyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic group, bridged ring, bridged heterocyclic ring, spirocyclic ring, spiro heterocyclic ring, aromatic ring, aromatic heterocyclic ring are optionally substituted by 1, 2 or 3 R B replace;

[0042] Preferably, the B ring is selected from 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-membered bridged ring, 6-membered bridged ring, 7-membered bridged ring, 8-membered bridged ring, 5-membered bridged heterocycle, 6-membered bridged heterocycle, 7-membered bridged heterocycle, 8-membered bridged heterocycle, 7-membered spirocycle, 8-membered spirocycle, 9-membered spirocycle, 10-membered spirocycle, 11-membered spirocycle, 7-membered spiroheterocycle, 8-membered spiroheterocycle, 9-membered spiroheterocycle, 10-membered spiroheterocycle, 11-membered spiroheterocycle; wherein the carbocyclyl, heterocyclyl, bridged ring, bridged heterocycle, spirocycle, spiroheterocycle are optionally replaced by 1, 2 or 3 R B replace;

[0043] The C ring is selected from 3-10 membered carbocyclic group, 4-10 membered heterocyclic group, 4-10 membered bridged ring, 4-10 membered bridged heterocyclic ring, 5-12 membered spirocyclic ring, 5-12 membered spiro heterocyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic group, bridged ring, bridged heterocyclic ring, spirocyclic ring, spiro heterocyclic ring, aromatic ring, aromatic heterocyclic ring are optionally replaced by 1, 2 or 3 R C replace;

[0044] Preferably, the C ring is selected from 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-membered bridged ring, 6-membered bridged ring, 7-membered bridged ring, 8-membered bridged ring, 5-membered bridged heterocycle, 6-membered bridged heterocycle, 7-membered bridged heterocycle, 8-membered bridged heterocycle, 7-membered spirocycle, 8-membered spirocycle, 9-membered spirocycle, 10-membered spirocycle, 11-membered spirocycle, 7-membered spiroheterocycle, 8-membered spiroheterocycle, 9-membered spiroheterocycle, 10-membered spiroheterocycle, 11-membered spiroheterocycle; wherein the carbocyclyl, heterocyclyl, bridged ring, bridged heterocycle, spirocycle, spiroheterocycle are optionally replaced by 1, 2 or 3 R C replace;

[0045] R B 、R C are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR B1 、-C 0～2 Alkylene-NR B1 R B2 ;

[0046] R B1 、R B2 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl;

[0047] L 1 Selected from chemical bonds, C 1～6 Alkylene, C 2～6 Alkenylene, C 2～6 wherein the carbon atoms in the alkylene, alkenylene, and alkynylene groups may be optionally substituted by 1, 2, or 3 heteroatoms, and the alkylene, alkenylene, and alkynylene groups may be optionally substituted by 1, 2, or 3 R L1 replace;

[0048] Each R L1 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl.

[0049] In some embodiments of the present invention,

[0050] Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from C, Y 4 Selected from CH, Y 5 Selected from N, Y 6 Selected from CH, Y 7 selected from CH; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH, Y 5 Selected from C, Y 6 Selected from CH, Y 7 selected from CH; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from N, Y 5 Selected from C, Y 6 Selected from CH, Y 7 selected from CH; or Y1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH, Y 5 Selected from C, Y 6 Selected from CH, Y 7 Selected from N; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH, Y 5 Selected from C, Y 6 Selected from N, Y 7 Selected from CH;

[0051] In some embodiments of the present invention,

[0052] Ring D is selected from

[0053] In some embodiments of the present invention, preferably, the compound represented by formula I is represented by the following formula:

[0054] Among them, V, T, Q, A ring, R 1 、R 2 , and L are defined as above.

[0055] R A1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, monomethylamino or dimethylamino.

[0056] R A11 Selected from methyl, ethyl, propyl, cyclopropyl, and halogen-substituted methyl, ethyl, propyl, cyclopropyl.

[0057] In some embodiments of the present invention,

[0058] R 1 Selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, monomethylamino, dimethylamino, deuterated monomethylamino, deuterated dimethylamino;

[0059] Or, R 1 A ring selected from the following:

[0060] In some embodiments of the present invention,

[0061] R 2 Select from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, monomethylamino or dimethylamino.

[0062] In some embodiments of the present invention, Q is selected from CH or N.

[0063] In some embodiments of the present invention,

[0064] Ring B is selected from Where q is 0, 1, 2 or 3;

[0065] Each R B are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR B1 、-C 0～2 Alkylene-NR B1 R B2 ;

[0066] R B1 、R B2 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl;

[0067] The C ring is selected from

[0068] L 1 Selected from chemical bonds, methylene, and ethylene.

[0069] In some embodiments of the present invention, preferably, L is selected from the following structures:

[0070] Among them, the aa end and R 1 The terminal aromatic heterocyclic nitrogen atom is connected, and the bb end is connected to the D ring.

[0071] In some specific embodiments of the present invention, the compound represented by formula I is specifically:

[0072] The present invention also provides the use of any of the above-mentioned compounds, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts in the preparation of a method for treating and preventing diseases related to or mediated by one or more of the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor, and tumor necrosis factor alpha (TNFα).

[0073] Furthermore, the diseases include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver disease, lesions caused by T cell activation, and cardiovascular diseases.

[0074] The present invention also provides a pharmaceutical composition comprising any of the above compounds, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts, and a pharmaceutically acceptable excipient.

[0075] The present invention also provides a treatment method, which comprises administering the above-mentioned pharmaceutical composition to a patient.

[0076] The administration methods include oral administration, external application and / or injection.

[0077] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, CoLumbus, OH) nomenclature system.

[0078] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0079] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0080] "Optionally substituted" means that "substitution" can but must not occur, and the description includes instances where it occurs and instances where it does not occur.

[0081] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0082] The term "alkyl" as used herein refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1～6 Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups, such as C 1～6 Alkoxy.

[0083] The "alkylene" mentioned in the present invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. a～b "Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, "C 1～6 The term "alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structures: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: For another example, "C0 alkylene" means a chemical bond directly connecting two parts.

[0084] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon group having a specified number of carbon atoms and at least one vinyl unsaturated site (>C=C<).a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0085] The term "alkynyl" as used herein refers to a linear monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0086] The "chemical bond" mentioned in the present invention refers to a direct connection via a single chemical bond;

[0087] The "halogen" mentioned in the present invention is fluorine, chlorine, bromine or iodine.

[0088] The "halogen alkyl" and "halogen substituted alkyl" mentioned in the present invention refer to alkyl groups in which the hydrogen atoms may be substituted by one or more halogen atoms. 1～4 Halogenalkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms, such as trifluoromethyl and difluoromethyl.

[0089] The substituents such as “═O” and “═S” described in the present invention refer to an oxygen atom or a sulfur atom replacing two hydrogen atoms to form a double bond, or replacing a lone pair of electrons to form a double bond.

[0090] The "-OR", "-NRR" and the like described in the present invention means that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0091] In the "-C(O)R", "-S(O)2R" and the like described in the present invention, the oxygen atom is double-bonded to a carbon atom, a sulfur atom or a phosphorus atom, and R is single-bonded to a carbon atom or a sulfur atom. In the "-C(O)NRR", "-S(O)2NRR" and the like described in the present invention, the oxygen atom is double-bonded to a carbon atom or a sulfur atom, the nitrogen atom is single-bonded to a carbon atom or a sulfur atom, and R is single-bonded to a nitrogen atom. In the "-NRC(O)R", "-NRS(O)2R" and the like described in the present invention, one R is single-bonded to a nitrogen atom, the other R is single-bonded to a carbon atom or a sulfur atom, the nitrogen atom is single-bonded to a carbon atom or a sulfur atom, and the oxygen atom is double-bonded to a carbon atom or a sulfur atom.

[0092] "Carbocycle" and "carbocyclyl" described in the present invention refer to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (fused). Wherein, the carbon atom includes its oxidation state, such as C (O). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, when the point of attachment is located at a non-aromatic carbon atom, the "carbocycle" and "carbocyclyl" of the term are applicable (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl). The "carbocycle" and "carbocyclyl" of the term include cycloalkenyl groups, such as cyclohexenyl. Examples of carbocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclyl groups including multi-bicarbocyclyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. Two such bicarbocyclyl polycyclic structures are exemplified and named below: Biscyclohexyl and Biscyclohexyl.

[0093] The term "bridged ring" as used herein refers to a saturated or partially saturated cyclic group formed by bridging multiple rings with multiple carbon atoms and no ring heteroatoms. The term "bridged ring" also includes adamantane systems, including but not limited to the following structures:

[0094] The "heterocycle" and "heterocyclic group" mentioned in the present invention refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom and having a single ring or multiple rings (fused); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Among them, carbon atoms and heteroatoms include their oxidation states, such as C(O), S(O), S(O)2, etc. For polycyclic systems with aromatic and non-aromatic rings containing ring heteroatoms, the terms "heterocycle" and "heterocyclic group" are also applicable, for example Typically represents a saturated or partially unsaturated monocyclic or bicyclic ring system of multiple ring atoms. Examples of monocyclic saturated heterocyclyls are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocyclyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, examples of partially unsaturated heterocyclyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl or dihydropyranyl.

[0095] The "bridged heterocycle" mentioned in the present invention refers to a saturated or partially saturated cyclic group formed by bridging multiple rings containing at least one heteroatom.

[0096] As used herein, "aromatic ring" or "aryl" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups typically include monocyclic, bicyclic, or tricyclic aromatic groups. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0097] As used herein, "aromatic heterocycle" and "aromatic heterocyclic group" refer to an aromatic unsaturated ring containing at least one heteroatom; a heteroatom includes a nitrogen atom, an oxygen atom, a sulfur atom, and the like. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Examples of heterocyclic aromatic groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0098] "Stereoisomers" include enantiomers and diastereomers, and racemic or partially racemic mixtures thereof;

[0099] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0100] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0101] In this application, "multiple" refers to two or more. "And / or" describes the relationship between associated objects, indicating that three possible relationships exist. For example, "A and / or B" can mean: A exists alone, A and B exist simultaneously, or B exists alone. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0102] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0103] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG1 shows the therapeutic effect of the compound TM-174 of the present invention on the IMQ psoriasis model.

[0105] FIG2 shows the therapeutic effect of the compound TM-205 of the present invention on the IMQ psoriasis model.

[0106] FIG3 is a statistical diagram showing the therapeutic effect of the compound TM-4 of the present invention on the DSS-induced enteritis model.

[0107] FIG4 is a statistical diagram showing the therapeutic effect of the compound TM-174 of the present invention on the DSS-induced enteritis model.

[0108] FIG5 is a statistical diagram showing the therapeutic effect of the compound TM-205 of the present invention on the DSS-induced enteritis model.

[0109] FIG6 is a statistical diagram showing the therapeutic effect of the compound TM-221 of the present invention on the DSS-induced enteritis model.

[0110] FIG7 is a statistical diagram showing the therapeutic effect of the compound TM-135 of the present invention on the CIA-induced rheumatoid arthritis model.

[0111] FIG8 is a statistical diagram showing the therapeutic results of the compound of the present invention on the MC903-induced idiopathic inflammation model on day 14. DETAILED DESCRIPTION

[0112] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0113] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0114] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-25° C. All temperatures are expressed in degrees Celsius.

[0115] Overnight is 14±1h.

[0116] High-performance liquid chromatography (HPLC) analysis conditions: Waters high-pressure liquid chromatograph (e2695 / e2487). Analytical HPLC conditions: C18 column (3.5 μm, 4.6 x 75 mm), UV detection at 220 and 254 nM, elution: 5-95% acetonitrile (containing 0.1% v / v TFA) gradient over 10 minutes.

[0117] Reverse-phase purification was performed using a Gilson GX-281 reverse-phase preparative chromatograph or a Biotage IsoLera One rapid purification system.

[0118] NMR measurements were performed using a Bruker Avance III 400 or 600 NMR spectrometer. The NMR shift (δ) was measured at 10 -6 The unit of ppm is given. The solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), etc. The internal standard is tetramethylsilane (TMS).

[0119] The known starting materials, reagents and solvents of the present invention can be synthesized by methods known in the art, or can be purchased from Chengdu Jinshan Chemical Reagent Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd.

[0120] The known starting materials, reagents and solvents of the present invention can be synthesized by methods known in the art, or can be purchased from Chengdu Jinshan Chemical Reagent Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd.

