Tricyclic compounds, their preparation methods, and applications

Abstract

This invention relates to tricyclic compounds, methods for preparing them, and their applications. Specifically, it concerns compounds represented by general formula (I), methods for preparing them, pharmaceutical compositions containing such compounds, and their applications in the preparation of drugs for the treatment or prevention of autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related diseases, or cardiovascular diseases. Each substituent in general formula (I) is defined as such in this specification. TIFF2026518867000202.tif42170

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to Chinese Patent Application No. 202310624222X filed on 30 May 2023 and Chinese Patent Application No. 2023117821298 filed on 22 December 2023. This application incorporates the full text of the aforementioned Chinese Patent Applications.

[0002] This invention relates to the field of pharmaceuticals, and more specifically to tricyclic compounds, methods for preparing them, and their applications. [Background technology]

[0003] Interleukin-1 receptor kinase 4 (IRAK4) is a member of the tyrosine kinase (TLK) family, a serine / threonine-specific protein kinase, and a key node in the innate immune response involving interleukin-1, 18, 33 receptors, and Toll-like receptors. After extracellular signaling molecules bind to interleukin receptors or Toll-like receptors, they recruit the formation of a MyD88:IRAK4:IRAK1 / 2 polyprotein complex. IRAK1 / 2 is then phosphorylated, mediated by a series of downstream signaling pathways, activating the p38, JNK, and NF-κB signaling pathways, ultimately leading to the expression of pro-inflammatory cytokines. Clinicopathological studies have shown resistance to chronic lung disease and inflammatory bowel disease in individuals with IRAK4 mutations. The IRAK4 mutation itself is non-lethal, individuals survive into adulthood, and the risk of infection decreases with age. Therefore, IRAK4 is attracting considerable attention from researchers as an important therapeutic target.

[0004] Proteolysis Targeting Chimeras (PROTACs) represent a different technology from conventional small molecule inhibitors. Conventional small molecule inhibitors typically need to act on the active site of the target protein to inhibit its activity. However, PROTACs are heterobifunctional molecules with one end being a small molecule inhibitor that can recognize the target protein and the other end being an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase, linked by a connecting chain. Such bifunctional molecules recognize the target protein and E3 ubiquitin ligase in the body, bringing the target protein closer to the E3 ubiquitin ligase to form a ternary complex, ubiquitinating the target protein, and then degrading the target protein in the body via the ubiquitin-protease pathway. Compared to conventional small molecule inhibitors, PROTACs only need to bring the target protein closer to the E3 ubiquitin ligase to degrade the substrate. This mechanism of action makes such technologies applicable to some targets that cannot be drug-formed. On the other hand, even after the target protein is degraded, the PROTAC molecule can be released and continue to participate in the degradation process of the next protein. This catalytic degradation action allows for efficient degradation with relatively low doses of PROTAC. Furthermore, while conventional small molecule inhibitors are generally prone to drug resistance because point mutations occur, causing the small molecule inhibitor to lose its inhibitory effect against the target, PROTAC can directly degrade the target protein, thus avoiding drug resistance due to point mutations to some extent. Therefore, compared to conventional small molecule inhibitors, using PROTAC technology in the research and development of new drug small molecules offers significant advantages and feasibility, and is expected to result in promising next-generation new drugs.

[0005] Therefore, the development of novel IRAK4 inhibitors and E3 ubiquitin ligase PROTAC drugs is necessary to treat IRAK4-related diseases. [Overview of the project]

[0006] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the structure of the compound represented by general formula (I) is as follows:

[0007] [ka]

[0008] During the ceremony, [ka] This indicates the presence or absence of a connection. M1 is selected from N or CR1. M2 is selected from N, C, or CR2. The M3 is available in either N or CR3. The M4 is selected from either N or CR4. The M5 is selected from either 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, aminoalkyl, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. Ring B1 is selected from aryl or heteroaryl rings. Ring B2 is selected from aryl, heteroaryl, or heterocyclyl. R a These are, independently, hydrogen, deuterium, hydroxyl, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, and -P(O)RR. ’ Selected from cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclyl are further optionally substituted with one or more substituents from deuterium, halogen, hydroxy, cyano, or alkyl. R and R ’is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, or haloalkoxy, R b , R c , R e and R f are each 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 are joined to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl, or, R2 and R f are joined to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl, or, R f is bonded to C or N on the ring where M2 is located to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl 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 These are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally further substituted with one or more substituents from among deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl groups. Alternatively, L2 and R e These are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally further substituted with one or more substituents from among deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl groups. L1 is selected from the following: 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 -(CH2) n3 -, -O-, -C(O)-, -NH-, -NR7-, -CH2NR7-, -(CR8R9) n4 -, selected from alkynylene, or bond, Cy1 and Cy2 are each independently bonded, selected from cycloalkylidene, heterocyclylene, arylene, or heteroarylene, and the cycloalkylidene, heterocyclylene, arylene, and heteroarylene are further optionally substituted with 1 to 4 substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, alkyl, haloalkyl, alkoxy, hydroxyalkyl, or haloalkoxy. 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 bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with one or more substituents from deuterium, halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, or hydroxyalkyl. Or, R a L2 and L2 combine to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents from among deuterium, halogen, amino, cyano, hydroxy, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. L3 is selected from the following bonds: -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. n1, n2, n3, and n4 are each independently selected from 0, 1, 2, or 3.

[0009] In a preferred embodiment of the present invention, the compound described above is further represented by general formula (II-A), [ka] During the ceremony, R d These are, independently, hydrogen, deuterium, halogen, oxo, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Preferably, R d These are, independently, hydrogen, deuterium, fluorine, chlorine, oxo, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R d L2 and C are joined together. 3-6 Forming a cycloalkyl or 3-6 membered heterocycline, the C 3-6 Cycloalkyls and 3-6 membered heterocyclines are deuterium, halogen, cyano, oxo, and C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 It is further optionally substituted with one or more substituents from cycloalkyl or 3- to 6-membered heterocyclines. 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.

[0010] In a preferred embodiment of the present invention, the compound described above is further represented by general formula (II-B), [ka] During the ceremony, R d These are hydrogen, deuterium, halogen, oxo, and C, respectively, independently. 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6Selected from cycloalkyl or 3-6 membered heterocyclyl, Ring A is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl. R d1 These are hydrogen, deuterium, halogen, oxo, and C, respectively, independently. 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, p and j are each independently selected from 0, 1, 2, 3, or 4.

[0011] In a preferred embodiment of the present invention, the general formula (II-A) described above [ka] teeth,

[0012] [ka] Selected from, Preferably, the above

[0013] [ka] teeth,

[0014] [ka] Selected from, more,

[0015] [ka] teeth,

[0016] [ka] Selected from, More preferably, the above

[0017] [ka] teeth,

[0018] [ka] Selected from, M7 is O, CH2, C(O), S, S(O), S(O)2, or NR 10 Selected from, R 10 is hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyls and 3- to 6-membered heterocyclines are further optionally substituted with one or more substituents 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 These are, independently, hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, the C1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyls and 3- to 6-membered heterocyclines are further optionally substituted with one or more substituents 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.

[0019] In a preferred embodiment of the present invention, the general formula (II-B) described above

[0020] [ka] teeth,

[0021] [ka] Selected from, Preferably, the above

[0022] [ka] teeth, [ka] Selected from, M9 and M 10 These are CH2, C(O), and NR, respectively, independently. 10 Selected from CH, O, S, S(O), or S(O)2, R 10 is hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6Selected from cycloalkyl or 3- to 6-membered heterocyclyl, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, hydroxy, cyano, amino, oxo, fluorine, or chlorine, R d4 is 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 haloalkoxy, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclyl, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, hydroxy, cyano, amino, oxo, fluorine, or chlorine, p4 is each independently selected from 1, 2, 3 or 4, <( n5 is selected from 1, 2 or 3.

[0023] In a preferred embodiment of the present invention, ring B1 described above is selected from indazolyl, pyrazolyl, benzimidazolyl, pyridotriazolyl, pyridopyrazolyl, pyridinoimidazolyl, or pyrimidinimidazolyl, Preferably, said ;

[0024]

Chemical formula

[0025]

Chemical formula

[0026] [ka] teeth,

[0027] [ka] Selected from, In the formula, R b1 , R b2 , R b3 and R b4 These are, independently, hydrogen, deuterium, halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R b1 and R b2 These combine to form a 5-6 member heterocycline, which consists of deuterium, halogen, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 It is further optionally substituted with one or more substituents from cycloalkyl or 3- to 6-membered heterocyclines.

[0028] In a preferred embodiment of the present invention, R described above a These are hydrogen, deuterium, halogen, cyano, and C, respectively, independently. 1-6 Alkyl, C1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -P(O)RR ’ , C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, the C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyls and 3-6 membered heterocyclines are composed of deuterium, halogens, hydroxyl, cyano, or C 1-3 The alkyl group is further optionally substituted with one or more substituents. Preferably, R a These are hydrogen, deuterium, halogen, cyano, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -P(O)RR ’ , C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, the C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyls and 3-6 membered heterocyclines are composed of deuterium, halogens, hydroxyl, cyano, or C 1-3 The alkyl group is further optionally substituted with one or more substituents. Or, the R b , R c , R e and R f These are, independently, hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, the C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyls and 3-6 membered heterocyclines contain deuterium, halogens, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 The haloalkoxy is further optionally substituted with one or more substituents. Preferably, the R b , R c , R e and R f These are hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloa Selected from lucyl or 3-6 member heterocyclyl, C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyls and 3-6 membered heterocyclines contain deuterium, fluorine, chlorine, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 The haloalkoxy is further optionally substituted with one or more substituents. Alternatively, R1, R2, R3, R4, R5, and R6 may each independently be hydrogen, deuterium, halogen, cyano, oxo, and C.1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Preferably, R1, R2, R3, R4, R5, and R6 are each independently hydrogen, deuterium, fluorine, chlorine, cyano, oxo, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R and R ’ These are hydrogen, deuterium, halogen, and C, respectively, independently. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 1-6 Selected from haloalkoxys, Preferably, R and R ’ These are hydrogen, deuterium, fluorine, chlorine, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys.

[0029] In a preferred embodiment of the present invention, L2 described above is -Ak1-Cy1-Ak2-Cy2-Ak3-, Cy1 and Cy2 are each independently bonded, selected from cycloalkylidene, heterocyclylene, arylene, or heteroarylene, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with 0 to 4 substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxy, hydroxyalkyl, haloalkoxy, or deuterated alkoxy. Preferably, Cy1 and Cy2 are independently bonded and selected from 5-6 member monocyclic cycloalkylene, 4-6 member monocyclic heterocyclylene alkyl, phenylene, 5-6 member heteroarylene, 6-12 member bicyclic cycloalkylene, 6-12 member bicyclic heterocyclylene, 7-12 member spiroalkylene, or 7-12 member spiroheterocyclylene, and the 5-6 member monocyclic cycloalkylene, 4-6 member monocyclic heterocyclylene alkyl, phenylene, 5-6 member heteroarylene, 6-12 member bicyclic cycloalkylene, 6-12 member bicyclic heterocyclylene, 7-12 member spiroalkylene, and 7-12 member spiroheterocyclylene are further optionally substituted with 0-4 substituents selected from deuterium, fluorine, amino, hydroxy, cyano, nitro, methyl, ethyl, methoxy, trifluoromethyl, or difluoromethyl. More preferably, Cy1 and Cy2 are independently bonded to cyclohexylidene, piperidinelene, phenylene, pyridinelene, pyrazolylene, piperazinelene, morpholinylene,

[0030] [ka] Selected from, the cyclohexylidene, piperidinelene, phenylene, pyridinelene, pyrazolylene, piperazinelene, morpholinylene,

[0031] [ka] It is further optionally substituted with 0 to 4 substituents selected from deuterium, fluorine, amino, hydroxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, propyloxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, or difluoromethyl.

