Tri-fused ring compound as well as preparation method and application thereof

Abstract

The invention discloses a tricyclic compound as well as a preparation method and application thereof. Relates to a compound shown in a general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound. The invention also relates to the application of the compound in preparation of medicines for treating or preventing autoimmune diseases, inflammatory diseases, cancers, viral diseases, neurodegenerative diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplantation-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases and the like. The invention also relates to the application of the medicine for treating diseases related to cell death or cardiovascular diseases. Wherein each substituent in the general formula (I) is as defined in the specification.

Description

Tricyclic compounds, preparation methods and applications thereof

[0001] This application claims priority to Chinese Patent Application No. 202310624222X, filed on May 30, 2023, and Chinese Patent Application No. 2023117821298, filed on December 22, 2023. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a tricyclic compound and a preparation method and application thereof. Background Art

[0003] Interleukin-1 receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase belonging to the tyrosine kinase (TLK) family. It is a key node in the innate immune response, involving interleukin-1, 18, and 33 receptors and Toll-like receptors. Binding of extracellular signaling molecules to interleukin receptors or Toll-like receptors recruits the MyD88:IRAK4:IRAK1 / 2 multiprotein complex, leading to phosphorylation of IRAK1 / 2 and mediating a series of downstream signaling pathways, thereby activating the p38, JNK, and NF-κB signaling pathways and ultimately leading to the expression of proinflammatory cytokines. Clinical and pathological studies have shown that individuals with IRAK4 mutations are protected against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal; individuals survive into adulthood and their risk of infection decreases with age. Therefore, IRAK4 has become an important therapeutic target and has attracted widespread research and development interest.

[0004] Proteolysis Targeting Chimeria (PROTAC) is a technology different from traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity. PROTAC is a heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein through a connecting chain, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein and E3 ubiquitin ligase in vivo, brings the target protein and E3 ubiquitin ligase closer to form a ternary complex, ubiquitinates the target protein, and then degrades the target protein through the ubiquitin-proteasome pathway in vivo. Compared to traditional small molecule inhibitors, PROTACs only need to bring the target protein closer to the E3 ubiquitin ligase to degrade the substrate. This mode of action allows this technology to be applied to some undruggable targets. On the other hand, since the PROTAC molecule can be released after the target protein is degraded and continues to participate in the degradation process of the next protein, this catalytic degradation effect allows a smaller PROTAC drug dose to achieve efficient degradation. On the other hand, traditional small molecule inhibitors are prone to drug resistance, which is often due to point mutations, causing the small molecule inhibitors to lose their inhibitory effect on the target. PROTACs can directly degrade the target protein, which can, to a certain extent, avoid the drug resistance caused by point mutations. Therefore, compared to traditional small molecule inhibitors, the use of PROTAC technology for the development of new drug small molecules has high advantages and feasibility, and is expected to become the next generation of promising new drugs.

[0005] Therefore, it is necessary to develop novel IRAK4 inhibitors and PROTAC drugs for E3 ubiquitin ligases to treat IRAK4-related diseases.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0008] in:

[0009] Indicates that the key does not exist;

[0010] M1 is selected from N or CR1;

[0011] M2 is selected from N, C or CR2;

[0012] M3 is selected from N or CR3;

[0013] M4 is selected from N or CR4;

[0014] M5 is selected from N or CR5;

[0015] M6 is selected from N or CR6;

[0016] R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, aminoalkyl, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0017] Ring B1 is selected from aryl or heteroaryl;

[0018] Ring B2 is selected from aryl, heteroaryl or heterocyclyl;

[0019] R a Each is independently selected from hydrogen, deuterium, hydroxy, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, -P(O)RR', cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano or alkyl;

[0020] R and R' are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;

[0021] R b 、R c 、R e and R f Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl or haloalkoxy;

[0022] Or, R e and R f Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0023] Or, R2 and R f Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0024] Or, R f Linked to the C or N on the ring where M2 is located to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0025] Or, any two R b Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0026] Or, L2 and R e Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0027] L1 is selected from a bond, -NH-, -S-, -O-, -CH2-, CH2CH2-, -C(O)NH-, -NHC(O)- or -C(O)-;

[0028] L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-,

[0029] Ak1, Ak2 and Ak3 are each independently selected from -(CH2) n3 -, -O-, -C(O)-, -NH-, -NR7-, -CH2NR7-, -(CR8R9) n4 -, alkynylene or a bond;

[0030] Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene group, a heterocyclylene group, an arylene group, or a heteroarylene group; said cycloalkylene group, heterocyclylene group, arylene group, and heteroarylene group are optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, alkyl, haloalkyl, alkoxy, hydroxyalkyl, or haloalkoxy;

[0031] R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, alkyl, cyano, hydroxy, cycloalkyl, haloalkyl, deuterated alkyl, halocycloalkyl, hydroxyalkyl or alkoxy; or, R8 and R9 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy or hydroxyalkyl;

[0032] Or, R a is linked to L2 to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0033] L3 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-C(S)- or -C(S)-NH-;

[0034] x, y, z and q are each independently selected from 0, 1, 2, 3 or 4; and

[0035] n1, n2, n3 and n4 are each independently selected from 0, 1, 2 or 3.

[0036] In a preferred embodiment of the present invention, the compound described above is further represented by the general formula (II-A):

[0037] in:

[0038] R d Each independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0039] Preferably, R d Each independently selected from hydrogen, deuterium, fluorine, chlorine, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0040] Or, R dLinked with L2 to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more substituents in a cycloalkyl group or a 3-6 membered heterocyclic group;

[0041] Ring A is selected from a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl;

[0042] p is selected from 0, 1, 2, 3 or 4.

[0043] In a preferred embodiment of the present invention, the compound described above is further represented by general formula (II-B):

[0044] in:

[0045] R d Each independently selected from hydrogen, deuterium, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0046] Ring A is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl;

[0047] R d1 Each independently selected from hydrogen, deuterium, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0048] p and j are each independently selected from 0, 1, 2, 3 or 4.

[0049] In a preferred embodiment of the present invention, Selected from

[0050] Preferably, the Selected from

[0051] More preferably, Selected from

[0052] Further preferably, the Selected from

[0053] M7 is selected from O, CH2, C(O), S, S(O), S(O)2 or NR 10 ; R 10 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, cyano, amino, oxo, fluorine or chlorine;

[0054] M8 is selected from N, O, S, C(O), CH2, CH, S(O) or S(O)2;

[0055] R d2 and R d3 Each independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, cyano, amino, oxo, fluorine or chlorine;

[0056] p2 and p3 are each independently selected from 1, 2, 3 or 4;

[0057] n9 is selected from 1, 2 or 3.

[0058] In a preferred embodiment of the present invention, Selected from

[0059] Preferably, the Selected from

[0060] M9 and M 10 Each independently selected from CH2, C(O), NR 10 , CH, O, S, S(O) or S(O)2;

[0061] R 10 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, cyano, amino, oxo, fluorine or chlorine;

[0062] R d4 Each independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, cyano, amino, oxo, fluorine or chlorine;

[0063] p4 are each independently selected from 1, 2, 3 or 4;

[0064] n5 is selected from 1, 2 or 3.

[0065] In a preferred embodiment of the present invention, the ring B1 described above is selected from indazolyl, pyrazolyl, benzimidazolyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl or pyrimidoimidazolyl;

[0066] Preferably, the Selected from

[0067] The ring B2 is selected from pyridyl, phenyl, pyridonyl, pyridazinonyl, pyrimidopyrazolyl, pyridopyrrolyl, pyrimidinyl, pyrimidopyrrolyl or pyridopyrazolyl;

[0068] Preferably, the Selected from

[0069] Among them, R b1 、R b2 、R b3 and R b4 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0070] Or, R b1 and R b2 The 5-6 membered heterocyclic group is linked to form a 5-6 membered heterocyclic group, which is optionally further substituted with deuterium, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy C 3-6 The cycloalkyl group or the 3-6 membered heterocyclic group is substituted by one or more substituents.

[0071] In a preferred embodiment of the present invention, the above R a Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, -P(O)RR', C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C1-3 The alkyl group is substituted by one or more substituents;

[0072] Preferably, R a Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, -P(O)RR', C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents;

[0073] Alternatively, the R b 、R c 、R e and R f Each independently selected from hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted with deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 substituted by one or more substituents in a haloalkoxy group;

[0074] Preferably, the R b 、R c 、R e and R f Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, C 1-3 Alkyl, C1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1- 3 alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted with deuterium, fluorine, chlorine, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 substituted by one or more substituents in a haloalkoxy group;

[0075] Alternatively, R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0076] Preferably, R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0077] Alternatively, R and R' are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0078] Preferably, R and R' are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy.

[0079] In a preferred embodiment of the present invention, the above L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-,

[0080] The Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene group, a heterocyclylene group, an arylene group, or a heteroarylene group; the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with 0 to 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxy, hydroxyalkyl, haloalkoxy, or deuterated alkoxy;

[0081] Preferably, the Cy1 and Cy2 are each independently selected from a bond, a 5-6 membered monocyclic cycloalkylene, a 4-6 membered monocyclic heterocycloalkylene, a phenylene, a 5-6 membered heteroarylene, a 6-12 membered bicyclic cycloalkylene, a 6-12 membered bicyclic heterocyclylene, a 7-12 membered spirocycloalkylene or a 7-12 membered spiroheterocyclylene, and the 5-6 membered monocyclic cycloalkylene, the 4-6 membered monocyclic heterocycloalkylene, the phenylene, the 5-6 membered heteroarylene, the 6-12 membered bicyclic cycloalkylene, the 6-12 membered bicyclic heterocyclylene, the 7-12 membered spirocycloalkylene and the 7-12 membered spiroheterocyclylene are optionally further substituted with 0 to 4 substituents selected from deuterium, fluorine, amino, hydroxyl, cyano, nitro, methyl, ethyl, methoxy, trifluoromethyl or difluoromethyl;

[0082] More preferably, Cy1 and Cy2 are each independently selected from a bond, a cyclohexylene group, a piperidinylene group, a phenylene group, a pyridinylene group, a pyrazolylene group, a piperazinylene group, a morpholinylene group, The cyclohexylene, piperidylene, phenylene, pyridylene, pyrazolylene, piperazinylene, morpholinylene, Optionally further substituted with 0 to 4 substituents selected from deuterium, fluorine, amino, hydroxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or difluoromethyl.

[0083] In a preferred embodiment of the present invention, the above L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-,

[0084] The Ak1, Ak2 and Ak3 are each independently selected from -(CH2) n3 -, -O-, -C(O)-, -NH-, -NR7-, -CH2NR7-, -(CR8R9) n4 - or key;

[0085] The Cy1 and Cy2 are each independently selected from a bond, a cyclohexylene, a piperidinylene or a piperazinylene, wherein the cyclohexylene, the piperidinylene and the piperazinylene are optionally further substituted with 1 to 4 deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1- 3 alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, C 1-3 Haloalkyl or C 1-3 substituted by a haloalkoxy substituent;

[0086] The R7, R8 and R9 are independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, cyano, hydroxyl, C 3-4 Cycloalkyl, C 1-3 Halogenated alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated cycloalkyl, hydroxyl C 1-3 Alkyl or C 1-3 alkoxy;

[0087] Preferably, L2 is selected from Wherein, M and M0 are independently selected from CR 11 or N; R 11 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0088] n6 and n7 are each independently selected from 0, 1, 2, 3 or 4; preferably, n6 is selected from 2 and n7 is selected from 0.

[0089] In a preferred embodiment of the present invention, the compound of the general formula (II-A) described above is further represented by the general formula (IV-0):

[0090] Where: R a 、R b , L3, R3, M0, M4, M5, M6 and M7 are as defined above in the present invention.

[0091] In a preferred embodiment of the present invention, the compound of the general formula (II-A) described above is further represented by the general formula (IV-1):

[0092] Where: R a 、R b , L3, R3, M0, M4, M5, M6 and M7 are as defined above in the present invention.

[0093] In a preferred embodiment of the present invention, the compound of the general formula (II-A) described above is further represented by the general formula (IV-2):

[0094] Where: R a 、R b , L3, R3, M0, M4, M5, M6 and M7 are as defined above in the present invention.

[0095] In a preferred embodiment of the present invention, the compound of the general formula (II-A) described above is further represented by the general formula (IV):

[0096] Where: R a 、R b , L3, R3, M4, M5, M6 and M7 are as defined above in the present invention.

[0097] In a preferred embodiment of the present invention, the compound of the general formula (II-A) described above is further represented by the general formula (IV-A) or the general formula (IV-B):

[0098] Where: R a 、R b , L3, R3, M4, M5, M6 and M7 are as defined above in the present invention.

[0099] In a preferred embodiment of the present invention, the compound of the general formula (II-A) described above is further represented by the general formula (IV-3):

[0100] Where: R a 、R b , L3, M4, M5, M6 and M7 are as defined above in the present invention.

[0101] In a preferred embodiment of the present invention, the compound of the general formula (II-B) described above is further represented by the general formula (V):

[0102] Where: R a 、R b , L3, R3, M4, M5, M6, M9 and M 10 As defined above in the present invention.

[0103] In a preferred embodiment of the present invention, the above R a and R b Each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, isopropylmethyl, morpholinyl, cyclopropyl, cyclobutyl,

[0104] In a preferred embodiment of the present invention, the above R c Each is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, cyclopropyl or cyclobutyl.