[0121] Example

[0122] Synthesis of intermediate IM-1

[0123] Step 1: Synthesis of IM-1c

[0124] IM-1a (876 mg) was dissolved in 16 mL of isopropanol, and IM-1b (919.60 mg) was added. The mixture was heated at 80°C for 4 hours and refluxed. After the formation of new spots, the reaction mixture was cooled to room temperature. Finally, tributylphosphine (1.62 g) was added and the mixture was heated at 80°C for overnight. LC-MS analysis confirmed the completion of the reaction and the formation of the desired product. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EA. The organic phase was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 20:1 to 10:1) to yield 1.23 g of the product. LCMS (ESI) m / z: [M+1] = 380.09.

[0125] Step 2: Synthesis of IM-1e

[0126] IM-1c (2g) and M-1d (2.19g) were dissolved in 20mL of dioxane / H2O (4 / 1). Pd(PPh3)4 (300mg) and potassium phosphate (2.23g) were added sequentially. The atmosphere was replaced with nitrogen and the mixture was heated under reflux at 90°C with stirring overnight. LC-MS analysis confirmed the completion of the reaction and the formation of the desired product. The reaction solution was extracted with EA, and the organic phase was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 5:1 to 1:1) to yield 2.53g of the product. LCMS (ESI) m / z: [M+1] = 591.4.

[0127] Step 3: Synthesis of IM-1

[0128] IM-1e (4.1 g) was dissolved in a mixed solvent of MeOH (164 mL) and DCM (82 mL), and Pd(OH)2 / C (1.23 g) was added. After hydrogen replacement, the mixture was hydrogenated under a hydrogen balloon at room temperature for 4 hours. LCMS confirmed the reaction was complete. The mixture was filtered through celite, and the filter cake was washed with dichloromethane / methanol = 1 / 1 (100 ml x 2). The combined filtrates were dried and dried. 2.8 g of the crude product was purified by high-pressure reverse-phase preparative purification to afford IM-1 (1.5 g). LCMS (ESI) m / z: [M+1] = 413.3.

[0129] Synthesis of intermediates IM-2 to IM-8: The preparation methods of intermediates IM-2 to IM-8 were similar to those of intermediate IM-1, as shown in Table 1.

[0130] Table 1 Compound numbers and structures

[0131] Synthesis of intermediate IM-9

[0132] Synthesis of intermediates IM-9 to IM-39: The preparation methods of intermediates IM-9 to IM-39 were similar to that of intermediate IM-9, as shown in Table 2.

[0133] Table 2 Compound numbers and structures

[0134] Synthesis of intermediate IM-40

[0135] Step 1: Synthesis of IM-40b

[0136] To a 25 mL eggplant-shaped flask, add IM-40a (1 g), Boc-piperazine (0.79 g), and NaCO (0.51 g), along with DMF (10 mL). Stir the mixture at 100°C overnight. Dilute with 4-5 times the original amount of H2O and extract three times with EA. The organic phase is collected, washed twice with H2O and then twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography (PE / EA = 3:1) to obtain the desired product (1.44 g). LCMS (ESI) m / z: [M+1] = 398.10.

[0137] Step 2: Synthesis of IM-40c

[0138] IM-40b (300 mg) and IM-40c (194 mg) were dissolved in dioxane (2 mL), and Cs2CO3 (613.49 mg) and Xantphos (43.58 mg) were added. The N2 atmosphere was replaced three times. Under N2 protection, Pd(OAc)2 (8.45 mg) was added and the N2 replacement was continued three times. The reaction system was stirred at 100°C overnight. The reaction solution was filtered through celite and concentrated. The crude product was purified by column chromatography (PE / EA = 1:1) to obtain the title compound (145 mg). LCMS (ESI) m / z: [M+1] = 552.49.

[0139] Step 3: Synthesis of IM-40

[0140] IM-40d (140 mg, 0.254 mmol) was dissolved in TFA (1 mL), and methanesulfonic acid (0.5 mL, 0.009 mmol) was added. The reaction was stirred at 70°C for 4 hours. The reaction solution was concentrated, the pH was adjusted to neutral with saturated NaOH solution, and then lyophilized. After lyophilization, the solution was reconstituted in DCM / MeOH (10:1), filtered, and concentrated. The product was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 332.29.

[0141] Synthesis of intermediates IM-41 to IM-110: The preparation methods of intermediates IM-41 to IM-110 are similar to that of intermediate IM-40, as shown in Table 3.

[0142] Table 3 Compound numbers and structures

[0143] Synthesis of intermediate IM-111

[0144] Step 1: Synthesis of IM-111a

[0145] IM-40b (1g) and M-1d (1.15g) were dissolved in 20mL dioxane / H2O (4 / 1), and Pd(PPh3)4 (145mg) and potassium phosphate (1.07g) were added successively. The atmosphere was replaced with nitrogen and the mixture was heated under reflux at 90°C with stirring overnight. LC-MS showed that the reaction of the raw materials was complete and the target product was generated. The reaction solution was extracted with EA, and the organic phase was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 1.2g of the product. LCMS (ESI) m / z: [M+1] = 637.3. Step 2: Synthesis of IM-111b

[0146] IM-111a (500 mg) was dissolved in 20 mL of methanol, and 100 mg of Pd / C was added. The hydrogen atmosphere was replaced three times, and the reaction was allowed to react at room temperature overnight. The mixture was filtered and the filtrate was concentrated to obtain 190 mg of crude product, which was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 431.1.

[0147] Step 3: Synthesis of IM-111

[0148] IM-111b (120 mg) was dissolved in 2 mL of dichloromethane and cooled in an ice bath. 0.5 mL of trifluoroacetic acid was added and the mixture was allowed to react at room temperature for 1 hour. The crude product was concentrated and used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 331.1. Synthesis of Intermediates IM-112 to IM-180: The preparation of Intermediates IM-112 to IM-180 was similar to that of Intermediate IM-111, as shown in Table 4.

[0149] Table 4 Compound numbers and structures

[0150] Synthesis of intermediate IM-181

[0151] Step 1: Synthesis of intermediate IM-181b

[0152] Disperse IM-181a (2 g), pyridine (1.3 g), and ammonium bicarbonate (1.3 g) in 15 mL of dioxane, and add Boc2O (2.6 g). After addition, heat the reaction mixture to 60°C and react for 3 hours. Add 45 mL of water to the reaction mixture, filter, and wash the filter cake with a small amount of dioxane. Collect the solid and dry to obtain 1.85 g of a white solid. LCMS (ESI) m / z: [M+1] = 248.1.

[0153] Step 2: Synthesis of intermediate IM-181d

[0154] IM-181c (1.56 g, preparation method adapted from WO2020 / 264499), IM-181b (1.25 g), Cs2CO3 (3.60 g), and Xantphos (532 mg) were dispersed in 20 mL of dioxane. Under nitrogen, Pd2(dba)3 (421 mg) was added, and the air in the reaction system was replaced with nitrogen. The reaction was continued at 80°C under nitrogen for 72 hours. 20 mL of dioxane was added to the reaction solution, and after ultrasonic dispersion, the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by column chromatography to obtain 320 mg of the desired product. LCMS (ESI) m / z: [M+1] = 506.2.

[0155] Step 3: Synthesis of intermediate IM-181

[0156] Compound IM-181d (100 mg) was dissolved in 3 mL of DCM, and DMP (1.3 eq) was added under ice-water bath and stirred for 3 h. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was filtered, separated, dried over anhydrous sodium sulfate, concentrated, and filtered through a chromatography column to obtain compound IM-181 (80 mg). LCMS (ESI) m / z: [M+1] = 504.2.

[0157] Synthesis of intermediates IM-182 to IM-185: The preparation methods of intermediates IM-182 to IM-185 were similar to those of intermediate IM-181, as shown in Table 5.

[0158] Table 5 Compound numbers and structures

[0159] Synthesis of intermediate IM-186

[0160] Step 1: Synthesis of IM-186b

[0161] 5-Bromo-4-fluoro-2-nitrobenzaldehyde (15g) and dimethylamine hydrochloride (9.86g) were dissolved in 150mL of DMSO, and diisopropylethylamine (15.63g) was added. The reaction mixture was allowed to react overnight at 90°C. After completion, the mixture was diluted with water (600mL) and extracted with EA (100mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (PE / DCM = 5 / 1) to obtain 7.53g of the desired product. LCMS (ESI) m / z: [M+1] = 272.98.

[0162] Step 2: Synthesis of IM-186

[0163] IM-186b (2.5 g) was dissolved in 30 mL of isopropanol, followed by the addition of IM-186c (1.43 g). The mixture was reacted at 80°C under a nitrogen atmosphere for four hours, then cooled to 25°C. Tributylphosphine (5.56 g) was then added to the reaction mixture, and the mixture was reacted at 80°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, the organic solvent was removed by vortexing, the mixture was diluted with water (100 mL), and extracted with EA (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 1:1) afforded 4.5 g of the product. LCMS (ESI) m / z: [M+1] = 352.1.

[0164] Synthesis of intermediates IM-187 to IM-196: The preparation methods of intermediates IM-187 to IM-196 were similar to that of intermediate IM-186, as shown in Table 6.

[0165] Table 6 Compound numbers and structures

[0166] Synthesis of intermediate IM-197

[0167] Step 1: Synthesis of IM-197b

[0168] Dissolve pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.5 g, 9.20 mmol) in 15 mL of 1,4-dioxane and stir until clear. Add pyridine (0.727 g, 9.19 mmol), BOC anhydride (3.01 g, 13.79 mmol), and NH4HCO3 (1.45 g, 18.34 mmol). Stir the reaction mixture in a water bath at room temperature for 12 hours. After completion, filter through celite, wash with water, then with 1,4-dioxane, and dry in a vacuum oven to constant weight to obtain the desired product in a 67% yield. LCMS (ESI) m / z: [M+1] = 163.19.

[0169] Step 2: Synthesis of IM-197c

[0170] IM-197b (1 g, 6.17 mmol), IM-175 (2.21 g, 5.60 mmol), Cs2CO3 (4.38 g, 13.44 mmol), and Xantphos (0.649 g, 1.12 mmol) were dissolved in 19 mL of 1,4-dioxane. Pd2(dba)3 (0.513 g, 0.56 mmol) was quickly added. The atmosphere was purged with nitrogen five times and the reaction was continued at 100°C for 16 h. After completion, the reaction was filtered through Celite, dried under vacuum, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford 1.168 g of the desired product. Yield: 61.47%. LCMS (ESI) m / z: [M+1] = 476.49.

[0171] Step 3: Synthesis of IM-197

[0172] Oxalyl chloride (0.434 g, 3.42 mmol) was added to DCM (18 mL). DMSO (0.544 g, 6.96 mmol) in DCM (1 mL) was added dropwise in a dry ice-ethanol bath at -70°C. The mixture was stirred for 0.5 h, followed by the addition of IM-47c (1.1 g, 2.28 mmol) in DCM (7 mL) and the stirring for 30 min. DIPEA (1.47 g, 11.37 mmol) in DCM (2 mL) was then added and stirred for 15-30 min. The mixture was analyzed with acetonitrile and analyzed by LCMS. After completion of the reaction, water (20 mL) was added and the mixture was extracted with DCM (30 mL x 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the desired product. 1 g of product was obtained with a yield of 93.46%. LCMS (ESI) m / z: [M+1] = 476.49.

[0173] Synthesis of intermediates IM-198 to IM-207: The preparation methods of intermediates IM-198 to IM-207 were similar to that of intermediate IM-197, as shown in Table 7.

[0174] Table 7 Compound numbers and structures

[0175] Synthesis of intermediate IM-208

[0176] Step 1: Synthesis of IM-208a

[0177] 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 allowed to react at 80°C for 1 hour. After completion, the reaction was diluted with water (890 mL) and extracted with EA (900 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 4) to obtain the desired product (35 g, 77.6% yield). LCMS (ESI) m / z: [M+1] = 316.12.

[0178] Step 2: Synthesis of IM-208b

[0179] IM-208a (7 g, 22.22 mmol) was dissolved in 231 mL of isopropanol, followed by the addition of tert-butyl 4-aminopiperidine-1-carboxylate (5.34 g, 26.66 mmol). The reaction mixture was reacted at 80°C under nitrogen for four hours, then cooled to 25°C. Tributylphosphine (13.48 g, 66.63 mmol) was then added and the reaction mixture was reacted at 80°C under nitrogen for 16 hours. After completion of the reaction, the organic solvent was removed by vortexing, the mixture was diluted with water (200 mL), and extracted with EA (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 10:1 to PE / EA = 5 / 1) afforded 10 g of the product in a 96.7% yield. LCMS (ESI) m / z: [M+1] = 467.29.