[0032] In a preferred embodiment of the present invention, L2 described above is -Ak1-Cy1-Ak2-Cy2-Ak3-, Ak1, Ak2, and Ak3 are each independently -(CH2) n3 -, -O-, -C(O)-, -NH-, -NR7-, -CH2NR7-, -(CR8R9) n4 -, or selected from combinations, Cy1 and Cy2 are each independently bonded, selected from cyclohexylidene, piperidine, or piperazinerene, and cyclohexylidene, piperidine, and piperazinerene are deuterium, halogen, hydroxyl, cyano, oxo, and C 1-3 Alkyl, hydroxy C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclyl, C 1-3 Haloalkyl, or C 1-3 They are further optionally substituted with 1 to 4 substituents selected from haloalkoxys. R7, R8, and R9 are each independently hydrogen, deuterium, halogen, and C 1-3 Alkyl, cyano, hydroxy, C 3-4 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Alkyl deuterated, C 1-3 Halocycloalkyl, hydroxyC 1-3 Alkyl, or C 1-3 Selected from alkoxy, Preferably, L2 is

[0033] [ka] Selected from, in the formula, M and M0 are each independently CR 11 Or selected from N, R 11 is hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, n6 and n7 are each independently selected from 0, 1, 2, 3, or 4, preferably n6 is 2 and n7 is 0.

[0034] In a preferred embodiment of the present invention, the compound of general formula (II-A) described above is further represented by general formula (IV-0).

[0035] [ka] In the formula, R a , R b L3, R3, M0, M4, M5, M6, and M7 are as defined above in this invention.

[0036] In a preferred embodiment of the present invention, the compound of general formula (II-A) described above is further represented by general formula (IV-1),

[0037] [ka] In the formula, R a , R b L3, R3, M0, M4, M5, M6, and M7 are as defined above in this invention.

[0038] In a preferred embodiment of the present invention, the compound of general formula (II-A) described above is further represented by general formula (IV-2),

[0039] [ka] In the formula, R a , R b L3, R3, M0, M4, M5, M6, and M7 are as defined above in this invention.

[0040] In a preferred embodiment of the present invention, the compound of general formula (II-A) described above is further represented by general formula (IV),

[0041] [ka] In the formula, R a , R b L3, R3, M4, M5, M6, and M7 are as defined above in this invention.

[0042] In a preferred embodiment of the present invention, the compound of general formula (II-A) described above is further represented by general formula (IV-A) or general formula (IV-B),

[0043] [ka] In the formula, R a , R b L3, R3, M4, M5, M6, and M7 are as defined above in this invention.

[0044] In a preferred embodiment of the present invention, the compound of general formula (II-A) described above is further This is shown by the general formula (IV-3),

[0045] [ka] In the formula, R a , R b L3, M4, M5, M6, and M7 are as defined above in this invention.

[0046] In a preferred embodiment of the present invention, the compound of general formula (II-B) described above is further represented by general formula (V),

[0047] [ka] In the formula, R a , R b L3, R3, M4, M5, M6, M9 and M 10 This is as defined above in the present invention.

[0048] In a preferred embodiment of the present invention, R described above a and Rb These are, independently, hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propyloxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, isopropylmethyl, morpholinyl, cyclopropyl, cyclobutyl,

[0049] [ka] Selected from.

[0050] In a preferred embodiment of the present invention, R described above c Each of these is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, cyclopropyl, or cyclobutyl.

[0051] In a preferred embodiment of the present invention, R described above d , R d1 , R d2 , R d3 and R d4 Each of these is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, cyclopropyl, or cyclobutyl.

[0052] In one preferred embodiment of the present invention, R described above a C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, preferably C 1-3 Alkoxy or hydroxy C 1-3 The alkyl group is more preferably methoxy, ethoxy, propyloxy, hydroxymethyl, hydroxyethyl, or hydroxypropyl.

[0053] In one preferred embodiment of the present invention, R described above b C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, preferably C 1-3 Haloalkyl or C 1-3 It is a haloalkoxy, more preferably difluoromethyl, trifluoromethyl, or trifluoromethoxy.

[0054] In a preferred embodiment of the present invention, L3 described above is selected from bond, -NH-C(O)-, or -C(O)-NH-.

[0055] In a preferred embodiment of the present invention, R3 described above is 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 Selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, and C 1-3 Alkyl, C 1-3 Alkoxy, or C 1-3 It is a haloalkyl, more preferably hydrogen, deuterium, fluorine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, or propyloxy.

[0056] In a preferred embodiment of the present invention, M0 described above is selected from N or CH.

[0057] In a preferred embodiment of the present invention, M4 described above is N or CR4, and R4 is hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, or C 1-3Selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

[0058] In a preferred embodiment of the present invention, M5 described above is N or CR5, and R5 is hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

[0059] In a preferred embodiment of the present invention, M6 described above is N or CR6, and R 6 is hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

[0060] In a preferred embodiment of the present invention, M7 described above is O, CH2, C(O), S, S(O), or S(O)2, preferably O, CH2, or S.

[0061] In a preferred embodiment of the present invention, M9 as described above is CH2, C(O), O, or S.

[0062] In a preferred embodiment of the present invention, M described above 10 CH2, C(O), NR 10 , O or S, R 10 is hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 Selected from haloalkyl or C 1-3 haloalkoxy, preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

[0063] 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.

[0064] In a preferred embodiment of the present invention, the compound described above is selected from the compounds in Table 5 below.

[0065]

Table 1-1

[0066]

Table 1-2

[0067]

Table 1-3

[0068]

Table 1-4

[0069]

Table 1-5

[0070]

Table 1-6

[0071]

Table 1-7

[0072]

Table 1-8

[0073] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by each of the general formulas described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0074] The present invention also provides a preferred embodiment regarding the use of a compound of each general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a drug for treating or preventing IRAK4-mediated diseases.

[0075] The present invention also provides a preferred embodiment regarding the use of a compound of each general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a drug for treating or preventing an autoimmune disease, an inflammatory disease, cancer, a viral disease, a neurodegenerative disease, a genetic disease, a hormone-related disease, a metabolic disease, an organ transplantation-related disease, an immunodeficiency disease, a destructive bone disease, a proliferative disease, an infectious disease, a cell death-related disease, or a cardiovascular disease. <000096�> The present invention also relates to a compound of formula (A-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and its specific structure is as follows:

[0077]

Chemical formula

[0078]

Chemical formula

[0079] The present invention also relates to a compound of formula (Aaa), its stereoisomer, or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

[0080] [ka] In the formula, M4 is N or CR4, M5 is N or CR5, M6 is N or CR6, M7 is O, S or CH2, and R3 is deuterium, halogen, or C 1-3 Alkyl, C 1-3 Alkoxy, or C 1-3 Selected from haloalkyls, R4 is hydrogen, deuterium, halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl, C 1-3 Alkoxy, or C 1-3 Selected from haloalkyls, R5 is hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, R6 is hydrogen, deuterium, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, or C 1-3 Selected from haloalkoxys, R 12 and R 13 Each of these is independently selected from either a hydrogen or an amino protecting group.

[0081] In a preferred embodiment of the present invention, the compound of formula (Aaa) is further represented by formulas (Aaa-1) and (Aaa-2).

[0082] [ka]

[0083] In a preferred embodiment of the present invention, R3 is selected from deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, or trifluoromethyl.

[0084] In a preferred embodiment of the present invention, R4 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, or trifluoromethyl.

[0085] In a preferred embodiment of the present invention, R5 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

[0086] In a preferred embodiment of the present invention, R6 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

[0087] In a preferred embodiment of the present invention, the R 12 and R 13 Each of these is independently selected from hydrogen, SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, benzyl, m-dimethoxybenzyl, -CH2COOH, or -COCH3.

[0088] 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 Body R, intermediate S, intermediate T, intermediate U, intermediate V, intermediate W, intermediate Y-5, intermediate Y-6, intermediate Y-8, intermediate Y-9, intermediate Y-10.

[0089] The present invention also relates to a compound of formula (Ba), its stereoisomer, or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

[0090] [ka] During the ceremony, R 14 and R 15 Each is independently selected from a hydrogen or amino protecting group, and M1, M3, M4, M5, M6,

[0091] [ka] L1, R c , R d , R d1 p, z, j, n1, and n2 are as defined above.

[0092] In a preferred embodiment of the present invention, R 14 and R 15 Each of these is independently selected from hydrogen, SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, benzyl, p-methoxybenzyl, -CH2COOH, or -COCH3.

[0093] In the present invention, the amino protecting group is preferably SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, -CH2COOH, -COCH3, ethoxycarbonyl, benzyl, p-methoxybenzyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, or allyloxycarbonyl.

[0094] The present invention also relates to the application of the structural unit of formula (Aa-1) or formula (Ba-1) as the E3 ubiquitin structural unit of a proteolytic inhibitor.

[0095] [ka] In the formula, M1, M2, M3, M4, M5, M6,

[0096] [ka] L1, R c , R d p and z are as defined above. Or,

[0097] [ka] During the ceremony, M1, M3, M4, M5, M6,

[0098] [ka] L1, R c , R d , R d1 p, z, j, n1, and n2 are as defined above.

[0099] The present invention also relates to a method for preparing compounds of general formula (IV-0), and includes the following:

[0100] [ka] Compound IV-A and compound IV-Y are reduced and aminated to obtain compound IV-0. In the formula, rings A, R a , R b , R c , R d M2, M3, M4, M5, M6, L1, p, and z are as defined above in this invention.

[0101] The present invention also relates to a method for preparing compounds of general formula (V-0), and includes the following:

[0102] [ka] The compound of formula VA and the compound of formula VY are reduced and aminated to obtain the compound of formula V-0. In the formula, rings 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 this invention.

[0103] The present invention also relates to compounds of general formula (III-A) or (III-B), stereoisomers thereof, or pharmaceutically acceptable salts thereof, the structures of which are as follows.

[0104] [ka] During the ceremony, PTM is selected from drugs or derivatives thereof that bind to the target protein. L2, M1, M2, M3, M4, M5, M6,

[0105] [ka] L1, R c , R d p and z are as defined above. Or,

[0106] [ka] During the ceremony, PTM is selected from drugs or derivatives thereof that bind to the target protein. L2, M1, M3, M4, M5, M6,

[0107] [ka] L1, Rc , R d , R d1 p, z, j, n1, and n2 are as defined above.

[0108] In preferred embodiments of the present invention, the PTM described above is AR, ER, kinase, phosphatase, MDM2, human BET bromodomain protein, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular growth factor, immunosuppression-related receptor or protein, aromatic hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease, or acyl protein thioesterase 1 or / and The PTM described above is selected from drugs or derivatives thereof that act on silprotein thioesterase 2, and preferably, the PTM described above is 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.

[0109] The present invention also comprises administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, or hydrate thereof to a mammal, thereby treating IRAK4-mediated disease. With regard to methods for treating or preventing a disease, the IRAK4-mediated disease is selected from autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related diseases, or cardiovascular diseases.

[0110] Detailed description of the invention Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0111] The term "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon 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. In the present invention, methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred.

[0112] The term "alkylene" refers to an alkyl group in which one hydrogen atom has been further substituted. For example, "methylene" means -CH2-, "ethylene" means -(CH2)2-, "propylene" means -(CH2)3-, and "butylene" means -(CH2)4-.

[0113] The term "alkenyl" means an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyls may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylalkylthio.

[0114] The term "alkenylene" refers to an alkenyl molecule in which one hydrogen atom is further substituted. For example, "vinylidene" means -(CH)2-.

[0115] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, chlorohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings, and crosslinked rings, and non-limiting examples include:

[0116] [ka] These are some examples.

[0117] The cycloalkyl ring may be condensed with an aryl ring, a heteroaryl ring, or a heterocyclylalkyl ring, and the ring bonded to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptylalkyl. The cycloalkyl may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, oxo, carboxy, or alkoxycarbonyl.