[0105] In a preferred embodiment of the present invention, the above R d 、R d1 、R d2 、R d3 and R d4 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, cyclopropyl or cyclobutyl.

[0106] In a preferred embodiment of the present invention, the above R a Selected from C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy; preferably C 1-3 Alkoxy or hydroxy C 1-3 Alkyl; more preferably methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl.

[0107] In a preferred embodiment of the present invention, the above R b Selected from C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy; preferably C 1-3 Haloalkyl or C 1-3 haloalkoxy; more preferably difluoromethyl, trifluoromethyl or trifluoromethoxy.

[0108] In a preferred embodiment of the present invention, L3 mentioned above is selected from a bond, -NH-C(O)- or -C(O)-NH-.

[0109] In a preferred embodiment of the present invention, R3 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy; preferably hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3Alkoxy or C 1-3 Haloalkyl; more preferably hydrogen, deuterium, fluorine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy or propoxy.

[0110] In a preferred embodiment of the present invention, the above-mentioned M0 is selected from N or CH.

[0111] In a preferred embodiment of the present invention, M4 is N or CR4, and R4 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 The haloalkoxy group is preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

[0112] In a preferred embodiment of the present invention, M5 is N or CR5, and R5 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 The haloalkoxy group is preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

[0113] In a preferred embodiment of the present invention, M6 is N or CR6, and R6 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 The haloalkoxy group is preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

[0114] In a preferred embodiment of the present invention, M7 mentioned above is O, CH2, C(O), S, S(O) or S(O)2; preferably O, CH2 or S.

[0115] In a preferred embodiment of the present invention, M9 mentioned above is CH2, C(O), O or S.

[0116] In a preferred embodiment of the present invention, the above-mentioned M 10 CH2, C(O), NR 10 , O or S, R 10 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C1-3 Haloalkoxy; preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

[0117] In a preferred embodiment of the present invention, the compound of the present invention is selected from Compound 1, Compound 46, Compound 120, Compound 121, Compound 126, Compound 128, Compound 129, Compound 130, Compound 131, Compound 120-a, Compound 120-b, Compound 120-a-1, Compound 120-a-2, Compound 120-b-1 or Compound 120-b-2.

[0118] In a preferred embodiment of the present invention, the compound described above is selected from the following compounds in Table 5:

[0119] Table 5

[0120] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the compound represented by the aforementioned general formula, its stereoisomers or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers.

[0121] The present invention also provides a preferred embodiment, involving the use of the compounds described in each general formula and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition described above in the preparation of drugs for treating or preventing IRAK4-mediated diseases.

[0122] The present invention also provides a preferred embodiment, involving the use of the compounds of each general formula and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions described above in the preparation of drugs for treating or preventing autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death or cardiovascular diseases.

[0123] The present invention also relates to a compound of formula (Aa), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

[0124] Among them: M1, M2, M3, M4, M5, M6, L1, R c 、Rd , p and z are as defined above.

[0125] The present invention also relates to a compound of formula (Aaa), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

[0126] Wherein: M4 is N or CR4; M5 is N or CR5; M6 is N or CR6; M7 is O, S or CH2; R3 is selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Haloalkyl; R4 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkyl; R5 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R6 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 12 and R 13 Each is independently selected from hydrogen or an amino protecting group.

[0127] In a preferred embodiment of the present invention, the compound of formula (Aaa) is further represented by formula (Aaa-1) and formula (Aaa-2):

[0128] In a preferred embodiment of the present invention, R3 is selected from deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or trifluoromethyl.

[0129] In a preferred embodiment of the present invention, R4 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or trifluoromethyl.

[0130] In a preferred embodiment of the present invention, R5 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

[0131] In a preferred embodiment of the present invention, R6 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

[0132] In a preferred embodiment of the present invention, the R 12 and R 13 Each is independently selected from hydrogen, SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, benzyl, m-dimethoxybenzyl, -CH2COOH or -COCH3.

[0133] The present invention also relates to the following compounds: intermediate A, intermediate B, intermediate C, intermediate D, intermediate E, intermediate Ea, intermediate Eb, intermediate F, intermediate G, intermediate H, intermediate I, intermediate J, intermediate K, intermediate L, intermediate M, intermediate N, intermediate O, intermediate P, intermediate Q, intermediate R, intermediate S, intermediate T, intermediate U, intermediate V, intermediate W, intermediate Y-5, intermediate Y-6, intermediate Y-8, intermediate Y-9, and intermediate Y-10.

[0134] The present invention also relates to a compound of formula (Ba), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

[0135] in:

[0136] R 14 and R 15 Each independently selected from hydrogen or amino protecting groups; M1, M3, M4, M5, M6, L1, R c 、R d 、R d1 , p, z, j, n1 and n2 are as defined above.

[0137] In a preferred embodiment of the present invention, R 14 and R 15 Each is independently selected from hydrogen, SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, benzyl, p-methoxybenzyl, -CH2COOH or -COCH3.

[0138] In the present invention, the amino protecting group is preferably SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, -CH2COOH, -COCH3, ethoxycarbonyl, benzyl, p-methoxybenzyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl or allyloxycarbonyl.

[0139] The present invention also relates to the use of a structural unit of formula (Aa-1) or formula (Ba-1) as an E3 ubiquitin structural unit of a protein degradation inhibitor:

[0140] Among them: M1, M2, M3, M4, M5, M6, L1, R c 、R d, p and z are as defined above; or,

[0141] in:

[0142] M1, M3, M4, M5, M6, L1, R c 、R d 、R d1 , p, z, j, n1 and n2 are as defined above.

[0143] The present invention also relates to a method for preparing a compound of general formula (IV-0), comprising:

[0144] The compound of formula IV-A is subjected to reductive amination with the compound of formula IV-Y to obtain the compound of formula IV-0;

[0145] Among them, ring A, R a 、R b 、R c 、R d , M2, M3, M4, M5, M6, L1, p and z are as defined above in the present invention.

[0146] The present invention also relates to a method for preparing a compound of general formula (V-0), comprising:

[0147] The compound of formula VA is subjected to reductive amination with formula VY to obtain a compound of formula V-0;

[0148] Among them, ring A, R a 、R b 、R c 、R d 、R d1 , M3, M4, M5, M6, L1, j, n1, n2, p and z are as defined above in the present invention.

[0149] The present invention also relates to a compound of formula (III-A) or (III-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the following structure:

[0150] in:

[0151] The PTM is selected from drugs or their derivatives that bind to the target protein;

[0152] L2, M1, M2, M3, M4, M5, M6, L1, R c 、R d , p and z are as defined above; or,

[0153] in:

[0154] The PTM is selected from drugs or their derivatives that bind to the target protein;

[0155] L2, M1, M3, M4, M5, M6, L1, R c 、R d 、R d1 , p, z, j, n1 and n2 are as defined above.

[0156] In a preferred embodiment of the present invention, the PTMs described above are selected from drugs or derivatives thereof that act on AR, ER, kinase, phosphatase, MDM2, human BET bromodomain proteins, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular endothelial growth factor, immunosuppression-related receptors or proteins, aryl hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease or acyl protein thioesterase 1 and / or acyl protein thioesterase 2; preferably, the PTMs described above are selected from drugs or derivatives thereof that act on ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEEI, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, Mtor, AR, ER, PDE, SRC, MDM2, RAF, IRAK4, STAT3 and c-Myc.

[0157] The present invention also relates to a method for treating or preventing an IRAK4-mediated disease, which comprises administering to a mammal an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate thereof; the IRAK4-mediated disease is selected from autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death or cardiovascular diseases.

[0158] Detailed Description of the Invention

[0159] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0160] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and various branched isomers thereof. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred in the present invention.

[0161] The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0162] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0163] The term "alkenylene" refers to an alkenyl group in which one of its hydrogen atoms is further substituted. For example, "ethenylene" refers to -(CH)2-.

[0164] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, and non-limiting examples include

[0165] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0166] The term "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is further substituted. Non-limiting examples include: cyclohexylene, The cycloalkylene group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0167] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 12 ring atoms; and most preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetane, thietanyl, azetidine, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetane, thietanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminoylidene-1-oxothiopyran, azepanyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, non-limiting examples of which include The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0168] The term "heterocyclylene" refers to a heterocyclyl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include: piperidinylene, piperazinylene, pyrrolopyrrolylene, diazaspiro[5.5]undecylene, azaspiro[5.5]undecylene, benzopiperidinylene, azetidinylene, diazetidinylene, pyrrolidinylene, azaspiro[3.5]nonylene, diazaspiro[3.5]nonylene, azabicyclo[3.1.1]heptanylene, azaspiro[2.5]octanylene, The heterocyclylene group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0169] The term "aryl" refers to a 6- to 14-membered, all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered, more preferably a phenyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0170] The term "arylene" refers to an aryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include: The arylene group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0171] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5-8 membered monoheteroaryl or an 8-14 membered biheteroaryl group, more preferably a 5-membered monoheteroaryl, a 6-membered monoheteroaryl or a 9-membered biheteroaryl group, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridoimidazolyl, pyrimidoimidazolyl and the like, preferably pyridoimidazolyl and pyrimidoimidazolyl.

[0172] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0173] The term "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include:

[0174] Pyridinylene, pyrimidinylene, pyrazolylene, pyridazinylene, pyrazinylene,

[0175] Term " alkoxy " refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), and wherein the definition of alkyl is as described above.The limiting examples of alkoxy comprises: methoxyl group, ethoxyl, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally substituted or non-substituted, and when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.Non-limiting examples comprise trifluoromethoxy, trifluoroethoxy, difluoromethoxy.

[0176] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0177] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0178] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. Non-limiting examples include: -C(CH3)2(OH).

[0179] “Hydroxy” refers to an -OH group. “Halogen” refers to fluorine, chlorine, bromine, or iodine. “Amino” refers to -NH2. “Cyano” refers to -CN. “Nitro” refers to -NO2. “Carboxy” refers to -C(O)OH. “THF” refers to tetrahydrofuran. “EtOAc” refers to ethyl acetate. “MeOH” refers to methanol. “DMF” refers to N,N-dimethylformamide. “TFA” refers to trifluoroacetic acid. “MeCN” refers to acetonitrile. “DMA” refers to N,N-dimethylacetamide. “Et2O” refers to diethyl ether. “DCE” refers to 1,2-dichloroethane. “DIPEA” refers to N,N-diisopropylethylamine. “NBS” refers to N-bromosuccinimide. “NIS” refers to N-iodosuccinimide. “Cbz-Cl” refers to benzyl chloroformate. “Pd2(dba)3” refers to tris(dibenzylideneacetone)dipalladium. “Dppf” refers to 1,1′-bis(diphenylphosphino)ferrocene. “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate. “KHMDS” refers to potassium hexamethyldisilazide. “LiHMDS” refers to lithium bis(trimethylsilylamide). “MeLi” refers to methyllithium. “n-BuLi” refers to n-butyllithium. “NMP” refers to N-methylpyrrolidone. “EDCI” refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. “TEA” refers to triethylamine. “EA” refers to ethyl acetate. “DCM” refers to dichloromethane. “DMAP” refers to 4-dimethylaminopyridine. “NMO” refers to N-methylmorpholine oxide. “DIBAL-H” refers to diisobutylaluminum hydride. “T3P” refers to 1-propylphosphoric anhydride. “DMP” refers to dimethyl phthalate. “Dess-Martin” refers to Dess-Martin periodinane. “Ruphos” refers to 2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl. “Ruphos Pd G3” refers to (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium(II) methanesulfonate. “LDA” refers to lithium diisopropylamide. “SEMCl” refers to 2-(trimethylsilyl)ethoxymethyl chloride. “STAB” refers to sodium triacetoxyborohydride. “P-TSA” refers to p-toluenesulfonic acid. “PCC” refers to pyridinium chlorochromate. "Pd-PEPPSI" refers to 1,3-bis[2,6-bis(pentyl-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yldichloro(2-methyl-1λ4-pyridin-1-yl)palladium. "LiBH4" refers to lithium borohydride. "DCE" refers to 1,2-dichloroethane. "SEM" refers to (trimethylsilyl)ethoxymethyl. "TEBAC" refers to benzyltriethylammonium chloride.

[0180] "wt%" means percent by mass.

[0181] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0182] In the present invention Indicates that the key does not exist;

[0183] Unless otherwise specified, the chiral carbon atoms in the compounds of the present invention are in the R or S configuration.

[0184] The absolute configuration of the chiral compound in the present invention can be obtained by performing separation using conventional chiral separation methods in the art or preparing the compound using chiral raw materials.

[0185] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atom in the example compounds of the present invention may also be replaced by a deuterium atom.

[0186] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0187] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0188] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0189] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0190] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0191] The starting materials and reagents used in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art. For example, compound 1-1 of the present invention can be prepared with reference to the method disclosed in WO2020264499A1; compound 46-1 of the present invention can be prepared with reference to the method disclosed in WO2022028547A1.