[0180] Step 3: Synthesis of IM-208

[0181] IM-208b (2 g, 4.30 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.77 g, 4.75 mmol), Cs2CO3 (3.36 g, 10.31 mmol), and Xantphos (0.50 g, 0.864 mmol) were dissolved in 20 mL of 1,4-dioxane. Pd2(dba)3 (0.39 g, 0.426 mmol) was quickly added. The atmosphere was purged with nitrogen five times, and the reaction mixture was stirred at 100°C for 16 h. After completion, the reaction was filtered through celite, dried, and purified by column chromatography (DCM / MeOH = 100:1 to DCM / MeOH = 40:1) to obtain 156 mg of the product in a 6.8% yield. LCMS (ESI) m / z: [M+1] = 547.63.

[0182] Synthesis of intermediates IM-209 to IM-212: The preparation methods of intermediates IM-209 to 212 were similar to the preparation of intermediate IM-208, as shown in Table 8.

[0183] Table 8 Compound numbers and structures

[0184] Synthesis of intermediate IM-213

[0185] Step 1: Synthesis of intermediate IM-213b

[0186] A solution of 5-chloro-2-methyl-4-nitroaniline (10 g, 53.6 mmol) in 3M sulfuric acid (100 mL) was placed in an ice bath at 0°C. A solution of sodium nitrite (3.70 g, 53.6 mmol) in water (10 mL) was slowly added dropwise (approximately 1 hour). After the addition was complete, the mixture was stirred in an ice bath for 10 minutes. A solution of potassium iodide (10.7 g, 64.3 mmol) in water was then added. The reaction temperature was maintained at 0°C in an ice bath for 1 hour, then slowly raised to room temperature (25°C). Stirring was continued at 25°C for 1 hour. TLC confirmed the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:0 to 100:1) to yield 1-chloro-5-iodo-4-methyl-2-nitrobenzene (11.6 g, 72% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.04 (s, 1H), 2.43 (s, 3H). Step 2: Synthesis of intermediate IM-213c

[0187] 1-Chloro-5-iodo-4-methyl-2-nitrobenzene (11.6 g, 39.2 mmol) was dissolved in DMF (80 mL). Tetrakistriphenylphosphine palladium (4.53 g, 3.92 mmol) and sodium carbonate (8.31 g, 78.4 mmol) were added, followed by solid zinc cyanide (2.76 g, 23.5 mmol). The mixture was evacuated and the atmosphere was exchanged with nitrogen three times. Stirring was continued at 50°C under nitrogen for 24 hours. TLC confirmed the reaction completion. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (3 x 300 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:0 to 80:1) to yield 5-chloro-2-methyl-4-nitrobenzonitrile (5.99 g, 78% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.82-7.79 (m, 2H), 2.64 (s, 3H).

[0188] Step 3: Synthesis of intermediate IM-213d

[0189] Dissolve 5-chloro-2-methyl-4-nitrobenzonitrile (1g, 5mmol) in glacial acetic acid (10mL). Add water (10mL) and concentrated sulfuric acid (10mL). Heat to 120°C and react overnight. Monitor the reaction by TLC until complete. After cooling the reaction mixture to room temperature, dilute with water (100mL) to precipitate a solid. Filter and dry to obtain an off-white solid, 5-chloro-2-methyl-4-nitrobenzoic acid (0.86g, 80% yield). 1 HNMR (400MHz, CDCl3) δ8.22(1H),7.76(s,1H),2.70(s,3H).

[0190] Step 4: Synthesis of intermediate IM-213e

[0191] 5-Chloro-2-methyl-4-nitrobenzoic acid (0.90 g, 4.15 mmol) was dissolved in methanol (10 mL). Thionyl chloride (0.3 mL, 4.15 mmol) was slowly added dropwise (approximately 1 hour). The mixture was heated to 80°C and refluxed overnight. The reaction was stopped after completion of the reaction as monitored by TLC. The reaction mixture was distilled under reduced pressure, and the solvent was evaporated to dryness. Dichloromethane (10 mL) and saturated sodium bicarbonate solution (20 mL) were added, and the mixture was extracted three times with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded methyl 5-chloro-2-methyl-4-nitrobenzoate (0.84 g, 87% yield) as a pale white solid. 1 H NMR (400MHz, CDCI3): δ8.08(s,1H),7.73(s,1H),3.95(s,3H),2.64(s,3H).

[0192] Step 5: Synthesis of intermediate IM-213f

[0193] Methyl 5-chloro-2-methyl-4-nitrobenzoate (3.1 g, 13.5 mmol) was dissolved in acetonitrile (60 mL). NBS (2.88 g, 16.2 mmol) and AIBN (0.11 g, 0.68 mmol) were added. The mixture was heated to 70°C under a nitrogen atmosphere and refluxed for 16 hours. The reaction was stopped after completion of the reaction as monitored by TLC. The reaction mixture was distilled under reduced pressure to dryness, followed by addition of ethyl acetate (100 mL) and water (100 mL). The mixture was extracted three times with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded methyl 2-bromomethyl-5-chloro-4-nitrobenzoate (3.80 g, 91% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ8.15(s,1H),7.99(s,1H),4.92(s,2H),4.01(s,3H).

[0194] Step 6: Synthesis of intermediate IM-213g

[0195] Methyl 2-bromomethyl-5-chloro-4-nitrobenzoate (3.1 g, 13.5 mmol) was dissolved in methanol (40 mL). (4-Aminocyclohexyl)methanol (2.01 g, 15.6 mmol) was added, followed by triethylamine (3.61 mL, 25.9 mmol) under nitrogen. The mixture was heated to 80°C and refluxed for 16 hours. The reaction was terminated after completion of the reaction as monitored by TLC. The reaction mixture was distilled under reduced pressure, the solvent evaporated, and then purified by silica gel column chromatography to yield a yellow solid (2.40 g, 57% yield). 1 H NMR(400MHz, CDCl3)δ8.01(s,1H),7.91(s,1H),4.44(s,2H),4.25(tt,J=3.6,12.1Hz,1H),3.53(d,J=6.2Hz ,2H),2.01-1.93(m,4H),1.62-1.55(m,2H),1.55-1.49(m,1H),1.46(s,1H),1.28-1.17(m,2H).

[0196] Step 7: Synthesis of intermediate IM-213

[0197] Dissolve IM-213g (4.5g) and diisopropylethylamine (7.2mL) in 45mL of DMSO. Add morpholine (2.42mL) to the reaction mixture, heat to 90°C, and react for 12 hours. Add 150mL of water to the reaction mixture, extract with ethyl acetate, collect the organic layer, wash with water, then with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (PE / EA = 1 / 1) to yield 3.3g. LCMS (ESI) m / z: [M+1] = 376.2.

[0198] Synthesis of intermediates IM-214 to IM-220: The preparation methods of intermediates IM-214 to 220 were similar to the preparation of intermediate IM-213, as shown in Table 9.

[0199] Table 9 Compound numbers and structures

[0200] Synthesis of intermediate IM-221

[0201] Step 1: Synthesis of intermediate IM-221a

[0202] IM-221 (5 g) was dissolved in 50 mL of MeOH / H2O (4 / 1), and iron powder (7.4 g) and ammonium chloride (7.1 g) were added successively. The mixture was heated at 70°C and refluxed for 4 hours. LC-MS confirmed the completion of the reaction. The reaction solution was filtered through celite, the filter cake was washed with DCM / MeOH (10 / 1) solution, the filtrate was collected, concentrated under reduced pressure, and the residue was extracted with DCM. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 4 g of crude product. The product was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 346.2.

[0203] Step 2: Synthesis of intermediate IM-221b

[0204] IM-197a (2.36 g) was dissolved in 30 mL of acetonitrile, and nitrogen-methylimidazole (3.57 g) was added. The mixture was cooled to 0°C, and TCFH (4.26 g) was added. After stirring for 10 minutes, IM-209a (5.00 g) was added. After addition, the reaction was allowed to react at room temperature for 2 hours and quenched with water. The organic solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound IM-221b (700 mg). LCMS (ESI) m / z: [M+1] = 491.24.

[0205] Step 3: Synthesis of intermediate IM-221

[0206] The preparation method of IM-221 is similar to step 3 of the preparation of intermediate IM-197. LCMS (ESI) m / z: [M+1]=489.24.

[0207] Synthesis of intermediates IM-222 to IM-224: The preparation methods of intermediates IM-222 to 224 were similar to the preparation of intermediate IM-221, as shown in Table 10.

[0208] Table 10 Compound numbers and structures

[0209] Synthesis of intermediate IM-225

[0210] Step 1: Synthesis of intermediate 225a

[0211] IM-217 (3.5 g) was dissolved in 50 mL of MeOH / H2O (4 / 1), and iron powder (4.4 g) and ammonium chloride (4.2 g) were added successively. The mixture was heated at 70°C and refluxed overnight. LC-MS confirmed the completion of the reaction. The reaction mixture was filtered through celite, the filter cake was washed with DCM / MeOH (10 / 1) solution, the filtrate was collected, concentrated under reduced pressure, and the residue was extracted with DCM. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2.68 g of crude product. The product was used directly in the next step without purification. LCMS (ESI) m / z: [M+1] = 417.2.

[0212] Step 2: Synthesis of intermediate 225b

[0213] IM-197a (1.1 g) was dissolved in 30 mL of acetonitrile, and nitrogen-methylimidazole (2.04 g) was added. The mixture was cooled to 0°C, and TCFH (2.27 g) was added. After stirring for 10 minutes, IM-225a (2.6 g) was added. After addition, the reaction was incubated at 40°C for 2 hours. The mixture was filtered, and the filter cake was washed with water and acetonitrile, then dried to yield 2.6 g of the product. LCMS (ESI) m / z: [M+1] = 562.2.

[0214] Step 3: Synthesis of Intermediate 225

[0215] IM-225b (200 mg) was dissolved in 4 mL of DCM, cooled to 0°C, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 hours. LC-MS confirmed the reaction was complete. The residue was concentrated and used directly in the next step. LCMS (ESI) m / z: [M+1] = 462.2.

[0216] Synthesis of intermediates IM-226 to IM-228: The preparation method of intermediates IM-226 to 228 was similar to that of intermediate IM-225, as shown in Table 11.

[0217] Table 11 Compound numbers and structures

[0218] Synthesis of intermediate IM-229

[0219] IM-39 (170 mg) was dissolved in 2 mL of acetonitrile, and IBX (208 mg) was added. The mixture was heated to 60°C and allowed to react for 2 hours. LC-MS indicated the reaction was complete. The mixture was cooled to room temperature and filtered through a silica gel pad to obtain the crude product, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+1] = 341.15.

[0220] Synthesis of intermediates IM-230 to IM-244: The preparation method of intermediates IM-230 to 244 is similar to the preparation of intermediate IM-229, as shown in Table 12.

[0221] Table 12 Compound numbers and structures

[0222] Synthesis of intermediate IM-245

[0223] Step 1: Synthesis of intermediate IM-245c

[0224] IM-245a (3 g) was dissolved in iPrOH (30 mL), and IM-245b (3.17 g) was added. The reaction was stirred at 80°C for 1 hour with a plate monitor. The reaction system was cooled to room temperature, nBu3P (9 mL, 36.289 mmol) was added, and the reaction was continued at 80°C for 2 hours. The iPrOH was removed by concentration, and MTBT was added. The temperature was raised to 50°C and the mixture was stirred for 30 minutes. After stirring in an ice-ethanol bath for 30 minutes, the product (3 g) was filtered. LCMS (ESI) m / z: [M-55] = 360.66.

[0225] Step 2: Synthesis of intermediate IM-245d

[0226] To a 50 mL eggplant-shaped flask were added reactants IM-245c (615 mg), IM-1d (616.54 mg), K₃PO₄ (627.19 mg), and a dioxane / H₂O solvent (7 mL, v / v = 4 / 1). Pd(PPh₃)₄ (85.36 mg) was added, and the atmosphere was purged with nitrogen three times. The reaction was stirred at 90°C for 12 h. LCMS indicated complete consumption of the starting material, with the target product detected at t = 1.96 min. The reaction solution was diluted with H₂O (15 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and weighed. The crude product was purified by column chromatography (PE / EA = 3 / 1 to 1 / 1) to yield the product (665 mg). LCMS (ESI) m / z: [M+H] = 627.56.