[0118] The term "cycloalkylidene" refers to a cycloalkyl group in which one hydrogen atom is further substituted. A non-limiting example is cyclohexylidene.

[0119] [ka] Examples include the following. The cycloalkylidene may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclylalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, oxo, carboxy, or alkoxycarbonyl.

[0120] The term "heterocyclyl" refers to a ring atom consisting of one or more nitrogen, oxygen, C(O), S(O)(=NH), or S(O). m (where m is an integer from 0 to 2) the heteroatoms selected from the range of heteroatoms, but excluding the -OO-, -OS-, or -SS- in the ring, the remaining ring atoms are carbon atoms, and the saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents comprise 3 to 20 ring atoms. Preferably, the substituent comprises 3 to 12 ring atoms, more preferably 3 to 12 ring atoms, and most preferably 3 to 6 ring atoms, with 1 to 4 of the atoms being heteroatoms. Non-limiting examples of monocyclic heterocyclils include oxetanil, thietanil, azetidinil, tetrahydropyranil, azepanil, pyrrolidinil, imidazolidinil, tetrahydrofuranil, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranil, dihydropyrazolyl, dihydropyrrolyl, piperidinil, piperazinil, morpholinil, thiomorpholinil, homopiperazinil, and pyranil, with oxetanil, thietanil, azetidinil, tetrahydrofuranil, tetrahydropyranil, 1-imino-1-oxothiopyran, azepanil, piperidinil, and piperazinil being preferred. Polycyclic heterocyclils include heterocyclils of spiro rings, fused rings, and cross-linking rings, and non-limiting examples include,

[0121] [ka] These include heterocyclyls, which may or may not be substituted. If substituted, the substituents can be alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, or heterocyclyl. Preferably, the group is one or more groups independently selected from alkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, oxo, carboxy, or alkoxycarbonyl.

[0122] The term "heterocyclylene" refers to a heterocycline in which one hydrogen atom is further substituted, and non-limiting examples include piperidinylene, piperadinylene, pyrrolopyrrolylene, diazaspiro[5.5]undecylen, azaspiro[5.5]undecylen, benzopiperidinylene, azetidinylene, diazetidinylene, pyrrolidinylene, azaspiro[3.5]nonylene, diazaspiro[3.5]nonylene, azabicyclo[3.1.1]heptanylene, azaspiro[2.5]octanylene,

[0123] [ka] Examples include the heterocyclylene, which may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclylalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, oxo, carboxy, or alkoxycarbonyl.

[0124] The term "aryl" refers to a 6-14 membered monocyclic or polycyclic fused ring (i.e., a ring sharing an adjacent pair of carbon atoms) having a conjugated π-electron system, preferably 6-10 membered, and more preferably phenyl. The aryl ring may be fused to a heteroaryl ring, a heterocyclyl ring, or a cycloalkyl ring, and the ring bonded to the parent structure is an aryl ring. The aryl may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclylalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carboxy, or alkoxycarbonyl.

[0125] The term "arylene" refers to an aryl compound in which one hydrogen atom is further substituted, and a non-limiting example of this is:

[0126] [ka] These include: Arylene may be substituted or unsubstituted. If substituted, the substituents may be alkyl, alkoxy, alkylthio, alkylamino, halogen, Preferably, it is one or more groups independently selected from mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclylalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carboxy, or alkoxycarbonyl.

[0127] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 5 to 14 ring atoms. Heteroaryls are preferably 5 to 8-membered monoheteroaryls or 8 to 14-membered biheteroaryls, more preferably 5-membered monoheteroaryls, 6-membered monoheteroaryls, or 9-membered biheteroaryls, such as imidazolyl, allyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, piperazinyl, pyridinoimidazolyl, pyrimidinoimidazolyl, and the like, with pyridinoimidazolyl and pyrimidinoimidazolyl being preferred.

[0128] The heteroaryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carboxy, or alkoxycarbonyl groups.

[0129] The term "heteroarylene" refers to a heteroaryl compound in which one hydrogen atom is further substituted, and a non-limiting example of this is: Pyridinylene, pyrimidinylene, pyrazolylene, pyridadinylene, pyrazinylene,

[0130] [ka] These are some examples.

[0131] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl) groups where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propyroxy, butoxy, cyclopropyroxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carboxy, or alkoxycarbonyl. Non-limiting examples include trifluoromethoxy, trifluoroethoxy, and difluoromethoxy.

[0132] "Haloalkyl" refers to an alkyl group in which the alkyl group is substituted with one or more halogens, as defined above. Non-limiting examples include trifluoromethyl and difluoromethyl.

[0133] "Haloalkoxy" refers to an alkoxy in which the alkoxy is substituted with one or more halogens, as defined above.

[0134] "Hydroxyalkyl" refers to an alkyl group that is substituted with a hydroxyl group, as defined above. A non-restrictive example is -C(CH3)2(OH).

[0135] "Hydroxy" means -OH group. "Halogen" means fluorine, chlorine, bromine, or iodine. "Amino" means -NH2. "Cyano" means -CN. "Nitro" means -NO2. "Carboxy" means -C(O)OH. "THF" means tetrahydrofuran. "Â" means ethyl acetate. "MeOH" means methanol. "DMF" means N,N-dimethylformamide. "TFA" means trifluoroacetic acid. "MeCN" means acetonitrile. "DMA" means N,N-dimethylacetamide. "Et2O" means diethyl ether. "DCE" means 1,2-dichloroethane. "DIPEA" means N,N-diisopropylethylamine. "NBS" means N-bromosuccinimide. "NIS" means N-iodosuccinimide. "Cbz-Cl" means benzyl chloroformate. "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium. "Dppf" means 1,1'-bis(diphenylphosphino)ferrocene. "HATU" means 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate. "KHMDS" means potassium hexamethyldisilazide. "LiHMDS" means lithium bis(trimethylsilyl)amide. "MeLi" means methyllithium. "n-BuLi" means n-butyllithium. "NMP" means N-methylpyrrolidone. "EDCI" means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. "TEA" means triethylamine. "EA" means ethyl acetate. "DCM" means dichloromethane. "DMAP" means 4-dimethylaminopyridine. "NMO" means N-methylmorpholine oxide. "DIBAL-H" stands for diisobutylaluminum hydride. "T3P" stands for 1-propyl anhydride. "DMP" stands for dimethyl phthalate. "Dess-Martin" stands for dess-martin periodinane."Ruphos" means 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl. "Ruphos Pd G3" means (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate. "LDA" means lithium diisopropylamide. "SEMCl" means 2-(trimethylsilyl)ethoxymethyl chloride. "STAB" means sodium triacetoxyborohydride. "P-TSA" means p-toluenesulfonic acid. "PCC" means pyridinium chlorochromate. "Pd-PEPPSI" means 1,3-bis[2,6-bis(pentyl-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazole-2-yldichloro(2-methyl-1λ4-pyridine-1-yl)palladium. "LiBH4" means lithium borohydride. "DCE" means 1,2-dichloroethane. "SEM" means (trimethylsilyl)ethoxymethyl. "TEBAC" means benzyltriethylammonium chloride.

[0136] "wt%" means mass percentage.

[0137] 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, meaning that X can be one or more of A, B, or C.

[0138] In the present invention [ka] This indicates the presence or absence of a connection. Unless otherwise specified, the chiral carbons in the compounds of the present invention are in either an R configuration or an S configuration.

[0139] The absolute configuration of the chiral compound of the present invention can be obtained by separation using conventional chiral separation methods in the art or by preparation using chiral raw materials.

[0140] Any hydrogen described in this invention may be replaced with its isotope, deuterium, and any hydrogen in the compounds related to the examples of this invention may also be replaced with deuterium.

[0141] "Optionally" or "optionally" means that the event or situation described below may occur, but is not necessarily to occur, and this statement includes whether or not such event or situation occurs. For example, "a heterocyclyl optionally substituted with an alkyl group" means that an alkyl group may be present, but is not necessarily to occur, and this statement includes cases where the heterocyclyl is substituted with an alkyl group and cases where the heterocyclyl is not substituted with an alkyl group.

[0142] "Substitution" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are independently substituted with a corresponding number of substituents. Needless to say, substituents exist only in their possible chemical positions. Those skilled in the art can determine (experimentally or theoretically) whether substitution is possible or impossible without excessive effort. For example, the bond between an amino or hydroxyl group with free hydrogen and a carbon atom with an unsaturated (e.g., olefinic) bond can be unstable.

[0143] "Pharmaceutical composition" means a mixture of one or more compounds described in the present invention, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living organism, which helps in the absorption of the active ingredient in order to exhibit biological activity.

[0144] "Pharmacologically acceptable salt" means a salt of the compound of the present invention that is safe and effective in mammals and possesses the desired biological activity. [Examples]

[0145] The present invention will be further described below with reference to examples, but these examples do not limit the scope of the present invention.

[0146] The starting materials and reagents used in the examples of the present invention are known and commercially available, or can be synthesized by or in accordance with methods known in the art. For example, compound 1-1 of the present invention can be prepared by referring to the method disclosed in WO2020264499A1. Compound 46-1 of the present invention can be prepared by referring to the method disclosed in WO2022028547A1.

[0147] Preparation of intermediate A [ka]

[0148] Step 1: Preparation of compound A-2 [ka] At room temperature, pulverized potassium hydroxide (11.6 g, 207 mmol) powder was added to a DMSO (100 mL) solution of racemized 1-BOC-3-hydroxymethylpiperazine A-1 (15 g, 69 mmol) and 3,4-difluoronitrobenzene (12.8 g, 80.05 mmol), and the mixture was heated to 60°C and reacted for 8 hours. After the reaction was complete, ice water was added to the reaction mixture. The resulting solid was collected by filtration, washed with water, and 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%). LCMS:(ESI,m / z):336.4[M+H] + .

[0149] Step 2: Preparation of Compound A-3 [ka] A methanol (30 mL) solution of compound A-2 (1 g, 2.982 mmol, 1 equiv) was added to an autoclave, followed by palladium / carbon (10%, 100 mg). The autoclave was purged with nitrogen, hydrogen (5 MPa) was introduced, and the mixture was reacted overnight at room temperature. Celite was then added, and the mixture was filtered by suction. The filtrate was concentrated under reduced pressure to obtain a brown solid compound A-3 (900 mg, 98.8%). LCMS:(ESI,m / z):306.5[M+H] + .

[0150] Step 3: Preparation of compound A-4 [ka] At room temperature, 4-methylbenzene-1-sulfonic acid (1.02 g, 5.89 mg) was added to a 10 mL solution of compound A-3 (900 mg, 2.947 mmol, 1 equiv) in acetonitrile. 4 mmol, 2 equiv) was added. After the addition was complete, the system was stirred at room temperature for 10 minutes. At 0°C, aqueous solutions of sodium nitrite (406.7 mg, 5.894 mmol, 2 equiv) and potassium iodide (1.47 g, 8.841 mmol, 3 equiv) were added to the above system. After the addition was complete, the system was stirred at room temperature for 4 hours. The target product was confirmed by liquid chromatography-mass spectrometry. The reaction mixture was quenched at 0°C with saturated sodium sulfite aqueous solution. The reaction mixture was extracted with dichloromethane (3 x 100 mL). The organic phase was combined, 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 (ethyl acetate: petroleum ether (0-50%)) to obtain a yellow solid compound A-4 (360 mg, 29.4%). LCMS:(ESI,m / z):361.3[M+H] + .

[0151] Step 4: Preparation of compound A-5 [ka] Under nitrogen protection at room temperature, 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) were dissolved in tetrahydrofuran (6 mL) and water (3 mL). Tetrakis(triphenylphosphine)palladium (299.82 mg, 0.260 mmol, 0.3 equiv) and potassium carbonate (239.05 mg, 1.730 mmol, 2 equiv) were added. After the addition was complete, the system was stirred overnight at 60°C. The target product was confirmed by liquid chromatography-mass spectrometry. The obtained residue was concentrated under vacuum. The obtained residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (0-50%)) to obtain the yellow solid compound A-5 (160 mg, 31.91%). LCMS:(ESI,m / z):580.6[M+H] + .