[0192] Preparation of intermediate A

[0193] Step 1: Preparation of compound A-2

[0194] At room temperature, ground potassium hydroxide (11.6 g, 207 mmol) powder was added to a DMSO (100 ml) solution of racemic 1-BOC-3-hydroxymethylpiperazine A-1 (15 g, 69 mmol) and 3,4-difluoronitrobenzene (12.8 g, 80.05 mmol), and the temperature was raised to 60 degrees for 8 hours. After the reaction was complete, ice water was added to the reaction solution. The solid formed was collected by filtration, washed with water, and then purified by flash column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a yellow solid product compound A-2 (16.2 g, yield 70%).

[0195] LCMS: (ESI, m / z): 336.4 [M+H] + .

[0196] Step 2: Preparation of compound A-3

[0197] A solution of compound A-2 (1 g, 2.982 mmol, 1 equiv) in methanol (30 mL) was added to an autoclave, followed by palladium on carbon (10%, 100 mg). The atmosphere was replaced with nitrogen and hydrogen (5 MPa) was introduced, allowing the reaction to proceed overnight at room temperature. Celite was then added for filtration, and the filtrate was concentrated under reduced pressure to yield compound A-3 (900 mg, 98.8%) as a brown solid.

[0198] LCMS: (ESI, m / z): 306.5 [M+H] + .

[0199] Step 3: Preparation of Compound A-4

[0200] To a solution of compound A-3 (900 mg, 2.947 mmol, 1 equiv) in acetonitrile (10 mL) at room temperature was added 4-methylbenzene-1-sulfonic acid (1.02 g, 5.894 mmol, 2 equiv). After the addition was complete, the system was stirred at room temperature for 10 minutes. At 0°C, an aqueous solution of sodium nitrite (406.7 mg, 5.894 mmol, 2 equiv) and an aqueous solution of potassium iodide (1.47 g, 8.841 mmol, 3 equiv) were added. After the addition was complete, the system was stirred at room temperature for 4 hours. The desired product was observed in the liquid. The reaction mixture was quenched with saturated aqueous sodium sulfite at 0°C. The reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic phases were backwashed with saturated sodium bicarbonate solution (2 x 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate: petroleum ether (0-50%) to obtain yellow solid compound A-4 (360 mg, 29.4%).

[0201] LCMS: (ESI, m / z): 361.3 [M+H] + .

[0202] Step 4: Preparation of compound A-5

[0203] Under nitrogen, to a solution of compound A-4 (360 mg, 0.865 mmol, 1 equiv) and 2,6-bisbenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (433.1 mg, 1.038 mmol, 1.2 equiv) in tetrahydrofuran (6 mL) and water (3 mL) were added tetrakis(triphenylphosphine)palladium (299.82 mg, 0.260 mmol, 0.3 equiv) and potassium carbonate (239.05 mg, 1.730 mmol, 2 equiv) at room temperature. After the addition was complete, the system was stirred at 60°C overnight. The desired product was found in the liquid phase. The resulting residue was concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate:petroleum ether (0-50%) to afford compound A-5 (160 mg, 31.91%) as a yellow solid.

[0204] LCMS: (ESI, m / z): 580.6 [M+H] + .

[0205] Step 5: Preparation of Compound A-6

[0206] A solution of compound A-5 (120 mg, 0.207 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added to an autoclave, followed by palladium on carbon (10%, 100 mg) and palladium hydroxide on carbon (20% palladium content, 100 mg). The atmosphere was replaced with nitrogen and hydrogen (5 MPa) was introduced. The reaction was allowed to proceed at 60°C overnight. Celite was then added for filtration, and the filtrate was concentrated under reduced pressure to yield compound A-6 (58 mg, 69.8%) as a brown solid.

[0207] LCMS: (ESI, m / z): 402.5 [M+H] + .

[0208] Step 6: Preparation of Compound A

[0209] To a solution of compound A-6 (58 mg, 0.144 mmol, 1 equiv) in 1,4-dioxane (1 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) at room temperature. After the addition was complete, the system was stirred at room temperature overnight. The desired product was observed in the liquid phase. The resulting residue was concentrated in vacuo to afford compound A (40 mg, 91.8%) as a brown solid.

[0210] LCMS: (ESI, m / z): 302.4 [M+H] + .

[0211] Intermediate A is split using conventional chiral splitting methods in the art to obtain intermediates J and H.

[0212] Preparation of intermediate B

[0213] Step 1: Synthesis of Compound B-2

[0214] Under nitrogen, isopropylmagnesium chloride-lithium chloride complex (0.47 g, 3.226 mmol, 1.1 equiv) was added to a solution of methyl 5-bromo-2-iodobenzoate (1 g, 2.933 mmol, 1 equiv) and tert-butyl 4-oxopiperidine-1-carboxylate (0.64 g, 3.226 mmol, 1.1 equiv) in tetrahydrofuran (40 mL) at -78°C and allowed to react for 2 hours at -78°C. After completion of the reaction, water (5 mL) was added at 0°C to quench the reaction. The mixture was then extracted with ethyl acetate (3 x 40 mL), and the combined organic layers were washed with water (3 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (5:1) to obtain compound B-2 (900 mg, 80.3%) as a white solid.

[0215] 1 H NMR(400MHz,Chloroform-d,ppm)δ8.03(d,J=1.8Hz,1H),7.80(dd,J=8.1,1.8Hz,1H),7.28(s,1H),4.20 (d,J=13.7Hz,2H),3.24(t,J=13.1Hz,2H),2.11–2.02(m,2H),1.68(dd,J=14.4,2.5Hz,2H),1.68(s,9H).

[0216] Step 2: Synthesis of Compound B-3

[0217] Under nitrogen, a solution of compound B-2 (900 mg, 2.354 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added dropwise with a 2 M solution of lithium borohydride in THF (17.7 mmol, 7.5 equiv) at 0°C. The reaction mixture was stirred at room temperature overnight. After completion, the reaction was quenched with water and a saturated sodium bicarbonate solution at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were backwashed with water (3 x 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (4:1) to afford compound B-3 (700 mg, 77.4%) as a white foam.

[0218] LCMS: (ESI, m / z): 384.2 [M+H] + .

[0219] Step 3: Synthesis of Compound B-4

[0220] To a solution of compound B-3 (300 mg, 0.781 mmol, 1 equiv) and triethylsilane (136.17 mg, 1.171 mmol, 1.5 equiv) in dichloromethane (3 mL) was added dropwise boron trifluoride etherate (221.61 mg, 1.562 mmol, 2.0 equiv) at 0°C and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with water at room temperature. The mixture was extracted with dichloromethane (3 x 10 mL), and the combined organic phases were backwashed with water (3 x 5 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with dichloromethane / methanol (10:1) to afford compound B-4 (160 mg, 76.4%) as a white solid.

[0221] LCMS: (ESI, m / z): 268.1 [M+H] + .

[0222] Step 4: Synthesis of Compound B-5

[0223] To a solution of compound B-4 (160 mg, 0.597 mmol, 1.0 equiv) and triethylamine (72.5 mg, 0.716 mmol, 1.5 equiv) in dichloromethane (2 mL) was added dropwise di-tert-butyl dicarbonate (260.5 mg, 1.194 mmol, 2.0 equiv) at room temperature. The reaction was stirred overnight. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (10:1) to obtain compound B-5 (215 mg, 97.8%) as a white solid.

[0224] 1 H NMR(400MHz,Chloroform-d,ppm)δ7.42–7.38(d,J=1.6Hz,1H),7.36(d,J=1.6Hz,1H),6.96(d,J=8.0H z,1H),5.04(s,2H),4.12–4.03(m,2H),3.15(td,J=12.9,3.1Hz,2H),1.82–1.67(m,4H),1.49(s,9H).

[0225] Step 5: Synthesis of Compound B-6

[0226] Under nitrogen protection, to a solution of compound B-5 (210 mg, 0.570 mmol, 1.0 equiv) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (309.35 mg, 0.741 mmol, 1.3 equiv) in 1,4-dioxane (5 mL) and water (1 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (46.5 mg, 0.057 mmol, 0.1 equiv) and potassium carbonate (157.6 mg, 1.14 mmol, 2.00 equiv) at room temperature. The reaction was stirred at 90°C for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with water (3 x 30 mL), and dried over anhydrous sodium sulfate. The resulting residue was purified by reverse-phase column chromatography using the following conditions: C18 column, mobile phase: water and acetonitrile, 50% to 95% gradient over 20 minutes, UV spectroscopy at 220 nm, to afford compound B-6 (160 mg, 48.5%) as a white solid.

[0227] LCMS: (ESI, m / z): 579.3 [M+H] + .

[0228] Step 6: Synthesis of Compound B-7

[0229] At room temperature, a solution of compound B-6 (120 mg, 0.207 mmol, 1.0 equiv) in anhydrous methanol (2 mL) was added to a 10 mL autoclave, and palladium / carbon (22.07 mg, 0.207 mmol, 1.0 equiv) was added. Under hydrogen protection, the reaction was stirred at room temperature for 8 hours. After the reaction was completed, the filter cake was washed with methanol (15 mL), and the filtrate was concentrated under reduced pressure to obtain a white solid compound B-7 (60 mg, 72.25%). The crude product was not further purified and was directly used in the next step.

[0230] LCMS: (ESI, m / z): 401.2 [M+H] + .

[0231] Step 7: Synthesis of Compound B

[0232] To a solution of compound B-7 (50 mg, 0.125 mmol) in tetrahydrofuran (2 mL) was added dropwise a solution of hydrogen chloride in 1,4-dioxane (1 M, 0.08 mL) at room temperature. The reaction was stirred for 2 hours. After completion of the reaction, the residue was concentrated under reduced pressure to give compound B (30 mg, 80%) as a white solid.

[0233] LCMS: (ESI, m / z): 301.2 [M+H] + .

[0234] Preparation of intermediate C

[0235] Step 1: Synthesis of compound C-3

[0236] Under nitrogen protection, to a solution of compound C-1 (500 mg, 1.36 mmol), C-2 (185.9 mg, 1.63 mmol), cesium carbonate (884.7 mg, 2.72 mmol), bicyclohexyl (3-isopropoxy-2′, 4′, 6′-triisopropyl-[1,1′-biphenyl]-2-yl) phosphine (145.2 mg, 0.27 mmol) in 1,4-dioxane (5 mL) was added (methanesulfonic acid {bicyclohexyl (3-isopropoxy-2′, 4′, 6′-triisopropyl-[1,1′-biphenyl]-2-yl) phosphine) (145.2 mg, 0.27 mmol) The reaction mixture was stirred at 100°C for 4 hours with 1,2-dimethylamino-2'-(2'-methylamino-1,1'-biphenyl-2-yl)-1,2-dimethylamino-2'-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (124.7 mg, 0.136 mmol). After the disappearance of the starting material on HPLC-MS / MS monitoring, the resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with dichloromethane:methanol (0-30%) to obtain compound C-3 (150 mg, 27.5%).

[0237] LCMS (ESI, m / z): 346.0 [M-55] + .

[0238] Step 2: Synthesis of Compound C

[0239] Compound C-3 (150 mg, 0.374 mmol) was dissolved in a 4 mol / L hydrogen chloride solution in 1,4-dioxane (3 mL) at room temperature. The reaction mixture was stirred for 2 hours. After the disappearance of the starting material by mass spectrometry, the residue was concentrated under reduced pressure to yield Intermediate C (100 mg, 88.8%). LCMS (ESI, m / z): 302.5 [M+H] + .

[0240] Preparation of intermediate D

[0241] Compound B-2 was substituted for compound B-5 and the preparation method of intermediate B was followed to obtain intermediate D. LCMS (ESI, m / z): 315.0 [M+H] + .

[0242] Preparation of intermediate E

[0243] Compounds replace Referring to the preparation method of intermediate A, intermediate E was obtained. LCMS (ESI, m / z): 320.5 [M+H] + .

[0244] Preparation of intermediate Ea

[0245] Compounds replace Substitute A-1 and refer to the preparation method of intermediate A to obtain intermediate Ea. LCMS (ESI, m / z): 320.1 [M+1] + .

[0246] Preparation of intermediate Eb

[0247] Compounds replace Substitute A-1 and refer to the preparation method of intermediate A to obtain intermediate Eb. LCMS (ESI, m / z): 320.1 [M+1] + .

[0248] Preparation of intermediate F

[0249] Compounds replace Intermediate F was obtained by referring to the preparation method of intermediate A. LCMS (ESI, m / z): 303.1 [M+H] + .

[0250] Preparation of intermediate G

[0251] Under nitrogen, potassium iodide (110.2 mg, 0.663 mmol, 0.5 eq) was added to a solution of Intermediate A (400 mg, 1.33 mmol, 1 eq), 2-bromo-1,1-dimethoxyethane (224.4 mg, 1.33 mmol, 1 eq), and potassium carbonate (366.9 mg, 2.66 mmol, 2 eq) in acetonitrile (4 mL) at room temperature. The temperature was then raised to 80°C and stirred overnight. The starting material disappeared upon liquid chromatography-mass spectrometry. The product was filtered, the filter cake washed with tetrahydrofuran (3 x 30 mL), and the filtrate concentrated under reduced pressure. The crude product was purified by HPLC to yield compound G-1 (200 mg, 38.7%) using the following conditions (column size: YMC Triart C18 ExRs 5 μm, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 23% B to 38% B over 10 minutes; detection wavelength: UV 254 nm; retention time (min): 9.97). LCMS (ESI, m / z): 390.1 [M+H] + .