[0227] Step 3: Synthesis of intermediate IM-245e

[0228] IM-245d (100 mg) was dissolved in DCM / EtOH (1:1) (100 mL). Palladium acetate (10 mg) and activated carbon (100 mg) were added. H₂ was replaced three times and the reaction was carried out at 40°C for 12 h. LCMS showed that the starting material was consumed, and the target product, mass-56, was detected at t = 1.35 min. The reaction solution was filtered through Celite and rinsed repeatedly with DCM / MeOH (10:1). The filtrate was collected and concentrated. The product was used in the next step without purification according to the theoretical yield. LCMS (ESI) m / z: [M+H] = 449.49.

[0229] Step 4: Synthesis of intermediate IM-245

[0230] IM-245e (70 mg) was dissolved in DCM (1 mL), and TFA (0.5 mL) was added under ice-water bath. The reaction was stirred for half an hour. The reaction solution was concentrated and used directly in the next step without purification. LCMS (ESI) m / z: [M+H] = 349.29.

[0231] Synthesis of intermediates IM-246 to IM-265: The preparation methods of intermediates IM-246 to 265 were similar to that of intermediate IM-245, as shown in Table 13.

[0232] Table 13 Compound numbers and structures

[0233] Synthesis of intermediate IM-266

[0234] Step 1: Synthesis of intermediate IM-266a

[0235] IM-245c (1.9 g), 4A molecular sieves (1 g), K₃PO₄ (1.94 g), and IM-40c (0.13 g) were dispersed in dioxane (20 mL). CuI (0.17 g, 0.913 mmol) was added. The atmosphere was replaced with nitrogen three times, then the temperature was raised to 120°C and the reaction was allowed to react for 48 hours. The reaction solution was filtered through celite, washed with dioxane, and dried to obtain the crude product. Purification by column chromatography (PE / EA = 3:1 to 0:1) afforded the product (1.5 g). LCMS (ESI) m / z: [M+23] = 592.36.

[0236] Step 2: Synthesis of intermediate IM-266

[0237] IM-266a (1.5 g) was added sequentially with TFA (27 mL) and TfOH (2.7 mL), then heated to 70°C and stirred for 12 h. The reaction mixture was concentrated in vacuo to yield a residue, which was then adjusted to pH 7-8 with TEA at 0°C. The crude product was then slurried with EA, stirred for 0.5 h, and filtered to yield the filter cake. LCMS (ESI) m / z: [M+H] = 350.29.

[0238] Synthesis of intermediates IM-267 to IM-273: The preparation methods of intermediates IM-267 to 273 were similar to the preparation of intermediate IM-266, as shown in Table 14.

[0239] Table 14 Compound numbers and structures

[0240] Synthesis of intermediate IM-274

[0241] Step 1: Synthesis of intermediate IM-274a

[0242] IM-186 (534 g) was dissolved in DMF (3000 mL), and imidazole (154.80 g) was added. TBSCl (239.89 g) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EA. The organic phase was collected, washed twice with water and twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 10:1 to 5:1) afforded the product (510.67 g). LCMS (ESI) m / z: [M+H] = 466.34.

[0243] Step 2: Synthesis of intermediate IM-274b

[0244] To a 100 mL three-necked flask, add reactant IM-24a (1.71 g, 2.876 mmol) and anhydrous THF (20 mL). Cool to -75°C. Add n-BuLi (5.573 mL, 13.932 mmol) dropwise via syringe. Stir for 1 hour. Under nitrogen, add crushed dry ice. After addition, gradually warm to room temperature and stir overnight. Quench the reaction with saturated ammonium chloride. Extract with EA. Collect the organic phase, wash twice with water and twice with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. LCMS (ESI) m / z: [M+H] = 432.18.

[0245] Step 3: Synthesis of intermediate IM-274d

[0246] IM-274b (300 mg) was dissolved in DMF (3 mL), and DIEA (0.233 mL) was added. HATU (244.57 mg) was then added at 0°C. After addition, the reaction was allowed to react for 5-10 minutes and monitored by LCMS. After activation, IM-274c (91.44 mg) was added and the system was allowed to react overnight at room temperature. The mixture was diluted with water and extracted with EA. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. Purification: Wet loading and column chromatography (PE / EA = 10:1 to 5:1) afforded 150 mg of the desired product. LCMS (ESI) m / z: [M+H] = 548.18.

[0247] Step 4: Synthesis of intermediate IM-274e

[0248] IM-274d (1 g) was dissolved in CH3CN (14 mL), and HF.Py (0.164 mL) was added under ice-cooling. The mixture was allowed to warm to room temperature for 4 h. LCMS (N230736-4411.17 min 435.24) indicated complete reaction of the starting material. Saturated Na2CO3 solution was added, and the mixture was extracted with EA. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. Column chromatography (DCM:MeOH = 60:1 to 20:1) afforded 400 mg of the product. LCMS (ESI) m / z: [M+H] = 434.66.

[0249] Step 5: Synthesis of intermediate IM-274

[0250] IM-274e (30 mg, 0.069 mmol) was dissolved in DCM (1 mL). DMP (38.16 mg, 0.090 mmol) was added in an ice-water bath and stirred for 3 h before detection. The mixture was diluted with water and extracted with DCM. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (DCM:MeOH = 80:1 to 60:1) afforded 11 mg of the product. LCMS (ESI) m / z: [M+H] = 432.2.

[0251] Synthesis of intermediate IM-275

[0252] Step 1: Synthesis of intermediate IM-275b

[0253] IM-275a (5 g) was added to a reaction flask containing ACN, followed by NBS (5 g) and AIBN (358 mg). The reaction was continued at 70°C under nitrogen for 16 hours. After completion, the reaction was cooled to room temperature, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and dried by spin drying. The product was then passed through a silica gel column (PE-PE:EA 50:1) to obtain 3 g of the desired product.

[0254] Step 2: Synthesis of intermediate IM-275c

[0255] IM-275b (2 g) was added to a reaction flask, followed by a methanol solution and 1-Boc-4-aminopiperidine (1.56 g). TEA (1.81 mL) was added dropwise with stirring, and the mixture was allowed to react at 80°C under nitrogen for 16 hours. After completion, the reaction was cooled to room temperature, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and dried by spin drying. The product was then passed through a silica gel column (PE:EA = 6:1-3:1) to yield 2.2 g. LCMS (ESI) m / z: [M+H] = 395.10.

[0256] Step 3: Synthesis of IM-275d

[0257] IM-275c (1 g) and IM-40c (0.65 g) were dissolved in dioxane (10 mL), and CsCO (2.06 g) and Xantphos (0.15 g) were added. The N2 atmosphere was replaced three times. Under N2 protection, Pd(OAc) (0.03 g) was added and N2 replacement was continued three more times. The reaction system was stirred at 100°C overnight. The reaction solution was filtered through celite and concentrated. The crude product was purified by column chromatography (pure EA) to give 1.34 g of a white solid. LCMS (ESI) m / z: [M+H] = 549.53.

[0258] Step 4: Synthesis of IM-275

[0259] IM-275d (100 mg) was dissolved in TFA (1 mL), and methanesulfonic acid (0.5 mL) was added. The reaction was stirred at 70°C for 4 hours. LCMS monitoring showed complete consumption of the starting material. The solvent was partially removed, and the pH was adjusted to neutral with saturated sodium hydroxide solution. The mixture was lyophilized and then rinsed with DCM / MeOH (10:1). The mixture was filtered and the filtrate was concentrated. The crude product was used directly in the next step without purification. LCMS (ESI) m / z: [M+H] = 329.36.

[0260] Synthesis of intermediate IM-276

[0261] The preparation method of intermediate IM-276 is similar to that of IM-275. LCMS (ESI) m / z: [M+H]=329.37.

[0262] Synthesis of intermediate IM-277

[0263] Step 1: Synthesis of intermediate IM-277b

[0264] Dissolve IM-277a (5 g), N-Boc-4-hydroxypiperidine (5.08 g), and triphenylphosphine (6.62 g) in 50 mL of anhydrous tetrahydrofuran, cool in an ice bath, and add DIAD (5 mL) dropwise. Stir at room temperature overnight. Concentrate, mix, and column chromatography (PE / EA = 1 / 1) to obtain 4 g of the title compound. LCMS (ESI) m / z: [M+H] = 381.06.

[0265] Step 2: Synthesis of intermediate IM-277c

[0266] IM-276c was replaced with IM-277b. The preparation method of IM-277c was the same as that of IM-276d. LCMS (ESI) m / z: [M+H] = 535.15.

[0267] Step 3: Synthesis of intermediate IM-277

[0268] IM-276d was replaced by IM-277c. The preparation method of IM-277 was the same as that of IM-276. LCMS (ESI) m / z: [M+H] = 315.08.

[0269] Synthesis of intermediate IM-278

[0270] Step 1: Synthesis of intermediate IM-278b

[0271] To a 250 mL eggplant flask, add the reactants IM-288a (10 g), NBS (9.13 g), and the solvent CH3CN (100 mL), followed by dibenzoyl peroxide (0.69 g). Reflux for 6 h, then add an additional 0.6 eq of NBS. After addition, let the reaction proceed overnight, concentrate, add dichloromethane to slurry, filter, and concentrate the filtrate. Column chromatography (0-20% EA in PE) yields the desired product (10 g). Step 2: Synthesis of Intermediate IM-278c

[0272] To a 100 mL eggplant-shaped flask, add IM-288b (5 g), 4A molecular sieves, and CHCN (50 mL) followed by N-methylmorpholine oxide (3.74 g). Stir at room temperature for 3 hours and extract with EA. The combined organic layers are washed with dilute hydrochloric acid, saturated brine, and dried over sodium sulfate. Filter, concentrate, and column chromatography (0-10% EA in PE) yields the desired product (3.2 g).

[0273] Step 3: Synthesis of intermediate IM-278d

[0274] IM-278c (2 g) was dissolved in 20 mL of isopropanol, and 1-Boc-4-aminopiperidine (1.94 g) was added. The mixture was heated at reflux at 80°C for 2 h. Tributylphosphine (4.08 g) was then added, and the mixture was heated at reflux at 80°C overnight. LC-MS analysis confirmed the completion of the reaction and the formation of the desired product. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EA. The organic phase was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 20:1 to 10:1) to yield 2.5 g of the product. LCMS (ESI) m / z: [M+1] = 398.10.

[0275] Step 4: Synthesis of intermediate IM-278e

[0276] IM-277b was replaced by IM-278d, and the preparation method of IM-278e was the same as IM-276d. LCMS (ESI) m / z: [M+H] = 552.14.

[0277] Step 5: Synthesis of intermediate IM-278

[0278] IM-277c was replaced by IM-278e. The preparation method of IM-278 was the same as that of IM-276. LCMS (ESI) m / z: [M+H] = 332.16.

[0279] Synthesis of intermediate IM-279

[0280] Step 1: Synthesis of intermediate IM-279b

[0281] IM-279a (10 g) was dissolved in DCM and stirred at 0°C for 10 min. 68% HNO₃ (6.93 mL) was then added dropwise. The solution turned from pale yellow to a clear orange-red color and reacted at room temperature for 4 h. After the reaction was complete, the product was extracted with DCM, dried over anhydrous sodium sulfate, filtered, spin-dried, and passed through a column (PE-PE:EA = 30:1). The product was a yellow solid.

[0282] Step 2: Synthesis of intermediate IM-279c

[0283] IM-279b (5 g) was dissolved in DMF, and 4,4'-bipyridine (0.17 g) was added. B2(OH)4 (5.7 g) was then added portionwise. A vigorous exotherm occurred, and the reaction solution turned from yellow to purple-red. The reaction was allowed to react at room temperature for 20 min. After completion, the solution was diluted with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the product. The product was a black oil. It was used directly in the next step without purification. LCMS (ESI) m / z: [M+H] = 207.

[0284] Step 3: Synthesis of intermediate IM-279e

[0285] IM-279c (4 g) and IM-279d (4.45 g) were added to a reaction flask, followed by the addition of polyphosphoric acid and toluene (1:1). The mixture was allowed to react at 190°C for 6 h. The pH was then adjusted to 9 with NaOH solution, and di-tert-butyl dicarbonate (6.36 g) was added and allowed to react for 3 h. The reaction solution was extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE:EA 10:1-6:1) to obtain 5 g of the desired product. LCMS (ESI) m / z: [M+H] = 399.06.