[0152] Step 5: Preparation of compound A-6 [ka] 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 / carbon (10%, 100 mg) and palladium hydroxide / carbon (palladium content 20%, 100 mg). The autoclave was purged with nitrogen, hydrogen (5 MPa) was introduced, and the mixture was reacted overnight at 60°C. Celite was then added, and the mixture was filtered by suction. The filtrate was concentrated under reduced pressure. A brown solid compound A-6 (58 mg, 69.8%) was obtained. LCMS:(ESI,m / z):402.5[M+H] + .

[0153] Step 6: Preparation of Compound A [ka] At room temperature, a 1 mL solution of compound A-6 (58 mg, 0.144 mmol, 1 equiv) in 1,4-dioxane solution (1 mL, 4 M) was added to a 1,4-dioxane solution of hydrogen chloride. After the addition was complete, the system was stirred overnight at room temperature. The target product was confirmed by liquid chromatography-mass spectrometry. The resulting residue was concentrated under vacuum. A brown solid compound A (40 mg, 91.8%) was obtained. LCMS:(ESI,m / z):302.4[M+H] + .

[0154] Intermediate A was separated using conventional chiral separation methods in this field, yielding intermediates J and H. [ka]

[0155] [ka]

[0156] Preparation of intermediate B [ka]

[0157] Step 1: Synthesis of compound B-2 [ka] Under nitrogen protection, at -78°C, methyl 5-bromo-2-iodobenzoate (1g, 2.93%) To a solution of 3 mmol, 1 equiv) and tert-butyl 4-oxopiperidine-1-carboxylate (0.64 g, 3.226 mmol, 1.1 equiv) in tetrahydrofuran (40 mL), isopropyl magnesium chloride-lithium chloride complex (0.47 g, 3.226 mmol, 1.1 equiv) was added and the mixture was reacted at -78°C for 2 hours. After the reaction was complete, the reaction was quenched by adding water (5 mL) at 0°C. Next, the mixture was extracted with ethyl acetate (3 x 40 mL), 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. Elution with petroleum ether / ethyl acetate (5:1) yielded compound B-2 (900 mg, 80.3%), a white solid. 1 H NMR (400 MHz,Chloroform-d,ppm) δ 8.03 (d,J=1.8 Hz,1H),7.80 (dd,J=8.1,1.8 Hz,1H),7.28 (s,1H),4.20 (d,J=13.7 Hz,2H),3.24 (t,J=13.1 Hz,2H),2.11 - 2.02 (m,2H),1.68 (dd,J=14.4,2.5 Hz,2H),1.68 (s,9H).

[0158] Step 2: Synthesis of Compound B-3 [ka] Under nitrogen protection, at 0°C, a solution of compound B-2 (900 mg, 2.354 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added dropwise to a THF solution of lithium borohydride (2 M, 17.7 mmol, 7.5 equiv), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched at 0°C with a saturated solution of water and sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, 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 resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (4:1)) to obtain compound B-3 (700 mg, 77.4%) as a white foam. LCMS:(ESI,m / z):384.2[M+H] + .

[0159] Step 3: Synthesis of compound B-4 [ka] At 0°C, 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 mixed dropwise with boron trifluoride etherate (221.61 mg, 1.562 mmol, 2.0 equiv) and stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water at room temperature. The mixture was extracted with dichloromethane (3 x 10 mL), the organic phase was combined, backwashed with water (3 x 5 mL), and the organic phase was dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The compound was purified using (dichloromethane / methanol (10:1)) to obtain a white solid compound B-4 (160 mg, 76.4%). LCMS:(ESI,m / z):268.1[M+H] + .

[0160] Step 4: Synthesis of compound B-5 [ka] At room temperature, di-tert-butyl dicarbonate (260.5 mg, 1.194 mmol, 2.0 equiv) was added dropwise 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). The mixture was reacted overnight and stirred. The resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (10:1)) to obtain a white solid compound B-5 (215 mg, 97.8%). 1 H NMR (400 MHz,Chloroform-d,ppm) δ 7.42 - 7.38 (d,J=1.6 Hz,1H),7.36 (d,J=1.6 Hz,1H),6.96 (d,J=8.0 Hz,1H),5.04 (s,2H),4.12 - 4.03 (m,2H),3.15 (td,J=12.9,3.1 Hz,2H),1.82 - 1.67 (m,4H),1.49 (s,9H).

[0161] Step 5: Synthesis of compound B-6 [ka] Under nitrogen protection at room temperature, 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-dioxyboran-2-yl)pyridine (309.35 mg, 0.741 mmol, 1.3 equiv) were mixed in 1,4-dioxane (5 mL) and water (1 mL). To this solution, [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) were added, and the mixture was stirred at 90°C for 2 hours to allow it to react. After the reaction was complete, the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, backwashed with water (3 x 30 mL), and dried over anhydrous sodium sulfate. The obtained residue was purified by reverse-phase column chromatography (conditions: C18 chromatography column; mobile phase: water and acetonitrile; gradient from 50% to 95% over 20 minutes; UV at 220 nm) to obtain a white solid compound B-6 (160 mg, 48.5%). LCMS:(ESI,m / z):579.3[M+H] + .

[0162] Step 6: Synthesis of compound B-7 [ka] 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, followed by the addition of palladium / carbon (22.07 mg, 0.207 mmol, 1.0 equiv). The mixture was stirred and reacted at room temperature for 8 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, 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 used directly in the next step. LCMS:(ESI,m / z):401.2[M+H] + .

[0163] Step 7: Synthesis of Compound B [ka] At room temperature, a solution of compound B-7 (50 mg, 0.125 mmol) in tetrahydrofuran (2 mL) was mixed dropwise with a 1,4-dioxane solution of hydrogen chloride (1 M, 0.08 mL) and stirred for 2 hours to allow the reaction to proceed. After the reaction was complete, the resulting residue was concentrated under reduced pressure to obtain a white solid compound B (30 mg, 80%). LCMS:(ESI,m / z):301.2[M+H] + .

[0164] Preparation of intermediate C [ka]

[0165] Step 1: Synthesis of compound C-3 Under nitrogen protection, compound C-1 (500 mg, 1.36 mmol), C-2 (185.9 mg, 1.63 mmol), cesium carbonate (884.7 mg, 2.72 mmol), and bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (145.2 mg, 0.27 mmol) were mixed in a 1,4-dioxane solution (5 mL) with (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl Ru-[1,1′-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (124.7 mg, 0.136 mmol) was added, and the reaction mixture was stirred at 100°C for 4 hours. After confirming the disappearance of the starting materials by liquid chromatography-mass spectrometry, the resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (0-30%)) to obtain compound C-3 (150 mg, 27.5%). LCMS(ESI,m / z):346.0[M-55] + .

[0166] Step 2: Synthesis of compound C At room temperature, compound C-3 (150 mg, 0.374 mmol) was dissolved in a 4 M hydrogen chloride solution of 1,4-dioxane (3 mL). The reaction mixture was stirred for 2 hours. After confirming the disappearance of the starting materials by liquid chromatography-mass spectrometry, the resulting residue was concentrated under reduced pressure to obtain intermediate C (100 mg, 88.8%). LCMS(ESI,m / z):302.5[M+H] + .

[0167] Preparation of intermediate D [ka] Compound B-2 was used instead of compound B-5, and intermediate D was obtained by referring to the preparation method for intermediate B. LCMS (ESI, m / z): 315.0 [M+H] + .

[0168] Preparation of intermediate E [ka]

[0169] [ka] Compound

[0170] [ka] Using the method described for preparing intermediate A, intermediate E was obtained. LCMS (ESI, m / z): 320.5 [M+H] + .

[0171] Preparation of intermediate Ea [ka]

[0172] [ka] Compound

[0173] [ka] Use instead of A-1

[0174] [ka] Using the method described for preparing intermediate A, intermediate Ea was obtained. LCMS(ESI,m / z):320.1[M+1] + .

[0175] Preparation of intermediate Eb [ka]

[0176] [ka] Compound

[0177] [ka] Use instead of A-1

[0178] [ka] Using the method described for preparing intermediate A, intermediate Eb was obtained. LCMS (ESI, m / z): 320.1 [M+1] + .

[0179] Preparation of intermediate F [ka]

[0180] [ka] Compound

[0181] [ka] Using the method described for preparing intermediate A, intermediate F was obtained. LCMS(ESI,m / z):303.1[M+H] + .

[0182] Preparation of intermediate G [ka] Under nitrogen protection at room temperature, 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). The mixture was then heated to 80 °C and stirred overnight, and the disappearance of the starting materials was monitored by liquid chromatography-mass spectrometry. The mixture was filtered, the filter cake was washed with tetrahydrofuran (3 x 30 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography to obtain compound G-1. (200 mg, 38.7%) was obtained (Conditions: Chromatography column specifications: YMC Triart C18 ExRs 5um, 30 mm*150 mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: Increase from 23%B to 38%B in 10 minutes; Detection wavelength: UV 254 nm; Retention time (min): 9.97). LCMS (ESI, m / z): 390.1 [M+H] + .

[0183] G-1 (70 mg, 0.18 mmol, 1 eq) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 3.6 mL) at room temperature, stirred overnight at room temperature, and the target product was confirmed by liquid chromatography-mass spectrometry. The resulting residue was concentrated under vacuum to obtain intermediate G (80 mg, crude product), which was a white solid. LC-MS (ESI, m / z): 344.2 [M+H] + .

[0184] Alternative preparation method for intermediate H Compound A-1 is replaced with compound [ka] Using the method described for preparing intermediate A, intermediate H was obtained. LCMS(ESI,m / z):301.9[M+H] + .

[0185] Preparation of Intermediate I [ka] Compound A-1 is replaced with compound

[0186] [ka] Using the method described above, compound H-6 was obtained by referring to the preparation method for compound A-6. Under nitrogen protection, at -78°C, lithium bis(trimethylsilyl)amide (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). After the addition was complete, the system was stirred at -78°C for 1 hour. Deuterated water (1.2 mL) was added to the system at -78°C. After the addition was complete, the system was stirred at room temperature overnight. The target product was confirmed by liquid chromatography-mass spectrometry. 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. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. A white solid, I-1 (140 mg, 44.6%), was obtained. LCMS(ESI,m / z):421.2[M+H] + .

[0187] At room temperature, 1,1'-carbonyldiimidazole (154.3 mg, 0.96 mmol, 4 eq) was added to a solution of I-1 (100 mg, 0.238 mmol, 1 eq) in acetonitrile (2.35 mL). After addition, the system was stirred at 90°C for 1 hour. The completion of the reaction was detected by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (0-60%)) to obtain I-2 (61 mg, 63.7%), a white solid. LCMS (ESI, m / z): 402.9 [M+H] + .

[0188] At room temperature, I-2 (73 mg, 0.181 mmol, 1 eq) was added to a 1,4-dioxane solution of hydrogen chloride (1.8 mL, 4 M). After addition, the system was stirred at room temperature for 1 hour. The end of the reaction was detected by liquid chromatography-mass spectrometry. The resulting residue was concentrated under vacuum. Intermediate I (65 mg), an off-white solid, was obtained. LC-MS (ESI, m / z): 303.4 [M+H] + .

[0189] Alternative preparation method for intermediate J Instead of compound A-1 [ka] Using the method described for preparing intermediate A, intermediate J was obtained. LCMS(ESI,m / z):302.4[M+H] + .

[0190] Preparation of intermediate K [ka] Compound B-2 was used instead of compound C-1, and intermediate K was obtained by referring to the preparation of intermediate C. LCMS (ESI, m / z): 316.1 [M+H] + .