[0252] G-1 (70 mg, 0.18 mmol, 1 eq) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 3.6 mL) at room temperature and stirred overnight. The desired product was found in the liquid. The resulting residue was concentrated in vacuo to obtain Intermediate G (80 mg, crude) as a white solid. LCMS (ESI, m / z): 344.2 [M+H] + .

[0253] Alternative preparation of intermediate H

[0254] Compounds Replace compound A-1 and refer to the preparation method of intermediate A to obtain intermediate H. LCMS (ESI, m / z): 301.9 [M+H] + .

[0255] Preparation of intermediate I

[0256] Compounds Substituting compound A-1 for compound H-6, the preparation method for compound A-6 was followed to obtain compound H-6. Under nitrogen, lithium bis(trimethylsilylamide) (1.9 mL, 1 M) was added dropwise to a solution of compound H-6 (300 mg, 0.747 mmol, 1 eq) in tetrahydrofuran (7.5 mL) at -78°C. After the addition was complete, the system was stirred at -78°C for 1 hour. Deuterated water (1.2 mL) was added to the above system at -78°C. After the addition was complete, the system was stirred at room temperature overnight. The desired product was observed in the liquid phase. The reaction mixture was quenched with aqueous citric acid at room temperature. The reaction mixture was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, backwashed with water (1 x 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain I-1 (140 mg, 44.6%) as a white solid. LCMS (ESI, m / z): 421.2 [M+H] + .

[0257] To a solution of I-1 (100 mg, 0.238 mmol, 1 eq) in acetonitrile (2.35 mL) at room temperature was added 1,1'-carbonyldiimidazole (154.3 mg, 0.96 mmol, 4 eq). After the addition was complete, the system was stirred at 90°C for 1 hour. The reaction was complete by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-60%) to obtain I-2 (61 mg, 63.7%) as a white solid. LCMS (ESI, m / z): 402.9 [M+H] + .

[0258] To a solution of hydrogen chloride in 1,4-dioxane (1.8 mL, 4 M) at room temperature was added I-2 (73 mg, 0.181 mmol, 1 eq). After the addition was complete, the system was stirred at room temperature for 1 hour. The reaction was complete by liquid chromatography-mass spectrometry. The resulting residue was concentrated in vacuo to afford Intermediate I (65 mg) as an off-white solid. LCMS (ESI, m / z): 303.4 [M+H] + .

[0259] Alternative preparation method of intermediate J

[0260] by Replace compound A-1 and refer to the preparation method of intermediate A to obtain intermediate J. LCMS (ESI, m / z): 302.4 [M+H] + .

[0261] Preparation of intermediate K

[0262] Compound B-2 was substituted for compound C-1, and the preparation method of intermediate C was referred to obtain intermediate K. LCMS (ESI, m / z): 316.1 [M+H] + .

[0263] Preparation of intermediate L

[0264] Compounds replace Replacing A-1 yielded compound L-1. Under nitrogen, sodium bicarbonate (779.4 mg, 9.3 mmol, 3 eq) was added to a solution of L-1 (1 g, 3.1 mmol, 1 eq) and 3-bromopiperidine-2,6-dione (890.7 mg, 4.64 mmol, 1.5 eq) in dimethylformamide (10 mL). After complete addition, the system was stirred at 65°C for 16 hours. Liquid chromatography-mass spectrometry confirmed the reaction was complete. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were backwashed with saturated brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to yield L-2 (600 mg, 44.7%) as a light green solid. LCMS (ESI, m / z): 435.2 [M+H] + .

[0265] A solution of L-2 (200 mg, 0.46 mmol, 1 eq) and a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 M) was stirred at room temperature for 1 hour. The reaction was complete by liquid chromatography-mass spectrometry (LC-MS / MS). The resulting residue was concentrated under reduced pressure to afford Intermediate L (150 mg, 97.5%) as an off-white solid. LCMS (ESI, m / z): 334.9 [M+H] + .

[0266] Preparation of intermediate M

[0267] M-1 (15 g, 73.9 mmol, 1.0 eq) was added to the reaction flask. After nitrogen substitution, THF (130 ml) was added. A THF solution (20 ml) of ethyl propiolate (7.97 g, 81.3 mmol, 1.1 eq) was added dropwise at -78°C. After the addition was complete, LDA (2 M, 40.6 ml, 81.3 mmol, 1.1 eq) was added dropwise at -78°C. The mixture was stirred at -78°C for 2 h. TLC monitored the reaction of the starting material. The reaction was returned to room temperature and quenched with aqueous ammonium chloride. After complete quenching, EA was added to extract the liquid. The organic phase was dried over sodium sulfate and then spin-dried to dryness. The resulting crude oil, M-2 (12.0 g, yield: 53.8%), was used directly in the next step. LCMS (ESI, m / z): 300.8 [M+H] + .

[0268] The crude product M-2 (12.0 g, 1.0 eq) obtained above was dissolved in 1,4-dioxane (100 ml), followed by the addition of triethylamine (14 ml, 121.7 mmol, 2.5 eq) and the reaction was carried out at 60°C for 3 h. TLC confirmed the complete reaction. The reaction solution was cooled to room temperature and then dried to give 7 g of an oily product, M-3, in a yield of 58.3%. LCMS (ESI, m / z): 300.8 [M+H] + .

[0269] The above-mentioned M-3 (5.1 g, 17 mmol, 1.0 eq) was dissolved in DMF (60 ml) in a sealed tube. Ethylenediamine (2.0 g, 34 mmol, 2.0 eq) and triethylamine (7 ml, 51 mmol, 3.0 eq) were added, and the mixture was heated to 60°C and stirred for 16 h. TLC confirmed the complete reaction. After the reaction solution was cooled to room temperature, water (10 mL) was added, and EA was extracted. The mixture was separated and dried, concentrated, and purified by chromatography to obtain 3.7 g of a yellow solid M-4 (yield: 74.03%). LCMS (ESI, m / z): 295.0 [M+H] + .

[0270] M-4 (300 mg, 1.02 mmol, 1.0 eq) was dissolved in THF (5 ml). After nitrogen replacement, borane tetrahydrofuran solution (4.08 ml, 4.08 mmol, 4 eq) was added dropwise under ice bath. The temperature was raised to 60 ° C overnight. TLC monitored the reaction to be complete. Methanol was slowly added dropwise at low temperature until no bubbles were generated. The mixture was stirred at 60 ° C for 2 h. 0.5 ml of 1 M aqueous hydrochloric acid solution was added and stirring was continued at 60 ° C overnight. After LCMS monitoring confirmed that the quenching was complete, the mixture was cooled to room temperature and triethylamine (412 mg, 4.08 mmol, 4.0 eq) was added and stirred for 0.5 h. After the solvent was dried, DCM (10 ml) and (BOC) 2 O (445 mg, 2.04 mmol, 2.0 eq) were added. The mixture was stirred at room temperature for 5 h. The reaction was monitored by TLC to be complete. Water (10 mL) was added, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a colorless oil M-6 (360 mg, yield: 96.4%). LCMS (ESI, m / z): 367.1 [M+H] + .

[0271] M-6 (140 mg, 0.38 mmol, 1.0 eq) was dissolved in 5 ml of DMF, and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (318 mg, 0.76 mmol, 2.0 eq), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (50.4 mg, 0.076 mmol, 0.2 eq), cesium fluoride (174 mg, 1.15 mmol, 3.0 eq), and water (1 ml) were added. After nitrogen substitution, the mixture was stirred at 80°C for 3 h. The reaction was stopped after completion of the reaction as monitored by TLC. After cooling the reaction solution to room temperature, water (10 mL) was added, and the mixture was extracted with EA. The separated layers were dried, concentrated, and purified by column chromatography to afford M-7 (120 mg, yield: 54.4%) as a pale yellow oil. LCMS (ESI, m / z): 578.3 [M+H] + .

[0272] M-7 (120 mg, 0.21 mmol, 1.0 eq) was dissolved in 2 ml of isopropanol, and Pd / C (12 mg) and palladium hydroxide on carbon (12 mg) were added. After hydrogen substitution, the mixture was stirred at room temperature for 16 h. The reaction was complete as monitored by TLC. The reaction solution was filtered through celite, and the mother liquor was concentrated to obtain a light yellow oil, M-8 (70 mg, yield: 84.4%). LCMS (ESI, m / z): 400.2 [M+H] + .

[0273] M-8 (70 mg, 0.18 mmol, 1.0 eq) was dissolved in 2 ml of DCM, and HCl-dioxane (4 M, 0.44 ml, 1.8 mmol, 10 eq) was added. The mixture was stirred at room temperature for 2 h. The reaction was complete after TLC monitoring. The reaction solution was concentrated, dispersed in DCM, and then dried to give M as a light yellow oil (40 mg, yield: 76.9%). LCMS (ESI, m / z): 300.2 [M+H] + .

[0274] Preparation of intermediate N

[0275] M-6 (90 mg, 0.25 mmol, 1.0 eq), dihydrouracil (42 mg, 0.37 mmol, 1.5 eq), Brettphos Pd G4 (45 mg, 0.05 mmol, 0.2 eq), cesium carbonate (240 mg, 0.74 mmol, 3.0 eq), and dioxane (2 ml) were added to the reaction flask. After nitrogen substitution, the mixture was stirred at 100°C for 4 h. TLC monitored the complete reaction of the starting materials. The reaction mixture was cooled to room temperature, extracted with water and EA, and the organic phase was dried over sodium sulfate and subjected to column chromatography to obtain an oily product, N-1 (45 mg, yield: 45.8%). LCMS (ESI, m / z): 400.8 [M+H] + .

[0276] N-1 (45 mg, 0.11 mmol, 1.0 eq) was dissolved in 2 ml of DCM, and HCl-dioxane (4 M, 0.28 ml, 1.1 mmol, 10 eq) was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by TLC. The reaction solution was directly spin-dried to give 35 mg of intermediate N as a light yellow oil. The crude yield was 103%. LCMS (ESI, m / z): 301.1 [M+H] + .

[0277] Preparation of intermediate O

[0278] To a solution of compound A-6 (1 g, 2.491 mmol, 1 eq) in N,N-dimethylformamide (20 mL) at 0°C was added sodium hydride (110 mg, 60%). After the addition was complete, the system was stirred at 0°C for 0.5 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (458 mg, 2.747 mmol, 1.10 eq) was added to the above system at 0°C. After the addition was complete, the system was stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry confirmed the reaction was complete. The reaction mixture was quenched with water at 0°C. The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate:petroleum ether (0-30%) to afford compound O-1 (770 mg, 58.14%) as a yellow oil. LCMS: (ESI, m / z): 532.5 [M+H] + .

[0279] Under nitrogen, a solution of compound O-1 (320 mg, 0.602 mmol, 1 eq) in tetrahydrofuran (5 mL) was added with a 1 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (0.72 mL) at -78°C. After the addition was complete, the mixture was stirred at -78°C for 1 hour. Methyl iodide (171 mg, 1.205 mmol, 2.00 eq) was added to the above mixture at -78°C. After the addition was complete, the mixture was stirred at -78°C for 1 hour. Stirring was then continued at room temperature for 0.5 hour. Liquid chromatography-mass spectrometry confirmed the reaction was complete, and the reaction mixture was quenched with water at 0°C. The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 x 100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate:petroleum ether (0-50%) to obtain compound O-2 (137 mg, 41.71%) as a brown oil. LCMS (ESI, m / z): 546.2 [M+H] + .

[0280] To a solution of compound O-2 (124 mg, 0.227 mmol, 1 eq) in dichloromethane (4 mL) at room temperature was added trifluoroacetic acid (0.6 mL, 8.078 mmol, 35.55 eq). The mixture was stirred at room temperature for 1 hour after the addition was complete. Liquid chromatography-mass spectrometry confirmed the complete reaction of the starting materials. Ethylenediamine (0.8 mL) was added to the mixture at 0°C. Stirring was continued at room temperature for 1 hour after the addition was complete. Liquid chromatography-mass spectrometry confirmed the reaction was complete, and the desired product was detected in the HPLC-mass spectrometry. The reaction mixture was neutralized to pH 7 with citric acid. 10 mL of water was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. Intermediate O (98 mg, 94.37%) was obtained as a crude yellow solid. LCMS: (ESI, m / z): 316.1 [M+H] + .

[0281] Preparation of intermediate P

[0282] by Replace compound A-1 and refer to the preparation method of compound A-6 to obtain compound H-6, and then refer to the preparation method of intermediate O to obtain intermediate P. LCMS: (ESI, m / z): 316.2 [M+H] + .

[0283] Preparation of intermediate Q

[0284] by Replace compound A-1 and refer to the preparation method of compound A-6 to obtain compound J-6, and then refer to the preparation method of intermediate O to obtain intermediate Q. LCMS: (ESI, m / z): 316.2 [M+H] + .

[0285] Preparation of intermediate R

[0286] Compounds replace Intermediate R was obtained by referring to the preparation method of intermediate A. LCMS (ESI, m / z): 336.1 [M+1] + .

[0287] Preparation of intermediate S

[0288] Compounds replace Referring to the preparation method of intermediate A, intermediate S was obtained. LCMS (ESI, m / z): 336.1 [M+1] + .

[0289] Preparation of intermediate T

[0290] Compounds Substitute A-1 and refer to the preparation method of intermediate A to obtain intermediate T. LCMS (ESI, m / z): 316.4 [M+1] + .