[0286] Step 4: Synthesis of intermediate IM-279f

[0287] In a 25 mL eggplant-shaped flask, reactants IM-279e (190 mg), IM-1d (198.59 mg), K3PO4 (202.02 mg) and solvent dioxane-water = 4:1 (3 mL) were added, and finally Pd(PPh3)4 (27.50 mg) was added. The reaction was heated at 90°C, replaced with nitrogen three times, and stirred under N2 protection for 12 h. LCMS showed that the starting material was completely consumed, and the mass value of the target product was detected at t = 2.10 min. The reaction solution was diluted with H2O (15 mL) and extracted with ethyl acetate (5 mL*3). The organic phase was collected, washed twice with saturated brine, and finally dried over anhydrous sodium sulfate, filtered, concentrated and weighed. The crude product was purified by column chromatography (PE / EA = 10 / 1-3 / 1) to obtain the product (145 mg). LCMS (ESI) m / z: [M+H] = 610.3.

[0288] Step 5: Synthesis of intermediate IM-279g

[0289] IM-279f (145 mg, 0.238 mmol) was dissolved in DCM / EtOH (1:1) (100 mL). Pd(OAc)2 (15 mg, 0.067 mmol) and activated carbon (145 mg, 0.033 mmol) were added. H2 was replaced three times and the mixture was allowed to react at 40°C for 12 h. The reaction mixture was filtered through Celite and rinsed repeatedly with DCM / EtOH (1:1). The filtrate was collected and concentrated. The crude product was used directly in the next step. LCMS (ESI) m / z: [M+Na] = 454.25.

[0290] Step 6: Synthesis of intermediate IM-279

[0291] IM-279g (40 mg) was dissolved in DCM (1 mL), and TFA (0.5 mL) was added under ice-water bath. The reaction was stirred for half an hour. The reaction solution was concentrated and used directly in the next step without purification. LCMS (ESI) m / z: [M+H] = 332.09.

[0292] Synthesis of intermediate IM-280

[0293] Step 1: Synthesis of intermediate IM-280b

[0294] IM-279c was replaced by IM-280a, and the preparation method of IM-280b was the same as IM-279e. LCMS (ESI) m / z: [M+H] = 381.01.

[0295] Step 2: Synthesis of intermediate IM-280c

[0296] IM-280b (1 g) and IM-40c (0.74 g) were dissolved in dioxane (10 mL). K₃PO₄ (1.11 g), CuI (100 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 68737-65-5, 70 mg), and 4A (500 mg) were added. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction system was stirred at 100°C overnight. The reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography to yield 700 mg. LCMS (ESI) m / z: [M+H] = 535.14.

[0297] Step 3: Synthesis of intermediate IM-280

[0298] IM-280c ​​(500 mg) was dissolved in TFA (5 mL) and TfOH (0.5 mL), then heated to 70°C and stirred for 12 h. The reaction mixture was concentrated in vacuo to yield a residue. The pH was adjusted to 7-8 with TEA at 0°C and concentrated to yield the crude product. The residue was then slurried with EA and filtered to yield the product. LCMS (ESI) m / z: [M+H] = 315.10.

[0299] Synthesis of intermediate IM-281

[0300] IM-280a was replaced by IM-281a. The preparation method of IM-281 was the same as that of IM-280. LCMS (ESI) m / z: [M+H]=315.13.

[0301] Synthesis of intermediates IM-282 and IM-283

[0302] Step 1: Synthesis of intermediate IM-282b

[0303] IM-282a (1 g) and (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (0.85 g) were dissolved in 10 mL of DMF, and KCO (0.67 g) was added. The mixture was stirred at 100°C overnight. Water (50 mL) was slowly added to the reaction system, and the mixture was extracted three times with EtOAc. The mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product. Column chromatography (PE:EA = 1:0 to PE:EA = 10:1) yielded 830 mg of the product. LCMS (ESI) m / z: [M+H] = 412.13.

[0304] Step 2: Synthesis of intermediate IM-282c

[0305] IM-280b was replaced by IM-282c, which was prepared by the same method as IM-280c. LCMS (ESI) m / z: [M+H] = 566.52.

[0306] Step 3: Synthesis of intermediate IM-282

[0307] IM-282c (80 mg) was dissolved in 2 mL of a 1:2 TFA:MsOH solution and stirred at 70°C overnight. The reaction mixture was concentrated, adjusted to pH 7-8 with aqueous NaOH, and lyophilized. The sample was dissolved in a 10:1 DCM:MeOH solution, filtered, and the filtrate was concentrated to obtain the product. LCMS (ESI) m / z: [M+H] = 346.33.

[0308] Steps 4 to 6: Synthesis of intermediate IM-283

[0309] IM-279e was replaced by IM-282b, and the preparation method of IM-283 was the same as that of IM-279. LCMS (ESI) m / z: [M+H]=345.14.

[0310] Synthesis of intermediates IM-284 to IM-289: The preparation method of intermediates IM-284 to 287 is similar to the preparation of intermediate IM-282, and the preparation method of intermediates IM-288 to 289 is similar to the preparation of intermediate IM-283, as shown in Table 15.

[0311] Table 15 Compound numbers and structures

[0312] Synthesis of intermediate IM-290

[0313] Step 1: Synthesis of intermediate IM-290b

[0314] IM-1a (2 g) was dissolved in isopropanol (20 mL), and IM-290a (2.07 g) was added. The temperature was raised to 80°C for 2 hours. The temperature was then lowered and tributylphosphine (6.515 mL) was added. The temperature was raised to 80°C and stirred overnight. The reaction mixture was concentrated under reduced pressure, MTBE was added to slurry, and the filter cake was collected by filtration to obtain 2 g of the product. LCMS (ESI) m / z: [M+H] = 378.29.

[0315] Steps 2 to 3: Synthesis of intermediate IM-290

[0316] IM-280b was replaced by IM-290b. The preparation method of IM-290 was the same as that of IM-280. LCMS (ESI) m / z: [M+H]=312.34.

[0317] Synthesis of intermediates IM-291 to IM-299: The preparation method of intermediates IM-281 to 299 was similar to that of intermediate IM-290, as shown in Table 16.

[0318] Table 16 Compound numbers and structures

[0319] Synthesis of intermediate IM-300

[0320] IM-1 (70 mg) was dissolved in DCM (3 mL), and TFA (1 mL) was added at 0°C. The mixture was allowed to react at room temperature for two hours. The DCM solution was redissolved several times and then dried to give the product, which was used directly in the next step without purification. LCMS (ESI) m / z: [M+H] = 313.41.

[0321] Synthesis of intermediates IM-301 to IM-308: The preparation methods of intermediates IM-301 to 308 were similar to the preparation of intermediate IM-300, as shown in Table 17.

[0322] Table 17 Compound numbers and structures

[0323] Synthesis of intermediate IM-309

[0324] Step 1: Synthesis of intermediate IM-309c

[0325] IM-309b (500 mg) and IM-309a (282.5 mg) were dissolved in EtOH (5 mL). The atmosphere was purged with nitrogen three times, then the temperature was raised to 60°C and allowed to react over the weekend. The mixture was concentrated, and saturated NaHCO₃ solution was added. Extraction with EA was performed, and the organic layer was dried over sodium sulfate, concentrated, and purified by column chromatography (25% EA in PE) to yield 496 mg of the product. LCMS (ESI) m / z: [M+H] = 380.10.

[0326] Steps 2 to 3: Synthesis of intermediate IM309

[0327] IM-280b was replaced by IM-309c. The preparation method of IM-309 was the same as that of IM-280. LCMS (ESI) m / z: [M+H]=314.14.

[0328] Synthesis of intermediates IM-310 to IM-314: The preparation method of intermediates IM-310 to 314 is similar to the preparation of intermediate IM-309, as shown in Table 18.

[0329] Table 18 Compound numbers and structures

[0330] Synthesis of intermediate IM-315

[0331] Step 1: Synthesis of intermediate IM-315b

[0332] IM-1a (2.5 g) was dissolved in iPrOH (25 mL), and IM-315a (2.66 g) was added. The reaction was stirred at 80°C for 2 hours with a plate monitor. The reaction system was cooled to room temperature, and nBu3P (8.14 mL) was added. The reaction was continued at 80°C for 16 hours. The iPrOH (25 mL) was removed by concentration, and the mixture was diluted with H2O (30 mL). The mixture was extracted with EA (20 mL x 3). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography (PE / EA = 20:1 to PE / EA = 5:1) yielded 4 g of the product. LCMS (ESI) m / z: [M+H] = 383.98, 386.42.

[0333] Step 2: Synthesis of intermediate IM-315c

[0334] IM-315b (430 mg) and IM-40c (288.35 mg) were dissolved in dioxane (5 mL), and Cs2CO3 (437.54 mg), Xantphos (64.75 mg), and Pd(OAc)2 (12.56 mg) were added. The atmosphere was purged with nitrogen three times, and the reaction was allowed to proceed at 100°C overnight. The reaction mixture was filtered through celite, washed with 1,4-dioxane, and dried to obtain the crude product. The product was purified by column chromatography (PE / EA = 1:1 to 0:1) to obtain 100 mg. LCMS (ESI) m / z: [M+H] = 538.59.

[0335] Step 3: Synthesis of intermediate IM-315

[0336] IM-315c (200 mg) was sequentially added with TFA (2 mL) and TfOH (0.2 mL), and the mixture was heated to 70°C and stirred for 3 h. The reaction mixture was concentrated in vacuo to obtain a residue, which was adjusted to pH 7-8 with TEA at 0°C and concentrated to yield the crude product. The product was used in the next step without purification. LCMS (ESI) m / z: [M+H] = 318.26.

[0337] Synthesis of intermediates IM-316 to IM-337: The preparation method of intermediates IM-316 to 337 is similar to the preparation of intermediate IM-315, as shown in Table 19.

[0338] Table 19 Compound numbers and structures

[0339] Synthesis of intermediate 338

[0340] Step 1: Synthesis of intermediate IM-338a

[0341] IM-1a (3 g) and IM-1d (6.53 g) were dissolved in dioxane:H2O = 4:1 (30 mL). K3PO4 (5.54 g) and Pd(PPh3)4 (0.75 g) were added. The atmosphere was replaced with nitrogen three times, then the temperature was raised to 90°C and the reaction was allowed to react for 12 h. The mixture was diluted with water and extracted with EA. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The product was purified by column chromatography (PE / EA = 10:1 to 5:1) to obtain the product (5.78 g). LCMS (ESI) m / z: [M+H] = 441.04.

[0342] Step 2: Synthesis of intermediate IM-338b

[0343] IM-338a (2.5 g) was dissolved in isopropanol (40 mL), IM-315a (1.28 g) was added, and the mixture was refluxed at 80 degrees for 30 min. Then tri-n-butylphosphine (15.107 mL, 60.481 mmol) was added and the mixture was reacted at 80 degrees overnight. The reaction solution was poured into water, extracted with ethyl acetate (40 mL) three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude product. Purification by column chromatography (PE / EA=5:1~1:1) gave 1.24 g of the product. LCMS (ESI) m / z: [M+H]=595.63. Step 3: Synthesis of intermediate IM-338c

[0344] IM-338b (500 mg) was dissolved in DCM:EtOH (500 mL), and activated carbon (20 mg) and palladium acetate (50 mg) were added. The mixture was replaced with hydrogen three times, then heated to 40°C and allowed to react for 48 hours. The product was filtered through Celite and dried to dryness. LCMS (ESI) m / z: [M+H] = 417.57.

[0345] Step 4: Synthesis of intermediate IM-338

[0346] In a 25 ml round-bottom flask, IM-338c (170 mg) was dissolved in DCM (2 mL). TFA (1 mL, 13.059 mmol) was added at 0-10°C and allowed to react for 1 h. The reaction solution was concentrated in vacuo to dryness, rinsed three times with DCM, and used directly in the next step, yielding 100%. LCMS (ESI) m / z: [M+H] = 317.18.

[0347] Synthesis of intermediates IM-339 to IM-345: The preparation methods of intermediates IM-339 to IM-345 were similar to the preparation of intermediate IM-338, as shown in Table 20.

[0348] Synthesis of intermediates IM-346 to IM-348: The preparation method of intermediates IM-346 to IM-348 is similar to the preparation of intermediate IM-280, as shown in Table 21.