[0191] Preparation of intermediate L [ka]

[0192] [ka] Compound

[0193] [ka] Use instead of A-1

[0194] [ka] Compound L-1 was obtained using [method / method]. Under nitrogen protection, 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 the addition was complete, the system was stirred at 65°C for 16 hours. Completion of the reaction was detected by liquid chromatography-mass spectrometry. The reaction mixture was extracted with ethyl acetate (3 x 100 mL), the organic phase was combined, 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 resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain L-2 (600 mg, 44.7%), a pale green solid. LCMS (ESI, m / z): 435.2 [M+H] + .

[0195] At room temperature, L-2 (200 mg, 0.46 mmol, 1 eq) and a 1,4-dioxane solution of hydrogen chloride (2 mL, 4 M) were stirred and reacted for 1 hour. The end of the reaction was detected by liquid chromatography-mass spectrometry, and the resulting residue was concentrated under reduced pressure. An off-white solid intermediate L (150 mg, 97.5%) was obtained. LC-MS (ESI, m / z): 334.9 [M+H] + .

[0196] Preparation of intermediate M [ka] M-1 (15g, 73.9 mmol, 1.0eq) was added to the reaction flask, and after purging with nitrogen, THF (130mL) was added. At -78°C, a THF solution (20mL) of ethyl propiolate (7.97g, 81.3 mmol, 1.1eq) was added dropwise. After the addition was complete, LDA (2M, 40.6mL, 81.3 mmol, 1.1eq) was added dropwise at -78°C. After the addition was complete, the mixture was stirred at -78°C for 2 hours. The completion of the reaction of the starting materials was monitored by TLC. The reaction was allowed to return to room temperature, and an aqueous solution of ammonium chloride was added to quench the mixture. After complete quenching, EA was added for extraction and separation. The organic phase was dried over sodium sulfate and then centrifuged to dry it. The resulting oily product, M-2 crude product (12.0g, yield: 53.8%), was supplied directly to the next step. LCMS(ESI,m / z):300.8[M+H] + .

[0197] The crude M-2 product obtained above (12.0 g, 1.0 eq) was dissolved in 1,4-dioxane (100 mL), and then triethylamine (14 mL, 121.7 mmol, 2.5 eq) was added. The reaction was carried out at 60°C for 3 hours. The completion of the reaction of the starting materials was monitored by TLC. After the reaction solution cooled to room temperature, it was centrifuged and dried to obtain 7 g of oily substance M-3 (yield 58.3%). LCMS (ESI, m / z): 300.8 [M+H] + .

[0198] In a sealed tube, M-3 (5.1 g, 17 mmol, 1.0 eq) was dissolved in DMF (60 ml), 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 hours. The completion of the reaction of the starting materials was monitored by TLC. After the reaction solution cooled to room temperature, water (10 mL) and EA were added for extraction, the solution was parried and dried, concentrated, and purified by chromatography to obtain 3.7 g of yellow solid M-4 (yield: 74.03%). LCMS (ESI, m / z): 295.0 [M+H] + .

[0199] M-4 (300 mg, 1.02 mmol, 1.0 eq) was dissolved in THF (5 mL), and after purging with nitrogen, boranetetrahydrofuran solution (4.08 mL, 4.08 mmol, 4 eq) was added dropwise in an ice bath. After the addition was complete, the temperature was raised to 60°C and maintained overnight. The reaction was monitored by TLC, and methanol was slowly added dropwise at a low temperature until no more bubbles were produced. Then, the mixture was stirred at 60°C for 2 hours, 0.5 mL of 1 M hydrochloric acid solution was added, and the mixture was continued to be stirred at 60°C overnight. After confirming complete quenching by LC-MS, the mixture was cooled to room temperature, triethylamine (412 mg, 4.08 mmol, 4.0 eq) was added, and the mixture was stirred for 0.5 hours. After centrifuging and drying the solvent, DCM (10 mL) and (BOC)2O (445 mg, 2.04 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 5 hours. The completion of the reaction was monitored by TLC. Water (10 mL) and EA were added, and the mixture was extracted and dried over anhydrous sodium sulfate. After concentration, a colorless oily substance, M-6 (360 mg, yield: 96.4%), was obtained by column chromatography. LC-MS (ESI, m / z): 367.1 [M+H] + .

[0200] 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-dioxyboran-2-yl)pyridine (318 mg, 0.76 mmol, 2.0 eq), [1,1'-bis(di-tert-butylphosphine)ferrocene]dichloropalladium (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 purging with nitrogen, the mixture was stirred at 80°C for 3 hours. After monitoring for completion of the reaction by TLC, the reaction was stopped. After the reaction mixture cooled to room temperature, water (10 mL) and EA were added for extraction, and the mixture was parried and dried. After concentration, the solution was purified by chromatography to obtain M-7 (120 mg, yield: 54.4%), a pale yellow oily substance. LCMS (ESI, m / z): 578.3 [M+H] + .

[0201] M-7 (120 mg, 0.21 mmol, 1.0 eq) was dissolved in 2 mL of isopropanol, Pd / C (12 mg) and palladium-carbon hydroxide (12 mg) were added, and after hydrogenation, the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC to confirm completion, the reaction mixture was filtered through Celite, and the mother liquor was concentrated to obtain M-8 (70 mg, yield: 84.4%), a pale yellow oily substance. LCMS (ESI, m / z): 400.2 [M+H] + .

[0202] 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 then stirred at room temperature for 2 hours. The reaction was monitored by TLC to confirm completion. After concentrating the reaction mixture, DCM was added to disperse it, and then the mixture was centrifuged to obtain M (40 mg, yield: 76.9%), a pale yellow oily substance. LCMS (ESI, m / z): 300.2 [M + H] + .

[0203] Preparation of intermediate N [ka] In a reaction flask, 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. After purging with nitrogen, the mixture was stirred at 100°C for 4 hours, and the completion of the reaction of the starting materials was monitored by TLC. After cooling the reaction to room temperature, water and EA were added, and the mixture was extracted and separated. The organic phase was dried over sodium sulfate and then centrifuged, and the oily substance N-1 (45 mg, yield: 45.8%) was obtained by column chromatography. LCMS (ESI, m / z): 400.8 [M+H] + .

[0204] 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 hours, and the completion of the reaction was monitored by TLC. The reaction mixture was directly centrifuged to obtain intermediate N, a pale yellow oily substance (35 mg, crude yield: 103%). LCMS (ESI, m / z): 301.1 [M+H] + .

[0205] Preparation of intermediate O [ka] At 0°C, sodium hydride (110 mg, 60%) was added to a solution of compound A-6 (1 g, 2.491 mmol, 1 eq) in N,N-dimethylformamide (20 mL). After the addition was complete, the system was stirred at 0°C for 0.5 hours. At 0°C, 2-(trimethylsilyl)ethoxymethyl chloride (458 mg, 2.747 mmol, 1.10 eq) was added to the system. After the addition was complete, the system was stirred at room temperature for 1 hour. The end of the reaction was detected by liquid chromatography-mass spectrometry. 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 obtained residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (0-30%)) to obtain a yellow, oily compound O-1 (770 mg, 58.14%). LCMS: (ESI, m / z): 532.5 [M+H] + .

[0206] Under nitrogen protection, at -78°C, a solution of compound O-1 (320 mg, 0.602 mmol, 1 eq) in tetrahydrofuran (5 mL) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.72 mL, 1 M). After the addition was complete, the system was stirred at -78°C for 1 hour. Methyl iodide (171 mg, 1.205 mmol, 2.00 eq) was added to the system at -78°C. After the addition was complete, the system was stirred at -78°C for 1 hour. Subsequently, the system was stirred at room temperature for 0.5 hours. The end of the reaction was detected by liquid chromatography-mass spectrometry, and 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 obtained residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (0-50%)) to obtain the brownish oily compound O-2 (137 mg, 41.71%). LCMS (ESI, m / z): 546.2 [M+H] + .

[0207] At room temperature, trifluoroacetic acid (0.6 mL, 8.078 mmol, 35.55 eq) was added to a solution of compound O-2 (124 mg, 0.227 mmol, 1 eq) in dichloromethane (4 mL). After the addition was complete, the system was stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry detected that the starting materials had completely reacted, and ethylenediamine (0.8 mL) was added to the system at 0°C. After the addition was complete, the system was stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry detected the end of the reaction, and the target product was confirmed by liquid chromatography-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. A crude yellow solid intermediate, O (98 mg, 94.37%), was obtained. LC-MS (ESI, m / z): 316.1 [M+H] + .

[0208] Preparation of intermediate P [ka] Instead of compound A-1

[0209] [ka] Using the method described for preparing compound A-6, compound H-6 was obtained. Then, intermediate P was obtained by referring to the method described for preparing intermediate O. LCMS:(ESI,m / z):316.2[M+H] + .

[0210] Preparation of intermediate Q [ka] Instead of compound A-1

[0211] [ka] Using the method described for preparing compound A-6, compound J-6 was obtained. Then, intermediate Q was obtained by referring to the preparation method for intermediate O. LCMS:(ESI,m / z):316.2[M+H] + .

[0212] Preparation of intermediate R [ka]

[0213] [ka] Compound

[0214] [ka] Using the method described for preparing intermediate A, intermediate R was obtained. LCMS(ESI,m / z):336.1[M+1] + .

[0215] Preparation of intermediate S [ka]

[0216] [ka] Compound

[0217] [ka] Using the method described for preparing intermediate A, intermediate S was obtained. LCMS(ESI,m / z):336.1[M+1] + .

[0218] Preparation of intermediate T [ka] Compound instead of A-1

[0219] [ka] Using the method described for preparing intermediate A, intermediate T was obtained. LCMS(ESI,m / z):316.4[M+1] + .

[0220] Preparation of intermediate U [ka] Compounds instead of M-6

[0221] [ka] Using the method described for preparing intermediate N, intermediate U was obtained. LCMS(ESI,m / z):303.1[M+1] + .

[0222] Preparation of intermediate V [ka] Compound instead of A-4

[0223] [ka] Using the method described for preparing intermediate A, intermediate V was obtained. LCMS(ESI,m / z):328.2[M+1] + .

[0224] Preparation of intermediate W [ka] Compounds instead of M-6

[0225] [ka] Using the method described for preparing intermediate N, intermediate W was obtained. LCMS(ESI,m / z):321.1[M+1] + .

[0226] Preparation of intermediate Y-1 [ka] Intermediate Y-1 was synthesized by referring to the prior art WO2023283610A1.

[0227] Preparation of intermediate Y-2 [ka] Intermediate Y-2 was synthesized by referring to the prior art WO02023283372A1.

[0228] Preparation of intermediate Y-3 [ka] Intermediate Y-3 was synthesized by referring to the prior art WO2022028547A1.

[0229] Preparation of intermediate Y-4 [ka] Intermediate Y-4 was synthesized by referring to the prior art WO2022028547A1.

[0230] Preparation of intermediate Y-5-1 [ka] At 5°C, 2-fluoro-4-methoxybenzaldehyde (24 g, 155.7 mmol, 1 eq) was added to a 310 mL aqueous solution of bromine (49.77 g, 311.4 mmol, 2 eq) and potassium bromide (92.6 g, 778.5 mmol, 5 eq) and stirred at room temperature for 2 hours. After the reaction was complete, 500 mL of water was added to the system, and a large amount of solid precipitated. The solution was filtered, the filter cake was collected, washed with saturated sodium bicarbonate solution (3 x 200 mL), and freeze-dried to obtain 5-bromo-2-fluoro-4-methoxybenzaldehyde (Y-5-1-1, 30 g, 82.7%), which was a yellow solid.