[0291] Preparation of intermediate U

[0292] Compounds Replace M-6 and refer to the preparation method of intermediate N to obtain intermediate U. LCMS (ESI, m / z): 303.1 [M+1] + .

[0293] Preparation of intermediate V

[0294] Compounds Substitute A-4 and refer to the preparation method of intermediate A to obtain intermediate V. LCMS (ESI, m / z): 328.2 [M+1] + .

[0295] Preparation of intermediate W

[0296] Compounds Replace M-6 and refer to the preparation method of intermediate N to obtain intermediate W. LCMS (ESI, m / z): 321.1 [M+1] + .

[0297] Preparation of intermediate Y-1

[0298] Intermediate Y-1 was synthesized with reference to the prior art WO2023283610 A1.

[0299] Preparation of intermediate Y-2

[0300] Intermediate Y-2 was synthesized with reference to the prior art WO02023283372A1.

[0301] Preparation of intermediate Y-3

[0302] Intermediate Y-3 was synthesized with reference to the prior art WO2022028547A1.

[0303] Preparation of intermediate Y-4

[0304] Intermediate Y-4 was synthesized with reference to the prior art WO2022028547A1.

[0305] Preparation of intermediate Y-5-1

[0306] At 5 ° C, 2-fluoro-4-methoxybenzaldehyde (24 g, 155.7 mmol, 1 eq) was added to a solution of bromine (49.77 g, 311.4 mmol, 2 eq) and potassium bromide (92.6 g, 778.5 mmol, 5 eq) in water (310 mL) and stirred at room temperature for 2 hours. After the reaction was completed, water (500 mL) was added to the system. A large amount of solid precipitation was observed. The filter cake was collected by filtration and washed with saturated sodium bicarbonate solution (3X200 mL). After freeze-drying, 5-bromo-2-fluoro-4-methoxybenzaldehyde (Y-5-1-1, 30 g, 82.7%) was obtained as a yellow solid.

[0307] In an autoclave, 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (3.50 g, 4.3 mmol, 0.05 eq) and triethylamine (17.37 g, 171.6 mmol, 2 eq) were added to a 300 mL methanol solution of compound Y-5-1-1 (20 g, 85.8 mmol, 1 eq). The atmosphere was replaced with nitrogen for 10 minutes, and carbon monoxide was introduced to 5 MPa. The reaction was continued at 120°C for 2 hours. Liquid chromatography-mass spectrometry was used to monitor the reaction completion. The system was cooled to room temperature, and the insoluble material was removed by filtration. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-60%) to obtain methyl 4-fluoro-5-formyl-2-methoxybenzoate Y-5-1-2 (8.7 g, 47%) as an off-white solid.

[0308] 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.17(d,J=8.3Hz,1H),7.25(d,J=13.1Hz,1H),3.94(s,3H),3.81(s,3H).

[0309] Under nitrogen protection, sodium azide (5.81 g, 89.4 mmol, 2 eq) was added portionwise to a solution of compound Y-5-1-2 (8.9 g, 42.9 mmol, 1 eq) in dimethyl sulfoxide (150 mL) at room temperature. After stirring for 4 h, the reaction was monitored for completion. The reaction mixture was quenched with ice water at 0 degrees Celsius. The reaction mixture was extracted with ethyl acetate (3 × 300 mL). The organic phases were combined, backwashed with saturated sodium bicarbonate aqueous solution (2 × 300 mL), and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure to give Y-5-1-3 (7.9 g, 75.2%) as a brown solid.

[0310] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.12(s,1H),7.10(s,1H),4.00(s,3H),3.80(s,3H).

[0311] Under nitrogen protection, triethylamine (10.2 g, 100.8 mmol, 3 eq) was added to a toluene (200 mL) solution of methyl 4-azido-5-formyl-2-methoxybenzoate Y-5-1-3 (7.9 g, 33.6 mmol, 1 eq) and Y-5-1-4 (5.77 g, 40.3 mmol, 1.2 eq) at 110 degrees Celsius. The reaction was stirred overnight and the reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3×200 mL), the organic phases were combined, and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to give Y-5-1-5 (3.5 g, 31.4%) as a yellow solid. LCMS: (ES, m / z): 333.4 [M+1] + .

[0312] Under nitrogen protection, silver oxide (4.88 g, 21.1 mmol, 2 eq) was added to a solution of Y-5-1-5 (3.5 g, 10.529 mmol, 1 eq) and benzyl bromide (18.01 g, 105.3 mmol, 10 eq) in dichloromethane (50 mL) at 50 degrees Celsius and stirred for 2 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography with petroleum ether / dichloromethane (0-50%) to obtain Y-5-1-6 (3.1 g, 69.7%) as a brown oil. LCMS: (ES, m / z): 423.5 [M+1] + .

[0313] To a solution of compound Y-5-1-6 (2.8 g, 6.6 mmol) and water (3 mL) in methanol (30 mL) was added lithium hydroxide (476.14 mg, 19.9 mmol) and the reaction was stirred at 50 degrees Celsius for 3 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was quenched with ice water at 0 degrees Celsius. The reaction mixture was acidified to pH = 4 with citric acid, and the reaction mixture was extracted with ethyl acetate (3X100 mL). The organic phases were combined and dried over sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. Y-5-1-7 (2 g, 73.8%) was obtained as a brown solid. LCMS: (ES, m / z): 409.5 [M+1] + .

[0314] Under nitrogen protection, at 50 degrees Celsius, to a solution of compound Y-5-1-7 (1.9 g, 4.6 mmol, 1 eq) and 6-(trifluoromethyl)pyridin-2-amine (754.03 mg, 4.65 mmol) in dichloromethane (30 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5.22 g, 18.6 mmol) and N-methylimidazole (3.82 g, 46.5 mmol) were added in batches. The reaction was stirred overnight and the reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to obtain Y-5-1 (1.5 g, 58.4%) as a yellow solid. LCMS: (ES, m / z): 553.5 [M+1] + .

[0315] Preparation of intermediate Y-5

[0316] Under nitrogen protection, at 110 degrees Celsius, triethylamine (10.2 g, 100.9 mmol) was added to a toluene (200 mL) solution of methyl 4-azido-5-formyl-2-methoxybenzoate (7.9 g, 33.62 mmol) and 2-[(1r, 4r)-4-aminocyclohexyl]ethanol (5.77 g, 40.3 mmol). The reaction was stirred overnight and the reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3×200 mL), the organic phases were combined, and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to give Y-5-1 (3.5 g, 31.4%) as a yellow solid. LCMS: (ES, m / z): 333.5 [M+1] + .

[0317] Under nitrogen protection, silver oxide (4.88 g, 21.1 mmol) was added to a solution of Y-5-1 (3.5 g, 10.5 mmol) and benzyl bromide (18 g, 105.3 mmol) in dichloromethane (50 mL) at 50 degrees Celsius and stirred for 2 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography with petroleum ether / dichloromethane (0-50%) to obtain Y-5-2 (3.1 g, 69.7%) as a brown oil. LCMS: (ES, m / z): 423.5 [M+1] + .

[0318] To a solution of compound Y-5-2 (2.8 g, 6.6 mmol) and water (3 mL) in methanol (30 mL) was added lithium hydroxide (476.2 mg, 19.9 mmol) and the reaction was stirred at 50 degrees Celsius for 3 hours. The reaction was completed by liquid chromatography-mass spectrometry. The reaction mixture was quenched with ice water at 0 degrees Celsius. The reaction mixture was acidified to pH = 4 with citric acid, and the reaction mixture was extracted with ethyl acetate (3X100 ml), the organic phases were combined, and dried over sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. Y-5-3 (2 g, 73.88%) was obtained as a brown solid. LCMS: (ES, m / z): 409.5 [M+1] + .

[0319] Under nitrogen protection, at 50 degrees Celsius, to a solution of Y-5-3 (1.9 g, 4.65 mmol) and 6-(trifluoromethyl)pyridin-2-amine (754.03 mg, 4.65 mmol) in dichloromethane (30 mL) were added in batches of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5.22 g, 18.6 mmol) and N-methylimidazole (3.82 g, 46.5 mmol). The mixture was stirred and reacted overnight. The reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to obtain Y-5-4 (1.5 g, 58.36%) as a yellow solid. LCMS: (ES, m / z): 553.5 [M+1] + .

[0320] Under nitrogen, boron trichloride (424.03 mg, 3.620 mmol, 5 equiv) was added to a solution of Y-5-4 (400 mg, 0.724 mmol, 1 equiv) in dichloromethane (5 mL) at 0°C. The reaction was stirred for 30 minutes. Liquid chromatography-mass spectrometry (LC-MS / MS) was used to monitor the reaction completion. The reaction mixture was quenched with saturated aqueous sodium bicarbonate at 0°C. The reaction mixture was extracted with dichloromethane (3 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford Y-5-5 (300 mg, 89.6%) as a pale yellow solid. LCMS (ESI, m / z): 463.1 [M+H] + .

[0321] Under nitrogen, Dess-Martin periodinane (275.14 mg, 0.649 mmol, 1.2 equiv) was added to a solution of Y-5-5 (250 mg, 0.54 mmol, 1 equiv) in dichloromethane (5 mL) at room temperature. After stirring for 2 hours, the reaction was complete by liquid chromatography-mass spectrometry (LC-MS / MS). The reaction mixture was quenched with water at 0°C. The reaction mixture was extracted with dichloromethane (3 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate Y-5 (200 mg, 80.35%) as a yellow solid. LCMS (ESI, m / z): 461.5 [M+H] + .

[0322] Preparation of intermediate Y-6

[0323] To a solution of Y-6-1 (10.3 g, 49.995 mmol, 1 eq) in dimethylformamide (100 mL) was added triethylamine (20.85 mL, 149.98 mmol, 3 eq) under ice-cooling, followed by the slow dropwise addition of Y-6-2 (8.23 g, 59.99 mmol, 1.2 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. LCMS monitoring indicated the disappearance of the starting material. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-30%) to afford Y-6-3 (14.3 g, 93.2%) as a white solid. LCMS (ESI, m / z): 307.0 [M+H] + .

[0324] Under nitrogen, to a solution of Y-6-3 (1.2 g, 3.91 mmol, 1 eq) in N,N-dimethylacetamide (19.6 mL) at room temperature were added Y-6-4 (2.29 g, 5.868 mmol, 1.5 eq), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (286.24 mg, 0.391 mmol, 0.1 eq), cuprous iodide (149.01 mg, 0.782 mmol, 0.2 eq), and triethylamine (5.44 mL, 39.120 mmol, 10 eq). The mixture was then heated to 80°C and stirred overnight. The reaction was monitored for completion by liquid chromatography-mass spectrometry. The reaction mixture was extracted with ethyl acetate (3 x 200 mL) and water (1 x 100 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 x 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) to obtain Y-6-5 (1.5 g, 58.0%) as a colorless oil. LCMS (ESI, m / z): 661.6 [M+H] + .

[0325] To a solution of Y-6-5 (1.05 g, 1.589 mmol, 1 eq) in dichloromethane (15 mL) was added amino 2,4,6-trimethylbenzenesulfonate (1.03 g, 4.767 mmol, 3 eq) at room temperature. After stirring for 2 hours, the desired product was found in the liquid. The resulting residue was concentrated under reduced pressure. This afforded Y-6-8 (1.3 g, crude product) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI, m / z): 676.6 [M+H] + .

[0326] Potassium carbonate (530.81 mg, 3.840 mmol, 2 eq) was added to a solution of Y-6-8 (1.3 g, 1.920 mmol, 1 eq) in methanol (8 mL) at room temperature. The reaction mixture was stirred for 2 hours, and the desired product was found in the liquid phase. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-30%) to obtain Y-6-9 (450 mg, 34.67%) as a light yellow oil. LCMS (ESI, m / z): 676.3 [M+H] + .

[0327] To a solution of Y-6-9 (360 mg, 0.533 mmol, 1 eq) in 1,2-dichloroethane (5.4 mL) was added trifluoroacetic acid (1.8 mL) at room temperature. The reaction mixture was heated to 50°C and stirred overnight. The desired product was found in the liquid phase. The resulting residue was concentrated under reduced pressure to afford compound Y-6-10 (220 mg, crude) as a light brown oil. LCMS (ESI, m / z): 318.5 [M+H] + .

[0328] To a solution of compound Y-6-10 (200 mg, 0.484 mmol, 1 eq) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (73.97 mg, 0.387 mmol, 0.8 eq) in tetrahydrofuran (4.8 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.452 mmol, 3 eq) and 2-chloro-1-methylpyridin-1-ium iodide (135.96 mg, 0.532 mmol, 1.1 eq) under ice-cooling. After the addition was complete, the system was stirred at room temperature for 4 hours. The desired product was observed in the liquid phase, and the starting material was essentially gone. The resulting residue was concentrated in vacuo and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-40%) to afford Y-6-11 (150 mg, 63.21%) as a yellow solid. LCMS (ESI, m / z): 491.1 [M+H] + .

[0329] Under nitrogen, methylmagnesium bromide (1.1 mL, 25.83 mmol, 10 eq) was added dropwise to a solution of Y-6-11 (150 mg, 0.306 mmol, 1 eq) in tetrahydrofuran (3 mL) at 0°C. After the addition was complete, the system was stirred at 0°C for 0.5 hours. The mixture was then warmed to room temperature and stirred for 3 hours. The desired product was found in the liquid phase. The reaction mixture was quenched by pouring it into saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate:dichloromethane (0-50%) to afford Y-6-12 (53 mg, 35.3%) as a yellow solid. LCMS (ESI, m / z): 491.5 [M+H] + .