[0349] Synthesis of intermediate IM-349

[0350] Step 1: Synthesis of intermediate IM-349b

[0351] IM-186b (5.0 g) was dissolved in isopropanol (60 mL), and IM-349a (2.88 g) was added. The mixture was refluxed at 80 degrees for 4 hours, and then tri-n-butylphosphine (13.72 mL) was added and the mixture was reacted at 80 degrees overnight. Part of the organic reagent was removed by vortexing, and the reaction solution was poured into water. The mixture was extracted with ethyl acetate (40 mL) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude product. Column chromatography purification (PE / EA=5:1~0:1) gave 4 g of the product. LCMS (ESI) m / z: [M+H]=355.13. Steps 2 to 3: Synthesis of intermediate IM-349

[0352] IM-187 was replaced by IM-349b. The preparation of IM-349 was the same as that of IM-197. LCMS (ESI) m / z: [M+H]=434.49.

[0353] Synthesis of intermediate IM-350

[0354] Step 1: Synthesis of intermediate IM-350b

[0355] IM-350a (4.8 g) was dissolved in DMSO (48 mL), and a solution of dimethylamine (48 mL) and DIEA (4.030 mL) were added. The mixture was allowed to react at 100°C for 48 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate:tetrahydrofuran (4:1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using a dry-phase loading method (PE / EA = 10:1 to PE / EA = 1:1) to obtain the product (1.76 g). LCMS (ESI) m / z: [M+H] = 216.17.

[0356] Step 2: Synthesis of intermediate IM-350d

[0357] IM-350b (670 mg) was dissolved in EtOH (10 mL), and IM-350c (1008.50 mg) and tetrahydropyrrole (0.026 mL) were added. The temperature was raised to 80°C and refluxed overnight. The reaction mixture was directly purified by column chromatography using PE / EA = 10 / 1 to 1 / 1 to obtain the desired product. LCMS (ESI) m / z: [M+H] = 442.34.

[0358] Step 3: Synthesis of intermediate IM-350f

[0359] IM-350d (757 mg) and IM-350e (0.316 mL) were dissolved in toluene (8 mL), and sodium tert-butoxide (246.66 mg), XantPhos (99.01 mg, and palladium acetate (19.21 mg) were added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 110° and refluxed overnight. The mixture was filtered through celite, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1-20 / 1) to give the product (0.92 g). LCMS (ESI) m / z: [M+H] = 543.77.

[0360] Step 4: Synthesis of intermediate IM-350g

[0361] IM-350f (920 mg) was dissolved in THF / 3N HCl (1 / 1) (10 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to remove THF and extracted with ethyl acetate. The aqueous phase was collected and the pH was adjusted to neutral with NaOH solution. The mixture was further extracted with DCM / MeOH (10 / 1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / 50 / 1 to 20 / 1) afforded 640 mg of the product. LCMS (ESI) m / z: [M+H] = 379.33.

[0362] Step 5: Synthesis of intermediate IM-350h

[0363] IM-350g (640 mg, 1.691 mmol) was dissolved in DCM (8 mL), and IM-197a (689.59 mg) and pyridine (0.684 mL) were added. Phosphorus oxychloride (0.394 mL, 4.227 mmol) was added under an ice-salt bath and stirred overnight. The reaction mixture was quenched with water and extracted three times with DCM. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) afforded 246 mg of the product. LCMS (ESI) m / z: [M+H] = 524.44.

[0364] Step 6: Synthesis of intermediate IM-350i

[0365] IM-350h (246 mg) was dissolved in DCM (3 mL), and boron trichloride (1.719 mL) was added at 0°C, and the reaction was stirred overnight. The reaction solution was quenched with sodium bicarbonate solution and extracted with DCM / MeOH = 10 / 1. Due to insufficient extraction, it was extracted three times with EA / THF = 4 / 1. The product was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) gave 190 mg of the product. LCMS (ESI) m / z: [M+H] = 434.41.

[0366] Step 7: Synthesis of intermediate IM-350

[0367] IM-350i (190 mg) was dissolved in DCM (3 mL), and DMP (241.66 mg) was added at zero degrees Celsius. The reaction mixture was washed with saturated sodium bicarbonate solution and extracted three times with DCM. The organic phase was collected, washed further with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) afforded 100 mg of the product. LCMS (ESI) m / z: [M+H] = 432.47.

[0368] Synthesis of intermediate IM-351

[0369] Step 1: Synthesis of intermediate IM-351b

[0370] IM-351a (3 g) was dissolved in EtOH (30 mL), and dimethylamine hydrochloride (1.76 g) and DIEA (3.761 mL) were added. The reaction system was heated to 60°C and refluxed overnight. The reaction solution was concentrated. Column chromatography (PE / EA = 10 / 1 to 1 / 1) afforded 1.6 g of the product. LCMS (ESI) m / z: [M+H] = 216.80, 218.80.

[0371] Steps 2 to 7: Synthesis of intermediate IM-351

[0372] IM-350b was replaced by IM-350b. The preparation method of IM-351 was the same as that of IM-350. LCMS (ESI) m / z: [M+H]=433.34.

[0373] Synthesis of intermediate IM-352

[0374] Step 1: Synthesis of intermediate IM-352b

[0375] IM-352a (25 g) was dissolved in DCM (250 mL). Dimethylamine hydrochloride (12.23 g) and DIEA (47.484 mL) were added at 0°C and allowed to react overnight at room temperature. The reaction mixture was poured into water and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 26 g of the crude product. This product was used directly in the next step without purification. LCMS (ESI) m / z: [M+H] = 193.53.

[0376] Step 2: Synthesis of intermediate IM-352c

[0377] IM-352b (26 g) and 4-methoxybenzylamine (26.5 mL) were dissolved in DMSO (400 mL). DIEA (67.3 mL) was added, the nitrogen atmosphere was replaced three times, and the reaction was allowed to proceed at 120°C overnight. The reaction solution was poured into water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Purification by column chromatography (PE / EA = 10:1 to 2:1) afforded 15.6 g of the product. LCMS (ESI) m / z: [M+H] = 293.96.

[0378] Step 3: Synthesis of intermediate IM-352d

[0379] IM-352c (14 g) was dissolved in TFA (11.770 mL) and reacted at 100 degrees overnight. The reaction solution was poured into water, and the pH was adjusted to neutral with TEA. The organic phase was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The crude product was passed through a normal phase column. A light yellow solid was obtained by pure EA. LCMS (ESI) m / z: [M+H] = 173.64. Step 4: Synthesis of intermediate IM-352e

[0380] IM-352d (1.5g) and IM-350c (3.11g) were dissolved in ethanol (15mL), and tetrahydropyrrole (0.073mL, 0.869mmol) and NaHCO3 (2.19g) were added. The nitrogen was replaced three times and the reaction was carried out at 80 degrees overnight. The reaction solution was poured into water, extracted three times with ethyl acetate (10mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The crude product was passed through a normal phase column. A light yellow oil (1.1g) was obtained by PE / EA=1:1. LCMS (ESI) m / z: [M+H]=399.2. Step 5: Synthesis of intermediate IM-352f

[0381] IM-352e (1.6 g), IM-197b (0.72 g), sodium tert-butoxide (0.54 g), BINAP (0.50 g), and Pd2(dba)3 (0.37 g) were dissolved in dioxane (20 mL). The atmosphere was replaced with nitrogen three times, then heated to 110°C for 12 h. The reaction mixture was filtered through celite, washed with 1,4-dioxane, and dried to obtain the crude product. Purification by column chromatography (PE / EA = 2:1 to 1:1 to DCM:MEOH = 80:1 to 40:1) afforded IM-352f (170 mg, 0.324 mmol, 8.08%) as a yellow solid. LCMS (ESI) m / z: [M+H] = 525.48.

[0382] Steps 6 to 7: Synthesis of intermediate IM-352

[0383] IM-350b was replaced by IM-352f. The preparation method of IM-352 was the same as that of IM-350. LCMS (ESI) m / z: [M+H]=433.21.

[0384] The following is the synthesis of the compound of the present invention.

[0385] Example 1: Synthesis of TM-1

[0386] IM-197 (106 mg) and IM-301 (70 mg) were dissolved in 5 mL of THF / DMF (4:1). Under an ice-salt bath, 100 mg of molecular sieves, DIPEA (43 mg), and NaBH(OAc)3 (71 mg) were added sequentially. The mixture was gradually warmed to room temperature and allowed to react overnight. Water was added to precipitate a solid, which was then filtered. The filter cake was dissolved in DCM / MEOH (10:1) and filtered through Celite. The filtrate was concentrated. The crude product was purified by preparative separation to yield 48.8 mg of a white solid. LCMS (ESI) m / z: [M+1] = 770.95. 1H NMR (600MHz, DMSO-d6) δ10.84(s,1H),10.67(s,1H),9.39(dd,J=7.0,1.6Hz,1H),8.98(dd,J=4.2,1.6Hz,1H),8.75(s,1H),8.7 2(s,1H),8.40(d,J=1.0Hz,1H),8.33(d,J=0.9Hz,1H),7.63(d,J=8.6Hz,1H),7.45(s,1H),7.42(s,1H),7.36(dd,J=7.0,4.2Hz ,1H),6.88(dd,J=8.6,1.4Hz,1H),4.58–4.27(m,2H),4.03–3.69(m,5H),3.29(s,2H),3.01(br,2H),2.97–2.82(m,4H),2.72-2 .65(m,1H),2.53-2.50(m,1H),2.34–2.20(m,3H),2.20–2.03(m,7H),2.03–1.87(m,4H),1.70-1.59(m,1H),1.19–1.09(m,2H).

[0387] Synthesis of compounds TM-2 to TM-251: The preparation methods of compounds TM-2 to TM-251 are similar to the preparation of product TM-1, as shown in Table 22.

[0388] Table 22 Compound numbers and structures

[0389] The following test examples illustrate the beneficial effects of the compounds of the present invention.

[0390] The positive compound used in this invention is from Kymera Therapeutics, Inc., patent number WO2020113233. The structure is as follows:

[0391] Test Example 1: Inhibitory effect of the compounds of the present invention on R848-induced IL-6 secretion in human peripheral blood mononuclear cells (PBMC)

[0392] (1) Experimental methods:

[0393] This experiment was performed in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin. The initial concentration of the compound was 1 μM. The compound was dissolved in DMSO to form a stock solution, and then diluted with culture medium in a 4-fold concentration gradient to form a series of working solutions. 10 μL was added to each well of a 96-well plate. PBMC (lot number: P122101102C, Miaoshun Biotechnology Co., Ltd.) cells were counted and diluted to a cell concentration of 1.25×10 6 160 μL of the above compound was added to each well of the 96-well plate, mixed, and incubated at 37°C, 5% CO2 for 20 hours. Then, 10 μL of R848 (final concentration of 2.5 μg / mL) was added and incubated at 37°C, 5% CO2 for another 24 hours. After the incubation, the 96-well plate was centrifuged at 2000 rpm for 4 minutes, the supernatant was taken and diluted 120 times, and the IL-6 ELISA kit was used for detection, and the OD was read. 450 The values ​​were converted into IL-6 concentrations according to the standard curve, and the IC was calculated by fitting the dose-effect curve using GraphPad 8.0. 50 The values ​​are shown in Table 23.

[0394] Table 23 Inhibitory effect of compound R848 on IL-6 secretion in PBMC cells

[0395] Test Example 2: Inhibitory effect of the compounds of the present invention on LPS / IL-1β-induced IL-6 secretion in human peripheral blood mononuclear cells (PBMC)

[0396] The experiment was performed in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin, and the initial assay concentration of the compound was 1 μM.

[0397] The compound was dissolved in DMSO to form a stock solution, and then diluted with culture medium in a 5-fold concentration gradient to form a series of working solutions. The working solutions were added to a 96-well plate, with 10 μL per well. PBMC (lot number: P122101102C, Miaoshun Biotechnology Co., Ltd.) cells were counted and diluted to a cell concentration of approximately 1.3×10 6 / mL, add 150μL to the 96-well plate containing the above compound, mix well, and culture in a 37°C, 5% CO2 incubator for 24h. Then add 5μL of LPS (final concentration of 10ng / mL) and 5μL of IL-1β (final concentration of 20ng / mL) to each well, and continue to culture in a 37°C, 5% CO2 incubator for 20h. After the incubation, centrifuge the 96-well plate at 2000rpm for 4min, take the supernatant and dilute 200 times, detect it according to the IL-6 ELISA detection kit, and read the OD 450 The values ​​were converted into IL-6 concentrations according to the standard curve, and the IC was calculated by fitting the dose-effect curve using GraphPad 8.0. 50 The experimental results are shown in Table 24 below.