[0231] In an autoclave, 300 mL of a methanol solution of compound Y-5-1-1 (20 g, 85.8 mmol, 1 eq) was mixed with 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (3.50 g, 4.3 mmol, 0.05 eq) and triethylamine (17.37 g, 171.6 mmol, 2 eq). After purging with nitrogen for 10 minutes, carbon monoxide was introduced to 5 MPa, and the reaction was carried out at 120°C for 2 hours. The completion of the reaction was monitored by liquid chromatography-mass spectrometry. The system was cooled to room temperature, insoluble matter was removed by filtration, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0-60%)) to obtain methyl 4-fluoro-5-formyl-2-methoxybenzoate Y-5-1-2 (8.7 g, 47%), an off-white solid. 1 H NMR (400 MHz,DMSO-d6) δ 10.06 (s,1H),8.17 (d,J=8.3 Hz,1H),7.25 (d,J=13.1 Hz,1H),3.94 (s,3H),3.81 (s,3H).

[0232] Under nitrogen protection, sodium azide (5.81 g, 89.4 mmol, 2 eqs) was added in several batches 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, and the mixture was stirred for 4 hours to allow the reaction to complete. The reaction mixture was then quenched with ice water at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 300 mL). The organic phases were combined, backwashed with saturated sodium bicarbonate aqueous solution (2 x 300 mL), and dried over sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure to obtain the brown solid Y-5-1-3 (7.9 g, 75.2%). 1 H NMR (400 MHz,DMSO-d6) δ 10.08 (s,1H),8.12 (s,1H),7.10 (s,1H),4.00 (s,3H),3.8 0 (s,3H).

[0233] Under nitrogen protection, at 110°C, 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) and reacted overnight with stirring. The completion of 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 x 200 mL), the organic phases were combined, and the mixture was dried over 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 (petroleum ether / ethyl acetate (0-50%)) to obtain Y-5-1-5 (3.5 g, 31.4%), a yellow solid. LCMS: (ES, m / z): 333.4 [M+1] + .

[0234] Under nitrogen protection, at 50°C, 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) was mixed with silver oxide (4.88 g, 21.1 mmol, 2 eq) and stirred for 2 hours to allow the reaction to proceed. The completion of the reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / dichloromethane (0-50%)) to obtain Y-5-1-6 (3.1 g, 69.7%), a brown oil. LCMS: (ES, m / z): 423.5 [M+1] + .

[0235] Compound Y-5-1-6 (2.8 g, 6.6 mmol) and water (3 mL) were dissolved in methanol (30 mL). Lithium hydroxide (476.14 mg, 19.9 mmol) was added, and the mixture was stirred at 50°C for 3 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was quenched at 0°C with ice water. The reaction mixture was oxidized to pH=4 with citric acid, and the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. A brown solid, Y-5-1-7 (2 g, 73.8%), was obtained. LCMS: (ES, m / z): 409.5 [M+1] + .

[0236] Under nitrogen protection, at 50°C, a solution of compound Y-5-1-7 (1.9 g, 4.6 mmol, 1 eq) and 6-(trifluoromethyl)pyridine-2-amine (754.03 mg, 4.65 mmol) in dichloromethane (30 mL) was prepared. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5.22 g, 18.6 mmol) and N-methylimidazole (3.82 g, 46.5 mmol) were added in several portions, and the mixture was stirred overnight. The reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain the yellow solid Y-5-1 (1.5 g, 58.4%). LCMS: (ES, m / z): 553.5 [M+1] + .

[0237] Preparation of intermediate Y-5 [ka] Under nitrogen protection, at 110°C, 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 mixture was reacted overnight with stirring, and the completion of 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 x 200 mL), the organic phases were combined, and the mixture was dried over sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain Y-5-1 (3.5 g, 31.4%), a yellow solid. LCMS: (ES, m / z): 333.5 [M+1] + .

[0238] Under nitrogen protection, at 50°C, a solution of Y-5-1 (3.5 g, 10.5 mmol) and benzyl bromide (18 g, 105.3 mmol) in dichloromethane (50 mL) was mixed with silver oxide (4.88 g, 21.1 mmol) and stirred for 2 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / dichloromethane (0-50%)) to obtain Y-5-2 (3.1 g, 69.7%), a brown oil. LCMS: (ES, m / z): 423.5 [M+1] + .

[0239] Compound Y-5-2 (2.8 g, 6.6 mmol) and water (3 mL) were dissolved in methanol (30 mL). Lithium hydroxide (476.2 mg, 19.9 mmol) was added, and the mixture was stirred at 50°C for 3 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was quenched at 0°C with ice water. The reaction mixture was oxidized to pH=4 with citric acid, extracted with ethyl acetate (3 x 100 mL), combined with the organic phase, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. A brown solid, Y-5-3 (2 g, 73.88%), was obtained. LCMS: (ES, m / z): 409.5 [M+1] + .

[0240] Under nitrogen protection, at 50°C, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5.22 g, 18.6 mmol) and N-methylimidazole (3.82 g, 46.5 mmol) were added in several batches to a solution of Y-5-3 (1.9 g, 4.65 mmol) and 6-(trifluoromethyl)pyridine-2-amine (754.03 mg, 4.65 mmol) in dichloromethane (30 mL) and stirred overnight. The reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain Y-5-4 (1.5 g, 58.36%), a yellow solid. LCMS: (ES, m / z): 553.5 [M+1] + .

[0241] Under nitrogen protection, at 0°C, a solution of Y-5-4 (400 mg, 0.724 mmol, 1 equiv) in dichloromethane (5 mL) was mixed with boron trichloride (424.03 mg, 3.620 mmol, 5 equiv) and stirred for 30 minutes. The reaction was then monitored by liquid chromatography-mass spectrometry, and the reaction mixture was quenched at 0°C with saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted with dichloromethane (3 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. A pale yellow solid, Y-5-5 (300 mg, 89.6%), was obtained. LC-MS (ESI, m / z): 463.1 [M+H] + .

[0242] Under nitrogen protection, at room temperature, a solution of Y-5-5 (250 mg, 0.54 mmol, 1 equiv) in dichloromethane (5 mL) was mixed with dess-martin periodinane (275.14 mg, 0.649 mmol, 1.2 equiv) and stirred for 2 hours. After monitoring the completion of the reaction by liquid chromatography-mass spectrometry, 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. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure to obtain the yellow solid intermediate Y-5 (200 mg, 80.35%). LC-MS (ESI, m / z): 461.5 [M+H] + .

[0243] Preparation of intermediate Y-6 [ka] In an ice bath, a solution of Y-6-1 (10.3 g, 49.995 mmol, 1 eq) in dimethylformamide (100 mL) was mixed with triethylamine (20.85 mL, 149.98 mmol, 3 eq). Then, Y-6-2 (8.23 g, 59.99 mmol, 1.2 eq) was slowly added dropwise. The reaction was heated to room temperature and stirred for 2 hours. The disappearance of the starting materials was confirmed by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0-30%)) to obtain Y-6-3 (14.3 g, 93.2%), a white solid. LC-MS (ESI, m / z): 307.0 [M+H] + .

[0244] Under nitrogen protection, at room temperature, a solution of Y-6-3 (1.2 g, 3.91 mmol, 1 eq) in N,N-dimethylacetamide (19.6 mL) was mixed with Y-6-4 (2.29 g, 5.868 mmol, 1.5 eq), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (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 to allow the reaction to complete. The completion of the reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was extracted with ethyl acetate (3 x 200 mL) and water (1 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 (ethyl acetate / petroleum ether (0-50%)) to obtain colorless oily Y-6-5 (1.5 g, 58.0%). LCMS (ESI, m / z): 661.6 [M+H] + .

[0245] To a solution of Y-6-5 (1.05 g, 1.589 mmol, 1 eq) in dichloromethane (15 mL) at room temperature, amino 2,4,6-trimethylbenzenesulfonic acid (1.03 g, 4.767 mmol, 3 eq) was added and stirred for 2 hours. The target product was then confirmed by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure to obtain a yellow, oily Y-6-8 (1.3 g, crude product). The crude product was supplied directly to the next step without further purification. LCMS (ESI, m / z): 676.6 [M+H] + .

[0246] At room temperature, potassium carbonate (530.81 mg, 3.840 mmol, 2 eqs) was added to a methanol (8 mL) solution of Y-6-8 (1.3 g, 1.920 mmol, 1 eq). The reaction mixture was stirred for 2 hours, and the target product was confirmed by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (0-30%)) to obtain pale yellow oily Y-6-9 (450 mg, 34.67%). LCMS (ESI, m / z): 676.3 [M+H] + .

[0247] At room temperature, a solution of Y-6-9 (360 mg, 0.533 mmol, 1 eq) in 1,2-dichloroethane (5.4 mL) was mixed with trifluoroacetic acid (1.8 mL). The reaction mixture was heated to 50°C and stirred overnight. The target product was confirmed by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure to obtain a light brown, oily compound, Y-6-10 (220 mg, crude product). LC-MS (ESI, m / z): 318.5 [M+H] + .

[0248] In an ice bath, 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 mixed with N,N-diisopropylethylamine (0.25 mL, 1.452 mmol, 3 eq) and 2-chloro-1-methylpyridine-1-ionium iodide (135.96 mg, 0.532 mmol, 1.1 eq). After the addition was complete, the system was stirred at room temperature for 4 hours. Liquid chromatography-mass spectrometry was performed. The target product was confirmed, and the starting material was almost completely eliminated. The resulting residue was vacuum concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0-40%)) to obtain Y-6-11 (150 mg, 63.21%), a yellow solid. LCMS (ESI, m / z): 491.1 [M+H] + .

[0249] Under nitrogen protection, at 0°C, 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). After addition, the system was stirred at 0°C for 0.5 hours, then the system was raised to room temperature and stirred for 3 hours. The target product was confirmed by liquid chromatography-mass spectrometry. The reaction mixture was quenched in saturated ammonium chloride solution and 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 resulting residue was purified by silica gel column chromatography (ethyl acetate:dichloromethane (0-50%)) to obtain Y-6-12 (53 mg, 35.3%), a yellow solid. LCMS (ESI, m / z): 491.5 [M+H] + .

[0250] At room temperature, a solution of Y-6-12 (50 mg, 0.102 mmol, 1 eq) in dichloromethane (5.0 mL) was mixed with dess-martin periodinane (64.85 mg, 0.153 mmol, 1.50 eq), and the reaction was continued for 2 hours. Liquid chromatography-mass spectrometry confirmed the target product and eliminated the starting material. A saturated sodium bicarbonate aqueous 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. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. A yellow solid intermediate, Y-6 (35 mg, 70.3%), was obtained. LC-MS (ESI, m / z): 489.5 [M+H] + .

[0251] Preparation of intermediate Y-7 [ka] Intermediate Y-7 was synthesized by referring to the prior art WO02023283372A1.

[0252] Preparation of intermediate Y-8 [ka]

[0253] compound [ka] Instead

[0254] [ka] Using the above, intermediate Y-8 was prepared by the method disclosed in WO2020264499A1 with reference to compound 1-1.

[0255] Preparation of intermediate Y-9 [ka]

[0256] [ka] Instead

[0257] [ka] Using the above, intermediate Y-9 was prepared by the method disclosed in WO2020264499A1 with reference to compound 1-1.

[0258] Preparation of intermediate Y-10 [ka]

[0259] Step 1: Synthesis of compound Y-10-2 At 0°C, 2-fluoro-4-hydroxybenzaldehyde (25g, 178.427m A mixture of nitric acid (12 mL, 267.568 mmol, 1.50 eq) and nitric acid (12 mL, 267.568 mmol, 1.50 eq) was added dropwise to a 150 mL solution of sulfuric acid (1 mol, 1 eq), and the mixture was stirred for 2 hours. After monitoring the completion of the reaction by gas chromatography-mass spectrometry, the reaction mixture was poured into ice water to precipitate the solid, filtered, and the filter cake was collected and washed with water (4 x 100 mL) to obtain the off-white solid 2-fluoro-4-hydroxy-5-nitrobenzaldehyde compound Y-10-2 (18 g, 54.50%). GCMS: 185.0[M-1] + .