[0330] To a solution of Y-6-12 (50 mg, 0.102 mmol, 1 eq) in dichloromethane (5.0 mL) at room temperature was added Dess-Martin periodinane (64.85 mg, 0.153 mmol, 1.50 eq). The reaction was continued for 2 hours, at which time the desired product was observed in the liquid phase and the starting material disappeared. Saturated aqueous sodium bicarbonate solution (20 mL) was added, and the reaction mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. Intermediate Y-6 (35 mg, 70.3%) was obtained as a yellow solid. LCMS (ESI, m / z): 489.5 [M+H] + .

[0331] Preparation of intermediate Y-7

[0332] Intermediate Y-7 was synthesized with reference to the prior art WO02023283372A1.

[0333] Preparation of intermediate Y-8

[0334] by Replacement compounds Intermediate Y-8 was prepared by the method disclosed in WO2020264499 A1 with reference to compound 1-1.

[0335] Preparation of intermediate Y-9

[0336] by Replacement compounds Intermediate Y-9 was prepared by the method disclosed in WO2020264499 A1 with reference to compound 1-1.

[0337] Preparation of intermediate Y-10

[0338] Step 1: Synthesis of compound Y-10-2

[0339] To a solution of 2-fluoro-4-hydroxybenzaldehyde (25 g, 178.427 mmol, 1 eq) in sulfuric acid (150 mL) was added dropwise a mixture of nitric acid (12 mL, 267.568 mmol, 1.50 eq) and nitric acid (12 mL, 267.568 mmol, 1.50 eq) at 0°C. The mixture was stirred for 2 hours. The reaction was then monitored by gas chromatography-mass spectrometry (GC-MS). The reaction mixture was poured into ice water to precipitate a solid. The solid was filtered, and the filter cake was collected and washed with water (4 x 100 mL) to afford 2-fluoro-4-hydroxy-5-nitrobenzaldehyde compound Y-10-2 (18 g, 54.50%) as an off-white solid. GCMS: 185.0 [M-1].+ .

[0340] Step 2: Synthesis of compound Y-10-3

[0341] Under nitrogen, sodium azide (10.54 g, 162.066 mmol, 2 eq) was added portionwise to a solution of compound Y-10-2 (15 g, 81.033 mmol, 1 eq) in dimethyl sulfoxide (80 mL) at room temperature. After stirring for four hours, the reaction was complete by liquid chromatography-mass spectrometry. The reaction mixture was quenched by adding ice water (200 mL) at 0°C and extracted with ethyl acetate (4 x 200 mL). The combined organic phases were backwashed with saturated brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 2-azido-4-hydroxy-5-nitrobenzaldehyde compound Y-10-3 (8 g, 47.43%) as a yellow liquid. LCMS: (ESI, m / z): 206.9 [M-1]. - .

[0342] Step 3: Synthesis of compound Y-10-4

[0343] Under nitrogen, triethylamine (5.48 g, 48.046 mmol, 2 eq) was added dropwise to a toluene (50 mL) solution of compound Y-10-3 (5 g, 24.023 mmol, 1 eq) and ethyl 2-[(1r,4r)-4-aminocyclohexyl]acetate (4.45 g, 24.023 mmol, 1 eq). After the addition was complete, the system was stirred at 110°C for 3 hours. The reaction was complete after liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography using petroleum ether / ethyl acetate (0-50%) to afford ethyl 2-[(1r,4r)-4-(6-hydroxy-5-nitroindazol-2-yl)cyclohexyl]acetate compound Y-10-4 (2.5 g, 29.96%) as a yellow solid. LCMS: (ESI, m / z): 348.0 [M+1]. + .

[0344] Step 4: Synthesis of compound Y-10-5

[0345] Under nitrogen, potassium carbonate (1.99 g, 14.394 mmol, 2 eq) was added to a solution of compound Y-10-4 (2.5 g, 7.197 mmol, 1 eq) and 2-iodopropane (2.45 g, 14.394 mmol, 2 eq) in N,N-dimethylformamide (30 mL) at 80°C. The reaction was stirred overnight. Upon completion of the reaction, the reaction mixture was poured into ice water. A solid precipitated, which was collected by filtration and washed with water (3 x 10 mL). This afforded ethyl 2-[(1r,4r)-4-(6-isopropoxy-5-nitroindazol-2-yl)cyclohexyl]acetate, compound Y-10-5 (3 g, 107.03%) as a yellow solid. LCMS: (ESI, m / z): 390.1 [M+1]. + .

[0346] Step 5: Synthesis of compound Y-10-6

[0347] Under nitrogen, iron powder (1.20 g, 21.570 mmol, 3 eq) and water (7 mL, 388.565 mmol, 54.05 eq) were added to a solution of compound Y-10-5 (2.8 g, 7.190 mmol, 1 eq) and ammonium chloride (0.38 g, 7.190 mmol, 1 eq) in ethanol (35 mL) at 80°C. The mixture was stirred for one hour. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS / MS). The reaction was filtered, the filter cake washed with ethanol (3 x 30 mL), and the filtrate concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, backwashed with saturated brine (1 x 100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl 2-[(1r,4r)-4-(5-amino-6-isopropoxyindol-2-yl)cyclohexyl]acetate compound Y-10-6 (2.4 g, 92.86%) as a pale yellow solid. LCMS: (ESI, m / z): 360.1 [M+1] + .

[0348] Step 6: Synthesis of compound Y-10-7

[0349] Under nitrogen, to a solution of compound Y-10-6 (2.4 g, 6.676 mmol, 1 eq) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (1.28 g, 6.676 mmol, 1 eq) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (1.73 g, 13.352 mmol, 2 eq). After stirring for 10 minutes, 2-chloro-1-methylpyridinium-1-iodonium (1.88 g, 7.344 mmol, 1.1 eq) was added dropwise at 0°C. After complete addition, the system was stirred at room temperature for 3 hours. The reaction was monitored by liquid chromatography-mass spectrometry to confirm completion, and the resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to give ethyl 2-[(1r,4r)-4-(6-isopropoxy-5-[6-(trifluoromethyl)pyridin-2-amino]indazol-2-ylcyclohexyl]acetate compound Y-10-7 (2.1 g, 59.06%) as a yellow solid.

[0350] LCMS: (ESI, m / z): 533.10 [M+1] + .

[0351] Step 7: Synthesis of compound Y-10

[0352] Under nitrogen protection, DIBAL-H (2.1 mL, 10.348 mmol, 5.51 eq) was added to a solution of morpholine (687.06 mg, 7.888 mmol, 4.2 eq) in tetrahydrofuran (20.0 mL) at 0°C. After stirring for 1 hour, compound Y-10-7 (1 g, 1.878 mmol, 1 eq) was added dropwise at 0°C. After stirring for 1 hour, the reaction was completed by liquid chromatography-mass spectrometry. The obtained residue was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether / ethyl acetate (0-50%) to give N-(6-isopropoxy-2-[(1r,4r)-4-(2-oxoethyl)cyclohexyl]indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide compound Y-10 (300 mg, 32.71%) as an off-white solid.

[0353] LCMS: (ESI, m / z): 487.05 [M+1] + .

[0354] General preparation method 1 of the compound of the present invention:

[0355] The compound of formula IV-A is subjected to reductive amination with the compound of formula IV-Y to obtain the compound of formula IV-0.

[0356] General preparation method 2 of the compound of the present invention:

[0357] The compound of formula VA is subjected to reductive amination with formula VY to obtain a compound of formula V-0.

[0358] The chiral compounds in the present invention can be resolved using conventional chiral resolution conditions in the art (for example: chromatography column specifications: CHIRALPAK-IA 2*25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: methanol:dichloromethane = 1:1; flow rate: 18 ml / min; elution gradient: isocratic 70; detection wavelength: UV 254 / 220 nm. The chromatography column specifications can be selected as needed, and the elution gradient, flow rate, etc. can be adjusted as needed). As an alternative preparation method, chiral synthesis can also be performed using chiral raw materials.

[0359] Example 1 Preparation of Compound 1

[0360] To a solution of Intermediate A (30 mg, 0.100 mmol, 1 equiv) in tetrahydrofuran (1 mL) at room temperature were added N,N-diisopropylethylamine (27 mg, 0.209 mmol, 2.10 equiv), compound 1-1 (35 mg, 0.072 mmol, 0.72 equiv), and tetraisopropyl titanate (85 mg, 0.299 mmol, 3.00 equiv). After the addition was complete, the system was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (30 mg, 0.142 mmol, 1.42 equiv) was added to the above system at 0°C. After the addition was complete, the system was stirred at room temperature for 2 hours. The desired product was found in the liquid. The crude product was purified by HPLC to obtain compound 1 (7.6 mg, 9.68%) using the following conditions (column specifications: XBridge BEH Shield RP18 5 μm, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 38% B to 62% B in 10 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 9.43).

[0361] LCMS: (ESI, m / z): 774.4 [M+H] + .

[0362] 1H NMR: (400MHz, DMSO-d6) δ12.36(s,1H),10.76(s,1H),8.71(s,1H),8.45(d,J=7.7Hz,1H),8.36(t,J=7.8Hz,2H),8.16(d,J=8.2Hz,1H ),7.57(s,1H),6.80(d,J=8.6Hz,1H),6.63(q,J=3.4Hz,1H),6.55(d,J=1.8Hz,1H),5.94(s,1H),4.42(t,J=11.6Hz,1H),4.24(q,J=4. 3Hz,1H),3.88(t,J=9.8Hz,1H),3.68(m,J=5.3Hz,2H),2.96(q,J=10.8Hz,3H),2.61(m,J=5.4Hz,2H),2.46(d,J=4.7Hz,1H),2.41(m, J=5.3Hz,2H),2.10(q,J=6.0Hz,1H),1.95(m,J=7.6Hz,5H),1.68(t,J=10.7Hz,1H),1.62(s,6H),1.45(s,3H),1.21(t,J=10.4Hz,2H).

[0363] Example 2 Synthesis of Compounds 120-a, 120-a-1 and 120-a-2

[0364] Intermediate 1-1 and intermediate Q were selected and prepared according to general preparation method 1 to obtain compound 120-a.

[0365] Chiral separation of 20.7 mg of compound 12-a yielded 6.1 mg of 120-a-1 and 6.5 mg of 120-a-2. The conditions were as follows (chromatographic column specifications: CHIRAL ART Cellulose-SB 3*25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol:dichloromethane = 1:1; flow rate: 40 mL / min; elution gradient: isocratic 50; detection wavelength: UV 254 / 220 nm; retention time (min) of 120-a-1: 7.093; retention time (min) of the subsequent peak 120-a-2: 8.23; solvent: ethanol; single injection volume: 1.0 mL; number of injections: 3). LCMS-120-a-1 (ESI, m / z): 788.1 [M+H] + .LCMS-120-a-2(ESI,m / z):787.9[M+H] + .

[0366] 1H NMR 120-a-1:(400MHz,DMSO-d6,ppm)δ12.54(s,1H),10.82(s,1H),9.06(s,1H),8.58(d,J=0.7Hz,1H),8.50-8.44(m,2H),8.39(t,J=7.9Hz,1H),8.21(dd,J=0.9,7.8Hz,1H),6.83(d,J=8.7Hz,1H),6.68(dd,J=2.2,8.5Hz,1H),6.60(d,J=2.3Hz,1H),4.59-4.48(m,1H),4.24(dd,J=2.6,10.5Hz,1H),3.89(dd,J=9.3,10.3Hz,3H),3.68(d,J=11.1Hz,1H),3.30-3.27(m,1H),3.07-2.95(m,3H),2.92(d,J=10.2Hz,1H),2.65-2.59(m,2H),2.48-2.41(m,2H),2.41-2.34(d,J=18.2Hz,2H),2.31-2.24(m,1H),2.22-2.14(m,2H),2.13-2.00(m,3H),2.00-1.87(m,4H),1.71-1.64(m,1H),1.52-1.41(m,3H),1.36(s,3H),1.31-1.13(m,J=7.5Hz,3H).

[0367] 1H NMR 120-a-2: (400MHz, DMSO-d6, ppm) δ12.54(s,1H),10.83(s,1H),9.06(s,1H),8.58(s,1H),8.49-8.44(m,2H),8.39(t,J=7.8Hz,1H),8.21(d,J=7. 7Hz,1H),6.83(d,J=8.7Hz,1H),6.68(dd,J=2.2,8.5Hz,1H),6.60(d,J=2.3Hz,1H),4.58-4.48(m,1H),4.24(dd,J=2.0,10.6Hz,1H),3.96(s,3H), 3.89(t,J=9.9Hz,1H),3.68(d,J=10.2Hz,1H),3.30-3.28(m,1H),3.06-2.90(m,3H) ,2.64-2.59(m,1H),2.49-2.45(m,2H),2.45-2.41(m,1H),2.41-2.36(m,2H),2.31-2 .23(m,1H),2.21-2.13(m,2H),2.13-2.08(m,1H),2.080-2.00(m,2H),2.00-1.88(m, 4H),1.74-1.61(m,1H),1.51-1.40(m,3H),1.36(s,3H),1.29-1.14(m,J=5.2Hz,3H).