[0398] Table 24 Inhibitory effect of compounds on LPS / IL-1β-induced IL-6 secretion in PBMC cells

[0399] Test Example 3: Effect of Compounds on IRAK4 Protein Degradation in THP1 Cells

[0400] The experiment was performed in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin. The initial concentration of the compound was 1 μM. THP-1 cells were seeded into 96-well cell culture plates, with 2×10 cells per well. 5Cells were cultured in 90 μL of culture medium. The cell culture plates were incubated overnight at 37°C, 5% CO₂ incubator. Compounds were dissolved in DMSO to create a stock solution, diluted in culture medium in a 5-fold concentration series to create a series of working solutions. 10 μL was added to each well of the 96-well plate. The cell culture plates were incubated for an additional 24 hours at 37°C, 5% CO₂. After incubation, the 96-well plates were centrifuged and the supernatant discarded. 40 μL of cell lysis buffer containing proteasome / phosphatase inhibitors was added to each well and thoroughly lysed on ice. Protein was quantified using a BCA protein quantification kit, and samples were prepared for Western blot. Samples were loaded at 10 μL per lane onto a 10-lane Tris SDS-PAGE gel with a 4% to 12% gradient and subjected to electrophoresis. After electrophoresis, proteins were transferred to a PVDF membrane on ice for 1 hour. After transfer, the PVDF membrane was blocked in 5% skim milk for 1 hour at room temperature with shaking. After blocking, the PVDF membrane was mixed with the primary antibody and incubated with shaking at 4°C overnight. The PVDF membrane was washed three times with TBST, and the secondary antibody was added and incubated with shaking at room temperature for 1 hour. The PVDF membrane was then washed three times with TBST. After washing, the luminescent solution was added, and the PVDF membrane was scanned using a Qinxiang developer. Semi-quantitative analysis was performed using ImagJ software, and DC was calculated using GraphPad Prism 8.0. 50 .

[0401] Table 25 Effects of compounds on IRAK4 protein degradation in THP1 cells

[0402] The above results indicate that the compound of the present invention has a better degradation effect in THP1 cells.

[0403] Test Example 4: Metabolic Stability Test

[0404] Preheat clean plates T60 and NCF60 at 37°C for 10 minutes. Dilute liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer. Transfer 445 μL of the 0.56 mg / mL microsome working solution to the preheated plates T60 and NCF60. Incubate the plates T60 and NCF60 at 37°C with constant shaking for 10 minutes. After incubation, transfer 54 μL of liver microsomes to a blank plate. Add 6 μL of NAPDH cofactor to the blank plate, followed by 180 μL of quenching solution. Add 5 μL of the complex working solution (100 μM) to the plates T60 and NCF60 containing microsomes and mix thoroughly three times. For the NCF60 plate, add 50 μL of buffer and mix thoroughly three times before starting the timer and incubating the plates at 37°C with shaking for 60 minutes. To the quenching plate, add 180 μL of quenching solution and 6 μL of NAPDH cofactor and ensure that the plate is cooled to prevent evaporation. For the T60 plate, mix thoroughly 3 times and immediately move 54 μL of the mixture to the quenching plate at the 0 minute time point. Then add 44 μL of NAPDH cofactor to the incubation plate (T60). Start timing and incubate the plate at 37°C with shaking for 60 minutes. At 5, 15, 30, 45 and 60 minute time points, add 180 μL of quenching solution to the quenching plate, mix once, and then transfer 60 μL of sample at each time point from the T60 plate to the quenching plate continuously. For NCF60, mix once and transfer 60 μL of sample from the NCF60 incubation to the quenching plate containing quenching solution at the 60 minute time point. All sampling plates were shaken for 10 minutes and then centrifuged at 4000 rpm for 20 minutes at 4°C. 80 μL of supernatant was transferred to 240 μL of HPLC water and mixed by plate shaker for 10 minutes. Each bioassay plate was sealed and shaken for 10 minutes before LC-MS / MS analysis.

[0405] Table 26 Metabolic stability of compounds in human liver microsomes

[0406] The results showed that the compounds of the present invention were more stable in liver microsomes than the positive compounds (positive drugs).

[0407] Test Example 5: In vivo drug metabolism test of the compound of the present invention

[0408] Pharmacokinetics in SD rats: This study used two administration routes: oral gavage and tail vein injection. The oral dose was 5 mg / kg, using the compound of this invention. The administration volume was 10 mL / kg. Immediately prior to use, an appropriate amount of drug was accurately weighed and dissolved in dimethyl sulfoxide (DMSO). Appropriate amounts of Solutol and H2O were added sequentially, with a final volume ratio of 5% DMSO, 10% Solutol, and 85% H2O. Ultrasonication and vortexing were performed to prepare a clear drug solution of 0.5 mg / mL. The intravenous dose was 1 mg / kg, using the compound of this invention. The administration volume was 10 mL / kg. Immediately prior to use, an appropriate amount of drug was accurately weighed and dissolved in dimethyl sulfoxide (DMSO). Appropriate amounts of Solutol and H2O were added sequentially, with a final volume ratio of 5% DMSO, 10% Solutol, and 85% H2O. Ultrasonication and vortexing were performed to prepare a clear drug solution of 0.5 mg / mL.

[0409] Six SD rats, weighing 180-220 g, were randomly divided into two groups. The first group was fasted overnight but had free access to water. The first group was given oral administration, and 200 μL of blood was collected from the eye socket at each time point 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. The blood samples were centrifuged at 10,000 rpm for 20 minutes at 4°C within one hour (stored on ice before centrifugation). The supernatant, i.e., plasma, was collected and stored at −20°C for LC-MS / MS analysis. The second group was given intravenous administration, and 200 μL of blood was collected from the eye socket at each time point 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. The blood samples were centrifuged at 10,000 rpm for 20 minutes at 4°C within one hour (stored on ice before centrifugation). The supernatant, i.e., plasma, was collected and stored at −20°C for LC-MS / MS analysis.

[0410] Table 27 Drug metabolism of compounds in rats

[0411] The results are as follows: The compound of the present invention has excellent oral bioavailability in rats.

[0412] Test Example 6: Therapeutic Effects of the Compounds of the Invention on Psoriasis Models

[0413] Male BALB / c mice, 6-8 weeks old, were randomly divided into 9 groups after 1 week of adaptive feeding, namely, blank group, imiquimod model group (ie, IMQ group, corresponding to the model group in Figures 1 and 2), clobetasol propionate cream group (ie, CLO group), TYKI (BMS-986165) group, IRAK4 protein degrader KT-474 (from patent WO2020113233) group (100 mg / kg) and the compound of the present invention (appropriate dose), with 6 to 7 mice in each group. The day before modeling, the back of the mice was depilated with a depilatory cream, and the depilatory area was 2×2 cm. 2 . IMQ cream was used to establish the model on the day of modeling, and the corresponding drug treatment was administered by gavage. The compound of the present invention (appropriate dose) was administered by gavage once a day, and the IMQ cream was applied to the depilatory area on the back of the mouse and the left ear 2 hours after the first administration. The positive compound KT-474 (from patent WO2020113233) group applied IMQ cream to the depilatory area on the back of the mouse and the left ear 4 hours after the first administration. The blank group and the IMQ group were gavaged with the solvent twice a day, morning and evening, with an interval of 8 hours between the two gavages, and vaseline and IMQ cream were applied to the depilatory area on the back of the mouse and the ear 2 hours after the first gavage. The dosage of IMQ cream for the depilatory area on the back and the left ear was 80 mg and 10 mg, respectively, and each group of mice was given the drug for 5 consecutive days.

[0414] Refer to the Psoriasis Area and Severity Index (PASI) scoring criteria. Starting from day 1 of modeling, the psoriasis, erythema, and thickness of the dorsal skin lesions were scored on a scale of 0 to 4 each morning. The scoring criteria are shown in Table 28. The three scores were summed to obtain the total PASI score. Starting from day 1 of modeling, the thickness of the left ear of the mice was measured three times each morning using a digital vernier caliper. The average of these measurements was used.

[0415] Table 28 Psoriasis Area and Severity Index (PASI) scoring criteria

[0416] The therapeutic effects of the compounds of the present invention on the IMQ psoriasis model are shown in Figures 1 and 2.

[0417] Figure 1A is a statistical graph showing the Psoriasis Area and Severity Index (PASI) score results for the therapeutic effect of the compound TM-174 of the present invention on the IMQ psoriasis model, and Figure 1B is a statistical graph showing the results of the skin thickness experiment for the therapeutic effect of the compound TM-174 of the present invention on the IMQ psoriasis model.

[0418] Figure 2A is a statistical graph showing the Psoriasis Area and Severity Index (PASI) score results for the therapeutic effect of the present compound TM-205 on the IMQ psoriasis model. Figure 2B is a statistical graph showing the skin thickness test results for the present compound TM-205.

[0419] Among them, control is the blank group, model is the imiquimod model group, CLO is the clobetasol propionate group, and TYKI (30 mg / kg, BID) is the BMS-986165 group.

[0420] Clobetasol propionate is an organic compound with the chemical formula C 25 H 32 ClFO5 is a white crystalline powder and an anti-inflammatory corticosteroid that can act on various skin diseases. It is suitable for external use for pruritic and non-infectious inflammatory skin diseases that are effectively treated with topical glucocorticoids, such as chronic eczema, neurodermatitis, psoriasis, palmoplantar pustulosis, lichen planus, and discoid lupus erythematosus.

[0421] BMS-986165 (also known as Deucravacitinib) is a novel, oral, selective TYK2 inhibitor.

[0422] KT-474 (100 mg / kg, QD) is a member of the IRAK4 protein degrader KT-474 (from patent WO2020113233). The compound TM-174 of the present invention was administered orally at different doses of TM-174 (3 mg / kg, QD), TM-174 (10 mg / kg, QD), and TM-174 (30 mg / kg, QD).

[0423] Specific experimental data related to Figures 1 and 2 are shown in Table 29.

[0424] Table 29. Effects of the compounds of the present invention on PASI scores and ear thickness difference in IMQ psoriasis model (Mean±SD, n=7)

[0425] Note: vs model, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0426] The results showed that the patented compound had an excellent control effect on the IMQ-induced psoriasis model and had a clear therapeutic effect on skin thickness.

[0427] Test Example 7: Therapeutic Effect of the Compounds of the Invention on Enteritis (DSS Model)

[0428] The experimental mice were pre-acclimated in the animal room for one week. At the start of the experiment, the drug was administered daily by gavage based on mouse body weight. After gavage, the water bottles of each group of mice were immediately replaced and allowed free access to water. The blank group received normal water, while the remaining groups received pre-prepared DSS water. Every afternoon, the mice were massaged on the abdomen. A pellet of feces was placed on a white porcelain plate, and fecal characteristics were assessed and recorded according to Table 30. Fecal occult blood was assessed using a fecal occult blood qualitative test kit (Yuanye Biotechnology, #R24187-300T), and the results were recorded according to Table 31.

[0429] Table 30DSS model scoring method

[0430] Table 31DSS model fecal occult blood evaluation method

[0431] FIG3 is a statistical diagram showing the therapeutic effect of the compound TM-4 of the present invention on the DSS-induced enteritis model.

[0432] FIG4 is a statistical diagram showing the therapeutic effect of the compound TM-174 of the present invention on the DSS-induced enteritis model.

[0433] FIG5 is a statistical diagram showing the therapeutic effect of the compound TM-205 of the present invention on the DSS-induced enteritis model.

[0434] FIG6 is a statistical diagram showing the therapeutic effect of the compound TM-221 of the present invention on the DSS-induced enteritis model.

[0435] The Normal group is the normal group, the Model group is the model group, and the Cyclosporine, 20 mpk, ip, QD group is the cyclosporine group. Cyclosporine is a widely used immunosuppressant in clinical practice that treats a variety of diseases by inhibiting the proliferation and function of T and B cells.

[0436] Specific experimental data related to Figures 3-6 are shown in Table 32.

[0437] Table 32. Effects of the compounds of the present invention on the DAI scores of colitis mice (Mean±SD, n=7)

[0438] Note: vs model, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0439] The results showed that the compound of the present invention had excellent therapeutic effect on the DSS-induced enteritis model.

[0440] Test Example 8: Therapeutic Effects of the Compounds of the Invention on Rheumatoid Arthritis (CIA Model)

[0441] 1. DBA / 1J male mice, SPF grade, were pre-adapted in the animal room for one week.