[0260] Step 2: Synthesis of compound Y-10-3 Under nitrogen protection, at room temperature, sodium azide (10.54 g, 162.066 mmol, 2 eqs) was added in several batches to a solution of compound Y-10-2 (15 g, 81.033 mmol, 1 eq) in dimethyl sulfoxide (80 mL). The mixture was stirred and reacted for 4 hours. After monitoring the completion of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was quenched with ice water (200 mL) at 0°C, and the reaction mixture was extracted with ethyl acetate (4 x 200 mL). The organic phases were combined, backwashed with saturated brine (2 x 100 mL), and dried over anhydrous sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure to obtain compound Y-10-3 (8 g, 47.43%), which is 2-azido-4-hydroxy-5-nitrobenzaldehyde, as a yellow liquid. LCMS:(ESI,m / z):206.9[M-1] - .

[0261] Step 3: Synthesis of compound Y-10-4 Under nitrogen protection, triethylamine (5.48 g, 48.046 mmol, 2 eq) was added dropwise to a solution of compound Y-10-3 (5 g, 24.023 mmol, 1 eq) and ethyl 2-[(1r,4r)-4-aminocyclohexyl]ethyl acetate (4.45 g, 24.023 mmol, 1 eq) in toluene (50 mL). After the addition was complete, the system was stirred at 110 °C for 3 hours, and the completion of the reaction was monitored by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain the yellow solid ethyl 2-[(1r,4r)-4-(6-hydroxy-5-nitroindazole-2-yl)cyclohexyl]acetate compound Y-10-4 (2.5 g, 29.96%). LCMS: (ESI, m / z): 348.0 [M+1] + .

[0262] Step 4: Synthesis of compound Y-10-5 Under nitrogen protection, at 80°C, 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 isopropyl iodide (2.45 g, 14.394 mmol, 2 eq) in N,N-dimethylformamide (30 mL), and the mixture was stirred overnight. The reaction was monitored by liquid chromatography-mass spectrometry, and the reaction mixture was poured into ice water to precipitate the solid. The mixture was filtered, and the filter cake was collected and washed with water (3 x 10 mL). A yellow solid, ethyl 2-[(1r,4r)-4-(6-isopropoxy-5-nitroindazole-2-yl)cyclohexyl]acetate compound Y-10-5 (3 g, 107.03%), was obtained. LCMS:(ESI,m / z):390.1[M+1] + .

[0263] Step 5: Synthesis of compound Y-10-6 Under nitrogen protection, at 80°C, 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) was mixed with iron powder (1.20 g, 21.570 mmol, 3 eq) and water (7 mL, 388.565 mmol, 54.05 eq). The mixture was stirred and allowed to react for 1 hour. The completion of the reaction was monitored by liquid chromatography-mass spectrometry. The mixture was filtered, the filter cake was washed with ethanol (3 x 30 mL), and the filtrate was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and backwashed with saturated brine (1 x 100 mL). Anhydrous sodium sulfate was used. The mixture was dried with thorium. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure to obtain the pale yellow solid ethyl 2-[(1r,4r)-4-(5-amino-6-isopropoxyindole-2-yl)cyclohexyl]acetate compound Y-10-6 (2.4 g, 92.86%). LCMS:(ESI,m / z):360.1[M+1] + .

[0264] Step 6: Synthesis of compound Y-10-7 Under nitrogen protection, 1.73 g (13.352 mmol, 2 eq) of N,N-diisopropylethylamine was added dropwise to a tetrahydrofuran (20 mL) 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). The mixture was stirred for 10 minutes to allow it to react. Then, at 0°C, 1.88 g (7.344 mmol, 1.1 eq) was added dropwise. After the addition was complete, the system was stirred at room temperature for 3 hours. The completion of the reaction was monitored by liquid chromatography-mass spectrometry, and the resulting residue was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain the yellow solid ethyl 2-[(1r,4r)-4-(6-isopropoxy-5-[6-(trifluoromethyl)pyridine-2-amino]indazole-2-ylcyclohexyl]acetate compound Y-10-7 (2.1g, 59.06%). LCMS:(ESI,m / z):533.10[M+1] + .

[0265] Step 7: Synthesis of compound Y-10 Under nitrogen protection, at 0°C, 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), and the mixture was stirred and reacted for 1 hour. Then, at 0°C, compound Y-10-7 (1 g, 1.878 mmol, 1 eq) was added dropwise, and the mixture was stirred and reacted for 1 hour. The completion of the reaction was monitored by liquid chromatography-mass spectrometry, and the resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (0-50%)) to obtain the off-white solid N-(6-isopropoxy-2-[(1r,4r)-4-(2-oxyethyl)cyclohexyl]indazole-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide compound Y-10 (300 mg, 32.71%). LCMS:(ESI,m / z):487.05[M+1] + .

[0266] General preparation method 1 of the compound of the present invention: [ka] Compound IV-A and compound IV-Y are reduced and aminated to obtain compound IV-0.

[0267] General preparation method 2 of the compound of the present invention: [ka] The compound of formula VA and the compound of formula VY are reduced and aminated to obtain the compound of formula V-0.

[0268] The chiral compounds of the present invention can be separated using conventional chiral separation conditions in the art (for example, chromatography column specifications: CHIRALPAK-IA 2*25cm, 5μm; 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; chromatography column specifications can be selected as needed, and the elution gradient, flow rate, etc. can be adjusted as needed). Alternatively, chiral synthesis can be performed using chiral starting materials.

[0269] Example 1: Preparation of Compound 1 [ka] At room temperature, 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) were added to a tetrahydrofuran (1 mL) solution of intermediate A (30 mg, 0.100 mmol, 1.10 equiv). After the addition was complete, the system was stirred at room temperature for 1 hour. At 0°C, sodium triacetoxyborohydride (30 mg, 0.142 mmol, 1.42 equiv) was added to the system. After the addition was complete, the system was stirred at room temperature for 2 hours. The target product was confirmed by liquid chromatography-mass spectrometry. The crude product was purified by high-performance liquid chromatography to obtain compound 1 (7.6 mg, 9.68%) (conditions: chromatography column specifications: XBridge BEH Shield RP18 5um, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: increasing from 38%B to 62%B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 9.43). LCMS:(ESI,m / z):774.4[M+H] + . 1 H NMR:(400 MHz,DMSO-d6) δ 12.36 (s,1H),10.76 (s,1H),8.71 (s,1H),8.45 (d,J=7.7 Hz,1H),8.36 (t,J=7.8 Hz,2H),8.16 (d,J=8. 2 Hz,1H),7.57 (s,1H),6.80 (d,J=8.6 Hz,1H),6.63 (q,J=3.4 Hz,1H),6.55 (d,J=1.8 Hz,1H),5.94 (s,1H),4.42 (t,J=11.6 Hz,1H),4.24 (q,J=4.3 Hz,1H),3.88 (t,J=9.8 Hz,1H),3.68 (m,J=5.3 Hz,2H),2.96 (q,J=10.8 Hz,3H),2.61 (m,J=5.4 Hz,2H),2.46 (d,J=4.7 Hz,1H),2.41 (m,J=5.3 Hz,2H),2.10 (q,J=6.0 Hz,1H),1.95 (m,J=7.6 Hz,5H),1.68 (t,J=10.7 Hz,1H),1.62 (s,6H),1.45 (s,3H),1.21 (t,J=10.4 Hz,2H).

[0270] Example 2 Synthesis of compounds 120-a, 120-a-1, and 120-a-2 Intermediate 1-1 and intermediate Q were selected and prepared according to general preparation method 1 to obtain compound 120-a. [ka] 20.7 mg of compound 12-a was chiral-separated to obtain 6.1 mg of 120-a-1 and 6.5 mg of 120-a-2 (Conditions: Chromatography column specifications: CHIRAL ART Cellulose-SB 3*25cm, 5um; 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 of 120-a-1 (min): 7.093; Retention time of post-peak 120-a-2 (min): 8.23; Sample 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] + . 1 H NMR 120-a-1:(400 MHz,DMSO-d6,ppm) δ 12.54 (s,1H),10.82 (s,1H),9.06 (s,1H),8.58 (d,J=0.7 Hz,1H),8.50-8.44(m,2H),8.39 (t,J=7.9 Hz,1H),8.21 (dd,J=0.9,7.8 Hz,1H),6.83 (d,J=8.7 Hz,1H),6.68 (dd,J=2.2,8.5 Hz,1H),6.60 (d,J=2.3 Hz,1H),4.59-4.48 (m,1H),4.24 (dd,J=2.6,10.5 Hz,1H),3.89 (dd,J=9.3,10.3 Hz,3H),3.68 (d,J=11.1 Hz,1H),3.30-3.27 (m,1H),3.07-2.95 (m,3H),2.92 (d,J=10.2 Hz,1H),2.65-2.59 (m,2H),2.48-2.41 (m,2H),2.41-2.34 (d,J=18.2 Hz,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=7.5 Hz,3H)。 1 H NMR 120-a-2:(400 MHz,DMSO-d6,ppm) δ 12.54 (s,1H),10.83 (s,1H),9.06 (s,1H),8.58 (s,1H),8.49-8.44 (m,2H),8.39 (t,J=7.8 Hz,1H),8.21 (d,J=7.7 Hz,1H),6.83 (d,J=8.7 Hz,1H),6.68 (dd,J=2.2,8.5 Hz,1H),6.60 (d,J=2.3 Hz,1H),4.58-4.48 (m,1H),4.24 (dd,J=2.0,10.6 Hz,1H),3.96 (s,3H),3.89 (t,J=9.9 Hz,1H),3.68 (d,J=10.2 Hz,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=5.2 Hz,3H).

[0271] Example 3: Preparation of compounds 120-b, 120-b-1, and 120-b-2 Intermediate 1-1 and intermediate P were selected and prepared according to general preparation method 1 to obtain compound 120-b.

[0272] [ka] 65 mg of compound 120-b was chiral-separated to obtain 21.7 mg of 120-b-1 and 22.5 mg of 120-b-2 (Conditions: Chromatography column specifications: CHIRAL) ART Cellulose-SB 2*25cm, 5um; 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; 120-b-1 retention time 1 (min): 8.716; 120-b-2 retention time 2 (min): 11.828; Sample solvent: ethanol + dichloromethane; Injection volume: 1.0 mL; Number of runs: 7). LCMS-120-b-1:(ESI,m / z):788.25[M+H] + . LCMS-120-b-2:(ESI,m / z):788.25[M+H] + 。 1 H NMR-120-b-1:(400 MHz,DMSO-d6,ppm) δ 12.36 (s,1H),10.82 (s,1H),8.71 (s,1H),8.45 (d,J=7.7 Hz,1H),8.39-8.31(m,2H),8.16 (q,J=2.8 Hz,1H),7.57 (s,1H),6.83 (d,J=8.7 Hz,1H),6.68 (q,J=3.6 Hz,1H),6.64-6.46 (m,1H),5.93 (s,1H),4.51-4.35 (m,1H),4.24 (q,J=4.4 Hz,1H),3.92-3.87 (m,1H),3.68 (d,J=11.4 Hz,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=10.7 Hz,1H),1.62 (s,6H),1.46-1.42 (m,3H),1.36 (s,3H),1.22-1.18 (m,3H)。 1 H NMR-120-b-2:(400 MHz,DMSO-d6,ppm) δ 12.36 (s,1H),10.83 (s,1H),8.71 (s,1H),8.45 (d,J=7.8 Hz,1H),8.40-8.33(m,2H),8.16 (d,J=8.0 Hz,1H),7.57 (s,1H),6.83 (d,J=8.6 Hz,1H),6.69-6.56 (m,2H),5.93 (s,1H),4.49-4.37(m,1H),4.24 (dd,J=2.5,10.6 Hz,1H),3.89 (t,J=9.8 Hz,1H),3.68 (d,J=11.1 Hz,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=10.6 Hz,1H),1.62 (s,6H),1.45 (t,J=6.2 Hz,3H),1.36 (s,3H),1.19 (m,J=6.3 Hz,3H).