[0368] Example 3 Preparation of Compounds 120-b, 120-b-1 and 120-b-2

[0369] Intermediate 1-1 and intermediate P were selected and prepared according to general preparation method 1 to obtain compound 120-b.

[0370] Chiral separation of 65 mg of compound 120-b afforded 21.7 mg of 120-b-1 and 22.5 mg of 120-b-2. The conditions were as follows (chromatographic column specifications: CHIRAL ART Cellulose-SB 2*25 cm, 5 um; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol:dichloromethane = 1:1; flow rate: 20 ml / min; elution gradient: isocratic 40; detection wavelength: UV 254 / 220 nm; retention time 1 (min) of 120-b-1: 8.716; retention time 2 (min) of 120-b-2: 11.828; sample solvent: ethanol + dichloromethane; injection volume: 1.0 mL; number of runs: 7).

[0371] LCMS-120-b-1:(ESI,m / z):788.25[M+H] + .

[0372] LCMS-120-b-2:(ESI,m / z):788.25[M+H] + .

[0373] 1 H NMR-120-b-1:(400MHz,DMSO-d6,ppm)δ12.36(s,1H),10.82(s,1H),8.71(s,1H),8.45(d,J=7.7Hz,1H),8.39-8.31(m,2H),8.16(q,J=2.8Hz,1H),7.57(s,1H),6.83(d,J=8.7Hz,1H),6.68(q,J=3.6Hz,1H),6.64-6.46(m,1H),5.93(s,1H),4.51-4.35(m,1H),4.24(q,J=4.4Hz,1H),3.92-3.87(m,1H),3.68(d,J=11.4Hz,1H),3.04-2.96(m,3H),2.66-2.62(m,1H),2.44-2.36(m,2H),2.32-2.26(m,1H),2.17-2.01(m,5H),1.95-1.86(m,4H),1.66(t,J=10.7Hz,1H),1.62(s,6H),1.46-1.42(m,3H),1.36(s,3H),1.22-1.18(m,3H).

[0374] 1H NMR-120-b-2: (400MHz, DMSO-d6, ppm) δ12.36 (s, 1H), 10.83 (s, 1H), 8.71 (s, 1H), 8.45 (d, J = 7.8Hz, 1H), 8.40-8.33 (m, 2H), 8.16 (d ,J=8.0Hz,1H),7.57(s,1H),6.83(d,J=8.6Hz,1H),6.69-6.56(m,2H),5.93(s,1H),4.49-4.37(m,1H),4.24(dd,J=2.5,10.6Hz,1H ),3.89(t,J=9.8Hz,1H),3.68(d,J=11.1Hz,1H),3.06-2.90(m,3H),2.66-2.57(m,1H),2.41-2.36(m,2H),2.30-2.23(m,1H),2.17 -2.01(m,5H),1.960-1.86(m,4H),1.66(t,J=10.6Hz,1H),1.62(s,6H),1.45(t,J=6.2Hz,3H),1.36(s,3H),1.19(m,J=6.3Hz,3H).

[0375] Example 4 Synthesis of Compound 126

[0376] Intermediate Y-8 and intermediate O were selected and prepared according to the general preparation method 1 to obtain compound 126 (16.6 mg, yield 22.8%). LCMS: (ESI, m / z): 784.4 [M+1] + .

[0377] 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),10.84(s,1H),8.94(d,J=2.1Hz,1H),8.75(d,J=2.1Hz,1H),8.55(s,1H),8.34(s,1 H),7.72(d,J=4.8Hz,1H),7.57(s,1H),7.09(d,J=4.8Hz,1H),6.83(s,1H),6.75–6.57(m,2H),5.74(s,1H),4.50–4.35(m ,1H),4.25(d,J=8.7Hz,1H),3.89(t,J=9.5Hz,1H),3.77–3.64(m,1H),3.01(s,3H),2.71–2.60(m,1H),2.45–2.36(m,3H) ,2.28(d,J=8.3Hz,1H),2.17–2.00(m,5H),1.94–1.88(m,4H),1.63(s,6H),1.45(s,3H),1.35(s,3H),1.28–1.14(m,3H).

[0378] Example 5 Synthesis of Compound 128

[0379] Intermediate 1-1 and intermediate S were selected and prepared according to the general preparation method 1 to obtain compound 128 (71 mg, yield 39.9%). LCMS: (ESI, m / z): 708.3 [M+1] + .

[0380] 1H NMR (400MHz, DMSO-d6) δ12.36(s,1H),10.82(d,J=2.7Hz,1H),8.71(s,1H),8.45(d,J=7.8Hz,1H),8.40–8.32(m,2H),8.16(d,J=7. 8Hz,1H),7.57(s,1H),6.89(s,1H),6.63(s,1H),5.94(s,1H),4.42(s,1H),4.27(dd,J=10.6,2.1Hz,1H),3.99(dd,J=12.2,4.9Hz, 1H),3.93–3.82(m,1H),3.72(d,J=11.6Hz,1H),3.05(s,1H),2.95(t,J=12.3Hz,2H),2.77–2.61(m,2H),2.39(d,J=7.7Hz,2H),2.2 9–2.17(m,1H),2.10(dd,J=18.7,5.7Hz,3H),1.91(d,J=11.0Hz,4H),1.74–1.54(m,8H),1.44(s,3H),1.19(dd,J=20.7,8.8Hz,3H).

[0381] Example 6 Synthesis of Compound 129

[0382] Intermediate Y-8 and intermediate A were selected and prepared according to the general preparation method 1 to obtain compound 129 (12 mg, yield 16.8%). LCMS: (ESI, m / z): 770.4 [M+1] + .

[0383] 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H),10.76(s,1H),8.93(d,J=2.2Hz,1H),8.74(d,J=2.2Hz,1H),8.55(s,1H),8.34(s,1H),7.72(d,J=4.8Hz,1H), 7.57(s,1H),7.09(d,J=4.8Hz,1H),6.80(d,J=8.5Hz,1H),6.63(dd,J=8. 4,1.8Hz,1H),6.55(d,J=1.8Hz,1H),5.72(s,1H),4.42(t,J=11.6Hz,1H), 4.24(dd,J=10.6,2.5Hz,1H),3.92–3.83(m,1H),3.74–3.59(m,2H),3.08–2.87(m,3H),2.68–2.55(m, 2H),2.48–2.35(m,3H),2.19–1.85(m,9H),1.68(s,1H),1.63(s,6H),1.45(s,3H),1.29–1.11(m,2H).

[0384] Example 7 Synthesis of Compound 130

[0385] Intermediate 1-1 and intermediate T were selected and prepared according to the general preparation method 1 to obtain compound 130 (9.2 mg, yield 14.7%). LCMS: (ESI, m / z): 788.4 [M+1] + .

[0386] 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),10.84(s,1H),8.77(s,1H),8.58–8.37(m,3H),8.22(d,J=7.8Hz ,1H),7.64(s,1H),6.97(d,J=8.3Hz,1H),6.81(d,J=7.9Hz,1H),6.68(s,1H),6.01(s,1H),4.47(d,J= 14.1Hz,2H),4.23–4.11(m,1H),3.77(dd,J=10.9,4.8Hz,1H),3.19(s,3H),2.82–2.62(m,4H),2.49(s ,1H),2.39(s,1H),2.19(d,J=10.1Hz,3H),2.11–1.93(m,8H),1.68(s,6H),1.51(s,3H),1.30(s,3H).

[0387] Example 8 Synthesis of Compound 131

[0388] Intermediate 1-1 and intermediate R were selected and prepared according to the general preparation method 1 to obtain compound 131 (29.4 mg, yield 25.0%). LCMS: (ESI, m / z): 708.3 [M+1] + .

[0389] 1 H NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.82(s,1H),8.72(s,1H),8.45(d,J=7.7Hz,1H),8.42–8.30(m,2H),8.16(d,J=7.8Hz,1H),7. 58(s,1H),6.84(s,1H),6.71(d,J=1.7Hz,1H),5.94(s,1H),4.41(t,J=10.4Hz,2H),4.16(dd,J=10.5,2.3Hz,1H),3.78(dd,J=11.9,4 .7Hz,1H),3.41(d,J=11.4Hz,1H),3.11(d,J=9.8Hz,1H),2.95(d,J=11.5Hz,1H),2.92–2.77(m,2H),2.70–2.56(m,1H),2.43(d,J=8. 4Hz,1H),2.33(s,2H),2.22(t,J=10.6Hz,2H),2.12(d,J=9.5Hz,2H),2.04–1.85(m,5H),1.62(s,6H),1.42(s,3H),1.28–1.13(m,3H).

[0390] Referring to the preparation method of Example 1 (select the corresponding intermediate according to the general preparation method 1), the following compound was prepared:

[0391] Example 9 Preparation of Compound 46

[0392] To a solution of intermediate B (35 mg, 0.117 mmol, 1 equiv) and compound 46-1 (53.66 mg, 0.117 mmol, 1.0 equiv) in tetrahydrofuran (1.0 mL) was added sodium triacetoxyborohydride (74.09 mg, 0.351 mmol, 3 equiv) in portions at 0°C. The resulting residue was stirred and reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water at 0°C. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, backwashed with water (3 x 5 mL), and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was prepared by high performance liquid chromatography under the following conditions (chromatographic column specifications: XBridge BEH C18 OBD Prep Column) 130, 5um, 30mm*150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 38% B to 60% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.47), to obtain compound 46.

[0393] LCMS: (ESI, m / z): 745.3 [M+H] + .

[0394] 1 H NMR: (400MHz, Chloroform-d, ppm) δ12.58 (s, 1H), δ10.70 (s, 1H), 8.82 (s, 1H), 8.49 (d, J = 7.8Hz, 1H), 8 .12(t,J=7.8Hz,1H),7.90(s,1H),7.88–7.84(m,2H),7.15(s,1H),7.07(d,J=6.9Hz,2H),5.07(s,2H), 4.32(t,J=11.9Hz,1H),4.03(s,3H),3.81–3.77(m,1H),3.07(s,2H),2.85(m,2H),2.75(t,J=5.0Hz,1H ),2.72–2.56(m,2H),2.43(m,2H),2.34–2.17(m,5H),1.99(t,J=13.4Hz,6H),1.83(s,2H),1.26(s,2H).

[0395] Example 10 Synthesis of Compound 121

[0396] Intermediate 1-1 and Intermediate V were selected and prepared according to General Preparation Method 2 to obtain Compound 121 (27.2 mg, 37.00%). LCMS: (ESI, m / z): 799.95 [M+1] + .

[0397] 1 H NMR (400MHz, DMSO-d6, ppm) δ12.36(s,1H),10.85(s,1H),8.71(s,1H),8.45(d,J=8.1Hz,1H),8.41-8.31(m,2H),8.16(q,J=2 .9Hz,1H),7.58(s,1H),7.48(d,J=7.6Hz,1H),6.92(s,1H),6.89(d,J=7.8Hz,1H),5.94(s,1H),4.44(t,J=11.5Hz,1H),3.87 (dd,J=4.9,11.8Hz,1H),3.11(s,3H),2.90-2.80(m,2H),2.71-2.67(m,1H),2.63-2.53(m,4H),2.30-2.22(m,1H),2.21-2.1 2(m,2H),2.12-2.05(m,1H),2.05-1.86(m,5H),1.86-1.72(m,2H),1.710-1.58(m,8H),1.55-1.39(m,3H),1.28-1.16(m,2H).

[0398] Referring to the preparation method of Example 9 (select the corresponding intermediate and follow the general preparation method 2), the following compounds were prepared:

[0399] The NMR data of the compound of the present invention are as follows:

[0400] Biological test evaluation

[0401] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0402] Test Example 1 Detection of the degradation level of HiBiT-IRAK4 protein in K562 IRAK4-HiBiT cells after co-incubation with the compound of the present invention

[0403] Experimental reagents, equipment and consumables:

[0404] Nano-Glo Lytic Detection Assay, purchased from Promega;

[0405] EnVision, purchased from PerkinElmer;

[0406] Cell line name: K562 IRAK4-HiBiT stably transfected cell line (can stably express IRAK4-HiBiT fusion protein) was constructed by Shanghai Runnuo Biotechnology Co., Ltd., where the K562 cell line was purchased from ATCC. The culture medium was IMDM + 10% FBS + 1% P / S (volume percentage, where FBS is fetal bovine serum and P / S is Penicillin-Streptomycin, an antibiotic solution of a 1:1 mixture of penicillin and streptomycin (10,000 units / mL)).

[0407] Experimental steps:

[0408] Cell culture: K562 IRAK4-HiBiT cells were cultured at 37°C and passaged every 2–3 days at a seeding density of 200,000 cells / mL.

[0409] IRAK4-HiBiT protein degradation assay:

[0410] Step 1: Cell seeding and compound treatment

[0411] 1. Prepare a 10 mM compound stock solution in DMSO and use the Bravo automated liquid handling platform to prepare a 1000-fold working concentration compound solution (maximum working concentration is 10 μM, 3.162-fold dilution, with a total of 10 concentration gradients).

[0412] 2. Transfer 40 nL of compound working solution to a 384-well plate and add an equal volume of DMSO to the positive control wells.

[0413] 3. Add 20 μL of culture medium to each well and shake for 10 minutes.