[0442] 2. On the first day, for the first immunization, 2 mg / mL of bovine type II collagen and an equal volume of Freund's complete adjuvant were thoroughly stirred and emulsified on ice using a homogenizer. 100 μL of collagen emulsion (final concentration of 1 mg / mL) was injected intradermally 2 cm from the base of the mouse tail. After the injection, the mouse tail was disinfected with medical iodine to prevent tail rot for 3 days.

[0443] 3. On the 21st day, the bovine type II collagen solution was thoroughly mixed and emulsified with an equal volume of Freund's incomplete adjuvant, using the same method as the first immunization.

[0444] 4. On day 26, LPS was injected intraperitoneally at a dose of 50 μg / mouse to induce disease.

[0445] 5. On day 28, the affected mice were scored and their ankle diameters were measured according to Table 33. Mice were randomly divided into groups based on the scores and ankle diameters and given medication.

[0446] Table 33 Arthritis Index (AI) calculation score

[0447] FIG7 is a statistical diagram showing the therapeutic effect of the compound TM-135 of the present invention on the CIA-induced rheumatoid arthritis model.

[0448] The Normal group represents the normal control group, and the Model group represents the model group. The tofacitinib (30 mg / kg)-BID group represents the tofacitinib group. Tofacitinib is a JAK inhibitor developed by Pfizer that effectively inhibits the activity of JAK1 and JAK3, blocking the signal transduction of multiple inflammatory cytokines. Specific experimental data related to Figure 7 are shown in Table 34.

[0449] Table 34. Effects of the compounds of the present invention on the AI ​​score of the CIA-induced rheumatoid arthritis model (Mean±SD, n=7)

[0450] The results showed that the compound of the present invention had excellent therapeutic effect on the rheumatoid arthritis model induced by CIA.

[0451] Test Example 9: Therapeutic Effects of the Compounds of the Invention on Atopic Dermatitis (AD Model)

[0452] 1. Female Balb / c mice, SPF grade, were pre-adapted in the animal room for one week.

[0453] 2. At the beginning of the experiment, the mice were weighed and recorded, and the mice were gavage-administered at a volume of 0.1 ml / 10 g. The ear thickness of the mice was measured every day (ear thickness was measured before administration on day 1).

[0454] 3. Apply MC903 2 hours after gavage. MC903 (2 nmol·ear -1 ) dissolved in 95% ethanol was applied to the left ear of each mouse, and an equal amount of ethanol was applied to the right ear, with a volume of 10 μL applied to each ear. Treatment was continued daily from day 1 to day 14. The results of the treatment of the MC903-induced idiopathic inflammation model with the compound of the invention on day 14 are shown in Figure 8.

[0455] Among them, Control was the blank group, MC903 (2 nmol) was the calcipotriol group, Upadacitinib (3 mg / kg)-BID was the upadacitinib group, and Upadacitinib (10 mg / kg)-BID was the upadacitinib group.

[0456] Calcipotriol (MC903) is a synthetic vitamin D3 analogue that is widely used to treat psoriasis and can inhibit the proliferation and differentiation of leukemia cells.

[0457] Upadacitinib is a selective JAK inhibitor developed and produced by AbbVie in the United States, mainly used to treat various inflammatory diseases.

[0458] The results show that the compound of the present invention has a good therapeutic effect on atopic dermatitis.

[0459] In summary, the present invention discloses compounds of Formula I, which can effectively degrade IRAK4 or inhibit IRAK4 activity in other ways. These compounds have excellent application prospects in IRAK4-mediated diseases, including immune diseases (such as psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, alcoholic liver disease, autoimmune liver disease, acne, etc.), tumors (such as multiple myeloma, lymphocytic leukemia and lymphoma, etc.), Alzheimer's disease, and fibrotic diseases. These compounds provide a new option for clinical screening and / or preparation of drugs for diseases related to IRAK4 activity.

Claims

1. A compound represented by formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: in, V is selected from -C(O)NH- or -NHC(O)-; T is selected from -NH- or a chemical bond; represents a single bond or a double bond; Y 2 , Y 3 are independently selected from C or N; Y 1 , Y 4 Independently selected from CR Y , CR Y R Y , N, NR Y , O, S, C(O), S(O) or S(O)2; Y 5 Selected from C or N; Y 6 , Y 7 Independently selected from CR 4 or N; Each R Y Selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl; Q is selected from CR Q or N; R Q Selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 1～6 Alkoxy, halogen substituted C 1～6 Alkyl, halogen substituted C 1～6 Alkoxy; Ring A is selected from a 5-10 membered aromatic heterocyclic ring; wherein the aromatic heterocyclic ring is optionally substituted by 1, 2 or 3 R A1 replace: Each R A1 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR A2 , -C 0～2 Alkylene-NR A2 R A3 , -C 0～2 Alkylene-3 to 10-membered carbocyclic group, -C 0～2 Alkylene-4- to 10-membered heterocyclic group; R A2 , R A3 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl; R 1 , R 4 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR 11 , -C 0～2 Alkylene-NR 11 R 12 , -C 0～2 Alkylene-NR 11 C(O)R 12 , -C 0～2 Alkylene-C(O)R 11 , -C 0～2 Alkylene-C(O)NR 11 R 12 , -C 0～2 Alkylene-3 to 10-membered carbocyclic group, -C 0～2 Alkylene-4- to 10-membered heterocyclic group, -C 0～2 Alkylene-4- to 10-membered bridge ring, -C 0～2 Alkylene-4- to 10-membered bridged heterocyclic ring, -C 0～2 Alkylene-5- to 12-membered spiro ring, -C 0～2 Alkylene-5- to 12-membered spiroheterocyclic ring, -C 0～2 Alkylene-6- to 10-membered aromatic ring, -C 0～2 wherein the carbocyclic group, heterocyclic group, bridged ring, bridged heterocyclic ring, spirocyclic ring, spiro heterocyclic ring, aromatic ring, aromatic heterocyclic ring are optionally substituted by 1, 2 or 3 R 13 replace: R 11 , R 12 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl; Each R 13 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR 14 , -C 0～2 Alkylene-NR 14 R 15 , -C 0～2 Alkylene-NR 14 C(O)R 15 , -C 0～2 Alkylene-C(O)R 14 , -C 0～2 Alkylene-C(O)NR 14 R 15 ; R 14 , R 15 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl; D ring is selected from The cc end is connected to L, and the dd end is connected to Q; represents a single bond or a double bond; X 2 , X 3 are independently selected from C or N; X 1 , X 4 Independently selected from CR X , CR X R X , N, NR X , O, S, C(O), S(O) or S(O)2; X 5 Selected from C or N; X 6 , X 7 Independently selected from CR 2 or N; X 8 , X 9 Independently selected from C, CR 2 or N; Each R X Selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl; Each R 2 are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR 21 , -C 0～2 Alkylene-NR 21 R 22 , -C 0～2 Alkylene-3 to 10-membered carbocyclic group, -C 0～2 Alkylene-4- to 10-membered heterocyclic group; R 21 , R 22 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl; L is The B ring and R 1 The terminal aromatic heterocyclic nitrogen atoms are connected, and the C ring is connected to the D ring; Ring B is selected from 3-10 membered carbocyclic group, 4-10 membered heterocyclic group, 4-10 membered bridged ring, 4-10 membered bridged heterocyclic ring, 5-12 membered spirocyclic ring, 5-12 membered spiro heterocyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic group, bridged ring, bridged heterocyclic ring, spirocyclic ring, spiro heterocyclic ring, aromatic ring, aromatic heterocyclic ring are optionally substituted by 1, 2 or 3 R B replace; Preferably, the B ring is selected from 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-membered bridged ring, 6-membered bridged ring, 7-membered bridged ring, 8-membered bridged ring, 5-membered bridged heterocycle, 6-membered bridged heterocycle, 7-membered bridged heterocycle, 8-membered bridged heterocycle, 7-membered spirocycle, 8-membered spirocycle, 9-membered spirocycle, 10-membered spirocycle, 11-membered spirocycle, 7-membered spiroheterocycle, 8-membered spiroheterocycle, 9-membered spiroheterocycle, 10-membered spiroheterocycle, 11-membered spiroheterocycle; wherein the carbocyclyl, heterocyclyl, bridged ring, bridged heterocycle, spirocycle, spiroheterocycle are optionally replaced by 1, 2 or 3 R B replace; The C ring is selected from a 3- to 10-membered carbocyclic group, a 4- to 10-membered heterocyclic group, a 4- to 10-membered bridged ring, a 4- to 10-membered bridged heterocyclic ring, a 5- to 12-membered spirocyclic ring, a 5- to 12-membered spiroheterocyclic ring, a 6- to 10-membered aromatic ring, and a 5- to 10-membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic group, bridged ring, bridged heterocyclic ring, spirocyclic ring, spiroheterocyclic ring, aromatic ring, aromatic heterocyclic ring are optionally substituted by 1, 2 or 3 R C replace; Preferably, the C ring is selected from 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-membered bridged ring, 6-membered bridged ring, 7-membered bridged ring, 8-membered bridged ring, 5-membered bridged heterocycle, 6-membered bridged heterocycle, 7-membered bridged heterocycle, 8-membered bridged heterocycle, 7-membered spirocycle, 8-membered spirocycle, 9-membered spirocycle, 10-membered spirocycle, 11-membered spirocycle, 7-membered spiroheterocycle, 8-membered spiroheterocycle, 9-membered spiroheterocycle, 10-membered spiroheterocycle, 11-membered spiroheterocycle; wherein the carbocyclyl, heterocyclyl, bridged ring, bridged heterocycle, spirocycle, spiroheterocycle are optionally replaced by 1, 2 or 3 R C replace; R B , R C are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR B1 , -C 0～2 Alkylene-NR B1 R B2 ; R B1 , R B2 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl; L 1 Selected from chemical bonds, C 1～6 Alkylene, C 2～6 Alkenylene, C 2～6 wherein the carbon atoms in the alkylene, alkenylene, alkynylene may be optionally substituted by 1, 2 or 3 heteroatoms, and the alkylene, alkenylene, alkynylene may be optionally substituted by 1, 2 or 3 R L1 replace; Each R L1 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl.

2. The compound according to claim 1, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from C, Y 4 Selected from CH, Y 5 Selected from N, Y 6 Selected from CH, Y 7 Selected from CH; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH, Y 5 Selected from C, Y 6 Selected from CH, Y 7 Selected from CH; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from N, Y 5 Selected from C, Y 6 Selected from CH, Y 7 Selected from CH; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH, Y 5 Selected from C, Y 6 Selected from CH, Y 7 Selected from N; or Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH, Y 5 Selected from C, Y 6 Selected from N, Y 7 Selected from CH; D ring is selected from 3. The compound according to claim 1, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: The compound shown in formula I is shown below: Among them, V, T, Q, A ring, R 1 , R 2 , L is defined as in claim 1.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from: R A1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, monomethylamino or dimethylamino. R A11 Selected from methyl, ethyl, propyl, cyclopropyl, and methyl, ethyl, propyl, cyclopropyl substituted with halogen.

5. The compound according to any one of claims 1 to 3, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: R 1 Selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, monomethylamino, dimethylamino, deuterated monomethylamino, deuterated dimethylamino; Or, R 1 Select from the following rings:

6. The compound according to any one of claims 1 to 3, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: R 2 Select from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl, ethoxymethyl, monomethylamino or dimethylamino.

7. The compound according to any one of claims 1 to 3, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: Q is selected from CH or N.

8. The compound according to any one of claims 1 to 3, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: Ring B is selected from Where q is 0, 1, 2 or 3; Each R B are independently selected from hydrogen, deuterium, halogen, cyano, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-OR B1 , -C 0～2 Alkylene-NR B1 R B2 ; R B1 , R B2 are independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen-substituted C 1～6 Alkyl, halogen substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkynyl, deuterated C 1～6 Alkyl, deuterated C 2～6 Alkenyl, deuterated C 2～6 Alkynyl; The C ring is selected from L 1 Selected from chemical bonds, methylene and ethylene.

9. The compound according to claim 8, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: L is selected from the following structures: Among them, the aa end and R 1 The terminal aromatic heterocyclic nitrogen atom is connected, and the bb end is connected to the D ring.

10. The compound according to any one of claims 1 to 9, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, characterized in that: The compound is specifically:

11. Use of the compound according to any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a composition for treating and preventing diseases related to or mediated by one or more of the interleukin-1 receptor associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor, and tumor necrosis factor α (TNFα).

12. The use according to claim 11, characterized in that: The diseases include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, and cardiovascular diseases.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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