[0414] 4. Add 20 μL of K562 IRAK4-HiBiT cell suspension (6000 cells / well) to each well and add an equal volume of culture medium to the negative control wells.

[0415] 5. Spin the plate at 1000 rpm for 1 minute.

[0416] 6. Incubate in a 37°C, 5% CO2 incubator for 2 hours or 6 hours.

[0417] Step 2: HiBiT Lytic Experiment

[0418] 1. Allow the plate to equilibrate at room temperature for 30 minutes.

[0419] 2. Add 20 μL Nano-Glo HiBiT Lytic Reagent (Trade Name: HiBiT Lytic Detection Reagent) and protect from light.

[0420] 3. Place the plate on an orbital shaker at 300 rpm for 5 minutes.

[0421] 4. Incubate at room temperature for 10 minutes.

[0422] 5. Envision reads the luminescence value.

[0423] 6. Calculate and process data. Degradation % = (negative control - experimental well) / (negative control - positive control) * 100%; Use XL-fit software to fit the degradation curve using a 4-parameter logistic model to obtain the Relative DC 50 (nM) and Absolute DC 50 The value of (nM).

[0424] The experimental results are shown in Table 1 and Table 2 below:

[0425] Table 1

[0426] Table 2

[0427] Refer to this experimental method to test other compounds of the present invention and obtain the Relative DC of the compounds of the present invention. 50 The value of (nM) is between 0.01 and 100. The Relative DC 50 The value of (nM) is less than 100; the Absolute DC 50 The value of (nM) is between 0.01 and 100. The Absolute DC 50 The value of (nM) is less than 100; the Dmax of the compound of the present invention is above 80%, and the Dmax of the preferred compound of the present invention is above 90%.

[0428] Experimental conclusion:

[0429] The compound of the present invention has good degradation activity on IRAK4 protein.

[0430] Test Example 2: Study on the inhibitory effect of the compounds of the present invention on LPS-induced IL-6 release from human PBMC cells

[0431] 1. PBMC Recovery and Inoculation and Compound Treatment (Human PBMC cells were purchased from Oricell, Cat. No. Fpb003F)

[0432] 1. Compound Preparation

[0433] A series of sample dilutions were prepared by diluting in DMSO using Bravo, and 80 nL was pipetted into the cell plate using ECHO. The final DMSO concentration in the cell culture medium was 0.1%.

[0434] 2. Thaw the frozen cells quickly in a 37°C water bath with constant stirring.

[0435] 3. Add 25 ml of fresh pre-warmed culture medium to a 50 ml centrifuge tube and then add the cells dropwise. Then centrifuge the cells at 2,000 rpm for 10 minutes.

[0436] 4. Discard the supernatant and resuspend the cells in 28.5 ml of fresh pre-warmed complete RPMI 1640 medium.

[0437] 5. Calculate the total number of cells required for the experiment based on the cell concentration. Add 7x10e4 cells (70 μl) to each well.

[0438] 6. Incubate the plate at 37°C in a 5% CO2 incubator for 2 hours.

[0439] 2. LPS Treatment and Supernatant Collection

[0440] 1. LPS: Dilute the 1 mg / mL stock solution in dH2O, aliquot, and store at -80°C.

[0441] 2. Add 10 μl / well of 8-fold LPS (final concentration 5 ng / mL) to each well and incubate at 37°C in a 5% CO2 incubator for 4 hours.

[0442] 3. Collect 70 μl of supernatant from each well using Bravo and then perform IL-6 HTRF assay. The supernatant can be stored at -80°C.

[0443] 3. HTRF test

[0444] 1. Prepare standard and sample dilutions.

[0445] 2. Use Bravo to add 16 μL of each sample to each well. Then add 16 μL of each standard to the corresponding wells.

[0446] 3. Add 4 μL of premixed IL6 antibody working solution to all wells.

[0447] 4. Seal the plate and incubate at room temperature for 2 hours.

[0448] 5. Read the results, as shown in Table 3 below:

[0449] Table 3

[0450] The other compounds of the present invention were tested by referring to the experimental method, and the IC of the compounds of the present invention on the inhibition of IL-6 release from human PBMC cells was obtained. 50 The value of (nM) is between 0.01 and 500. The IC 50 The value of (nM) is less than 100.

[0451] Experimental conclusion:

[0452] The compound of the present invention has a good inhibitory effect on the IL-6 release of human PBMC cells induced by LPS.

[0453] Test Example 3: Study on the pharmacokinetic behavior of the compound of the present invention in mice

[0454] Experimental drugs: Compounds of the present invention, homemade.

[0455] Experimental plan:

[0456] Three healthy male ICR mice (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 18-25 g, were intravenously injected with 1 mg / kg of the compound in a volume of 5 ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0457] Three healthy male ICR mice (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 18-25 g, were orally administered with 5 mg / kg of the compound in a volume of 10 ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0458] Blood samples were collected from the cheek at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours after intravenous administration and at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours after oral administration. Approximately 0.05 mL of blood was collected for each sample. Blood samples were anticoagulated with sodium heparin and placed on ice. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 6000 g, 3 minutes, 2-8°C). Plasma compound concentrations were determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored at -80°C until analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 using plasma concentration data at different time points. The results are shown in Table 4.

[0459] Table 4

[0460] The experimental results show that the compound of the present invention has low clearance rate, high plasma exposure, good oral availability, and good pharmacokinetic properties.

[0461] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compounds represented by general formula (I): in: Indicates that a key may not exist; M1 is selected from N or CR1; M2 is selected from N, C or CR2; M3 is selected from N or CR3; M4 is selected from N or CR4; M5 is selected from N or CR5; M6 is selected from N or CR6; R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, aminoalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; Ring B1 is selected from aryl or heteroaryl; Ring B2 is selected from aryl, heteroaryl or heterocyclyl; R a Each is independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, -P(O)RR', cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano or alkyl; R and R' are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; R b , R c , R e and R f Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl or haloalkoxy; Or, R e and R f The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl groups; Or, R2 and R f The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl groups; Or, R f Linked to C or N on the ring where M2 is located to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; Or, any two R b The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl groups; Or, L2 and R e The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl groups; L1 is selected from a bond, -NH-, -S-, -O-, -CH2-, CH2CH2-, -C(O)NH-, -NHC(O)- or -C(O)-; L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-, Ak1, Ak2 and Ak3 are each independently selected from -(CH2) n3 -, -O-, -C(O)-, -NH-, -NR7-, -CH2NR7-, -(CR8R9) n4 -, alkynylene or a bond; Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene, a heterocyclylene, an arylene or a heteroarylene; the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, alkyl, haloalkyl, alkoxy, hydroxyalkyl or haloalkoxy; R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, alkyl, cyano, hydroxyl, cycloalkyl, haloalkyl, deuterated alkyl, halocycloalkyl, hydroxyalkyl or alkoxy; or, R8 and R9 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl, and the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy or hydroxyalkyl; Or, R a Linked to L2 to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; L3 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-C(S)- or -C(S)-NH-; x, y, z and q are each independently selected from 0, 1, 2, 3 or 4; and n1, n2, n3 and n4 are each independently selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (II-A): in: R d Each independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R d Each independently selected from hydrogen, deuterium, fluorine, chlorine, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Or, R d Linked with L2 to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 is substituted by one or more substituents in a cycloalkyl group or a 3-6-membered heterocyclic group; Ring A is selected from a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl; p is selected from 0, 1, 2, 3 or 4.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (II-B): in: R d Each independently selected from hydrogen, deuterium, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Ring A is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; R d1 Each independently selected from hydrogen, deuterium, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; p and j are each independently selected from 0, 1, 2, 3 or 4.

4. The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Said Selected from Preferably, Selected from M7 is selected from O, CH2, C(O), S, S(O), S(O)2 or NR 10 ; R 10 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, hydroxyl, cyano, amino, oxo, fluorine or chlorine; M8 is selected from N, O, S, C(O), CH2, CH, S(O) or S(O)2; R d2 and R d3 Each independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, hydroxyl, cyano, amino, oxo, fluorine or chlorine; p2 and p3 are each independently selected from 1, 2, 3 or 4; n9 is selected from 1, 2 or 3.

5. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Said Selected from Preferably, the Selected from M9 and M 10 Each independently selected from CH2, C(O), NR 10 , CH, O, S, S(O) or S(O)2; R 10 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, hydroxyl, cyano, amino, oxo, fluorine or chlorine; R d4 Each independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, hydroxyl, cyano, amino, oxo, fluorine or chlorine; p4 are each independently selected from 1, 2, 3 or 4; n5 is selected from 1, 2 or 3.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring B1 is selected from indazolyl, pyrazolyl, benzimidazolyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl or pyrimidoimidazolyl; Preferably, the Selected from The ring B2 is selected from pyridyl, phenyl, pyridonyl, pyridazinonyl, pyrimidopyrazolyl, pyridopyrrolyl, pyrimidinyl, pyrimidopyrrolyl or pyridopyrazolyl; Preferably, the Selected from Among them, R b1 , R b2 , R b3 and R b4 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Or, R b1 and R b2 The 5-6 membered heterocyclic group is linked to form a 5-6 membered heterocyclic group, which is optionally further substituted with deuterium, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy C 3-6 The cycloalkyl group or the 3-6-membered heterocyclic group may be substituted by one or more substituents.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R a Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -P(O)RR ’ , C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents; Preferably, R a Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1- 3 haloalkyl, C 1-3 Haloalkoxy, -P(O)RR', C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents; Alternatively, the R b , R c , R e and R f Each independently selected from hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1- 6 alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted with deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Halogenation substituted by one or more substituents in the alkoxy group; Preferably, the R b , R c , R e and R f Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C3 -6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted with deuterium, fluorine, chlorine, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted by one or more substituents in a haloalkoxy group; Alternatively, R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Alternatively, R and R' are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; Preferably, R and R' are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-, The Ak1, Ak2 and Ak3 are each independently selected from -(CH2) n3 -, -O-, -C(O)-, -NH-, -NR7-, -CH2NR7-, -(CR8R9) n4 - or key; The Cy1 and Cy2 are each independently selected from a bond, a cyclohexylene, a piperidinylene or a piperazinylene, wherein the cyclohexylene, the piperidinylene and the piperazinylene are optionally further substituted with 1 to 4 deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1- 3 alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, C 1-3 Haloalkyl or C 1-3 substituted by a haloalkoxy substituent; The R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, cyano, hydroxyl, C 3-4 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated cycloalkyl, hydroxyl C 1-3 Alkyl or C 1-3 Alkoxy; Preferably, L2 is selected from Wherein, M and M0 are independently selected from CR 11 or N; R 11 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; n6 and n7 are each independently selected from 0, 1, 2, 3 or 4.

9. The compound according to any one of claims 2, 4, 6 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of general formula (II-A) is further represented by general formula (IV), general formula (IV-1) or general formula (IV-2):

10. The compound according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of general formula (II-A) is further represented by general formula (IV-A) or general formula (IV-B):

11. The compound according to any one of claims 3, 5 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of general formula (II-B) is further represented by general formula (V):

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) R a Selected from C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy; preferably C 1-3 Alkoxy or hydroxy C 1-3 Alkyl; more preferably methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl; (2) R b Selected from C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy; preferably C 1-3 Haloalkyl or C 1-3 Haloalkoxy; more preferably difluoromethyl, trifluoromethyl or trifluoromethoxy; (3) L3 is selected from a bond, -NH-C(O)- or -C(O)-NH-; (4) R3 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Halogenated alkoxy; preferably hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Haloalkyl; more preferably hydrogen, deuterium, fluorine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy or propoxy; (5) M0 is selected from N or CH; (6) wherein M4 is N or CR4, and R4 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1- 3 haloalkyl or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl; (7) wherein M5 is N or CR5, and R5 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1- 3 haloalkyl or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl; (8) wherein M6 is N or CR6, and R6 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1- 3 haloalkyl or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl; (9) M7 is O, CH2, C(O), S, S(O) or S(O)2; preferably O, CH2 or S; (10) M9 is CH2, C(O), O or S; (11)M 10 CH2, C(O), NR 10 , O or S, R 10 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl or trifluoromethyl.

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the compounds in Table 5.

14. Compound represented by formula (Aaa): in: M4 is N or CR4; M5 is N or CR5; M6 is N or CR6; M7 is O, S or CH2; R3 is selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 haloalkyl; R4 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl, C 1-3 Alkoxy or C 1-3 haloalkyl; R5 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R6 is selected from hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 12 and R 13 Each is independently selected from hydrogen or an amino protecting group.

15. The compound of formula (Aaa) according to claim 14, characterized in that The compound of formula (Aaa) is further represented by formula (Aaa-1) and formula (Aaa-2): Preferably, the compound of formula (Aaa) is selected from intermediate E, intermediate Ea, intermediate Eb, intermediate F, intermediate G, intermediate I, intermediate M, intermediate O, intermediate P, intermediate Q, intermediate R or intermediate S.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating or preventing an IRAK4-mediated disease.

18. The use according to claim 17, characterized in that The disease is selected from an autoimmune disease, an inflammatory disease, cancer, a viral disease, a neurodegenerative disease, a genetic disorder, a hormone-related disease, a metabolic disorder, a disease related to organ transplantation, an immunodeficiency disorder, a destructive bone disease, a proliferative disorder, an infectious disease, a condition associated with cell death, or a cardiovascular disease.

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