[0273] Example 4 Synthesis of Compound 126

change

[0274] Example 5 Synthesis of Compound 128

change

[0275] Example 6 Synthesis of Compound 129 [ka] Intermediate Y-8 and intermediate A were selected and prepared according to general preparation method 1 to obtain compound 129 (12 mg, yield 16.8%). LCMS: (ESI, m / z): 770.4 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s,1H),10.76 (s,1H),8.93 (d,J=2.2 Hz,1H),8.74 (d,J=2.2 Hz,1H),8.55 (s,1H),8.34 (s,1H),7.72 (d,J=4.8 Hz,1H),7.57 (s,1H),7.09 (d,J=4.8 Hz,1H),6.80 (d,J=8.5 Hz,1H),6.63 (dd,J=8.4,1.8 Hz,1H),6.55 (d,J=1.8 Hz,1H),5.72 (s,1H),4.42 (t,J=11.6 Hz,1H),4.24 (dd,J=10.6,2.5 Hz,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).

[0276] Example 7 Synthesis of Compound 130

change

[0277] Example 8 Synthesis of Compound 131 [ka] Intermediate 1-1 and intermediate R were selected and prepared according to general preparation method 1 to obtain compound 131 (29.4 mg, yield 25.0%). LCMS:(ESI,m / z):708.3[M+1] + . 1H NMR (400 MHz,DMSO-d6) δ 12.37 (s,1H),10.82 (s,1H),8.72 (s,1H),8.45 (d,J=7.7 Hz,1H),8.42 - 8.30 (m,2H),8.16 (d,J=7.8 Hz,1H),7.58 (s,1H),6.84 (s,1H),6.71 (d,J=1.7 Hz,1H),5.94 (s,1H),4.41 (t,J=10.4 Hz,2H),4.16 (dd,J=10.5,2.3 Hz,1H),3.78 (dd,J=11.9,4.7 Hz,1H),3.41 (d,J=11.4 Hz,1H),3.11 (d,J=9.8 Hz,1H),2.95 (d,J=11.5 Hz,1H),2.92 - 2.77 (m,2H),2.70 - 2.56 (m,1H),2.43 (d,J=8.4 Hz,1H),2.33 (s,2H),2.22 (t,J=10.6 Hz,2H),2.12 (d,J=9.5 Hz,2H),2.04 - 1.85 (m,5H),1.62 (s,6H),1.42 (s,3H),1.28 - 1.13 (m,3H).

[0278] Referring to the preparation method of Example 1 (by selecting the corresponding intermediate and following the general preparation method 1), the following compounds were prepared.

[0279] [Table 2-1]

[0280] [Table 2-2]

[0281] [Table 2-3]

[0282] [Table 2-4]

[0283] [Table 2-5]

[0284] [Table 2-6]

[0285] [Table 2-7]

[0286] Example 9 Preparation of Compound 46 [ka] At 0°C, sodium triacetoxyborohydride (74.09 mg, 0.351 mmol, 3 equiv) was added in several batches 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). The resulting residue was stirred and reacted at room temperature for 2 hours. After the reaction was complete, 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. The mixture was backwashed with water (3 x 5 mL) and dried over sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. The resulting residue was prepared by high-performance liquid chromatography (conditions: chromatography column specifications: XBridge BEH C18 OBD Prep Column 130.5 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: rising from 38% B to 60% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 8.47) to obtain compound 46. LCMS:(ESI,m / z):745.3[M+H] + . 1 H NMR: (400 MHz, Chloroform-d, ppm) δ 12.58 (s,1H), δ 10.70 (s,1H),8.82 (s,1H),8.49 (d,J=7.8 Hz,1H),8.12 (t,J=7.8 Hz,1H),7.90 (s,1H),7.88 - 7.84 (m,2H),7.15 (s,1H),7.07 (d,J=6.9 Hz,2H),5.07 (s,2H),4.32 (t,J=11.9 Hz,1H),4.03 (s,3H),3.81 - 3.77 (m,1H),3.07 (s,2H),2.85 (m,2H),2.75 (t,J=5.0 Hz,1H),2.72 - 2.56 (m,2H),2.43 (m,2H),2.34 - 2.17 (m,5H),1.99 (t,J=13.4 Hz,6H),1.83 (s,2H),1.26 (s,2H).

[0287] Example 10 Synthesis of Compound 121

change

[0288] Referring to the preparation method of Example 9 (by selecting the corresponding intermediate and following general preparation method 2), the following compounds were prepared.

[0289] [Table 3-1]

[0290] [Table 3-2]

[0291] [Table 3-3]

[0292] [Table 3-4]

[0293] [Table 3-5]

[0294] The NMR data for the compound of the present invention is as follows:

[0295] [Table 4-1]

[0296] [Table 4-2]

[0297] [Table 4-3]

[0298] [Table 4-4]

[0299] [Table 4-5]

[0300] [Table 4-6]

[0301] [Table 4-7]

[0302] [Table 4-8]

[0303] [Table 4-9]

[0304] Biological assays and evaluations The present invention will be further described with reference to the following test examples, but these examples should not be considered to limit the scope of the present invention.

[0305] Test Example 1: Detection of HiBiT-IRAK4 protein degradation levels in K562 IRAK4-HiBiT cells after co-incubation with the compound of the present invention. Laboratory reagents, equipment, and consumables: Nano-Glo Lytic Detection Assay (purchased from Promega) EnVision (purchased from PerkinElmer) Cell line name: K562 IRAK4-HiBiT stable expression cell line (capable of stably expressing IRAK4-HiBiT fusion protein) The cells were constructed by Shanghai Runnuo Biotechnology Co., Ltd., the K562 cell line was purchased from ATCC, and the culture medium was IMDM + 10% FBS + 1% P / S (expressed as a volume percentage, where FBS is fetal bovine serum and P / S is penicillin-streptomycin, an antibiotic solution of penicillin and streptomycin mixed in a 1:1 ratio (10,000 units / mL)).

[0306] Experimental procedure: Cell culture: K562 IRAK4-HiBiT cells were incubated at 37°C and subcultured every 2-3 days, with an inoculation density of 200,000 cells / mL.

[0307] IRAK4-HiBiT protein degradation experiment: Step 1: Cell inoculation and compound treatment 1. A 10 mM compound mother liquor was prepared with DMSO, and a 1000-fold working concentration compound solution (maximum working concentration of 10 μM, 3.162-fold dilution, total concentration gradient of 10) was prepared using the Bravo automated liquid processing platform. 2.40 nL of compound working solution was transferred to a 384-well plate, and an equal volume of DMSO was added to the positive control well. 3. Add 20 μL of culture medium to each well and shake for 10 minutes. 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 well. 5. The well plate was rotated at 1000 rpm for 1 minute. The samples were incubated in a 5% CO2 incubator at 6.37°C for 2 or 6 hours.

[0308] Step 2: HiBiT Lytic Experiment 1. The well plate was allowed to equilibrate at room temperature for 30 minutes. 2. Add 20 μL of Nano-Glo HiBiT Lytic reagent (product name: Nano-Glo® HiBiT Lytic Detection Reagent) to each well and keep away from light. 3. The well plate was placed in an orbital shaker and shaken at 300 rpm for 5 minutes. 4. Incubate at room temperature for 10 minutes. 5. The emission value was read using Envision. 6. Data calculation and processing. Resolution % = (Negative control - Experimental well) / (Negative control - Positive control) * 100%; The resolution curve is fitted using a 4-Parameter Logistic Model with XL-fit software, and Relative DC 50 (nM) and Absolute DC 50 The value of (nM) was obtained.

[0309] The experimental results are shown in Tables 1 and 2 below.

[0310] [Table 5]

[0311] [Table 6]

[0312] Other compounds of the present invention were also tested by referring to the same experimental method, and the relative DC of the compounds of the present invention was found to be 50 The (nM) value is 0.01 to 100, and the Relative DC of preferred compounds of the present invention. 50 The (nM) value is less than 100, and the Absolute DC of the compound of the present invention 50 The (nM) value is 0.01 to 100, and the Absolute DC of the preferred compound of the present invention is 0.01 to 100. 50 The (nM) value is less than 100, the Dmax of the compound of the present invention is 80% or more, and the Dmax of the preferred compound of the present invention is 90% or more.

[0313] Conclusion of the experiment: The compounds of the present invention exhibit good degradation activity against the IRAK4 protein.

[0314] Test Example 2: Investigation of the inhibitory effect of the compound of the present invention on IL-6 release from human PBMC cells induced by LPS. 1. Resuscitation, inoculation, and compound treatment of PBMCs (Human PBMC cells purchased from Oricell, product number Fpb003F) 1. Preparation of the compound The samples were diluted with DMSO using Bravo to obtain a series of sample dilutions, and then 80 nL each was transferred to a cell plate using ECHO. The final DMSO concentration in the cell medium was 0.1%. The frozen cells were rapidly thawed in a 2.37°C water bath with constant agitation. 3. 25 mL of pre-warmed fresh culture medium was added to a 50 mL centrifuge tube, and the cells were added dropwise. The cells were then centrifuged at 2,000 rpm for 10 minutes. 4. Discard the supernatant and resuspend the cells in 28.5 mL of fresh, pre-warmed complete RPMI 1640 medium. 5. The total number of cells required was calculated and tested based on the cell concentration. 7 x 10 e4 cells (70 μl) were added to each well. The plates were incubated in a 6.5% CO2 incubator at 37°C for 2 hours.

[0315] 2. LPS treatment and collection of supernatant 1. A stock solution containing 1 mg / mL of LPS was diluted with dH2O, divided into smaller portions, and stored at -80°C. 2. 10 μL / well of 8x LPS (final concentration 5 ng / mL) was added to each well. The samples were incubated in a 5% CO2 incubator at 37°C for 4 hours. 3. Using Bravo, 70 μL of supernatant was collected from each well, and then the IL-6 HTRF test was performed. The supernatant can be stored at -80°C.

[0316] 3. HTRF test 1. Prepare the standard solution and the sample diluent. 2. Using Bravo, 16 μL of each sample was taken and added to the well. Then, 16 μL of each standard solution was taken and added to the corresponding well. 3. Add 4 μL of the pre-mixed IL6 antibody working solution to each well. 4. The plate was sealed and incubated at room temperature for 2 hours. 5. Read the results and show them in Table 3.

[0317] [Table 7]

[0318] Other compounds of the present invention were also tested by referring to the same experimental method, and the IC of inhibition of IL-6 release by the compounds of the present invention in human PBMC cells was observed. 50 The (nM) value is 0.01 to 500, and the IC of preferred compounds of the present invention 50 It can be seen that the value of (nM) is less than 100.

[0319] Conclusion of the experiment: The compounds of the present invention have a favorable inhibitory effect on LPS-induced IL-6 release from human PBMC cells.

[0320] Test Example 3: Investigation of the pharmacokinetic behavior of the compound of the present invention in mice. Experimental drug: Compound of the present invention (in-house manufactured).

[0321] Experimental method: Three healthy male ICR mice (SPF grade, supplied by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) weighing 18-25g were administered 1 mg / kg of the compound intravenously (administered in a volume of 5 ml / kg). The compound was prepared from 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0322] Three healthy male ICR mice (SPF grade, supplied by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) weighing 18-25g were intragastricly administered a compound at a dose of 5mg / kg (administered in 10ml / kg). The compound was prepared from 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0323] Blood samples were collected from the cheek at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intravenous administration, and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intragastric administration. Approximately 0.05 mL of blood was collected as each sample, anticoagulated with heparin sodium, and placed on ice after blood sample collection. The plasma was centrifuged within 1 hour (centrifugation conditions: 6000 g, 3 minutes, 2-8°C), and the concentration of the compound in the plasma was measured by liquid chromatography-tandem mass spectrometry. Before analysis, the plasma samples were stored in a refrigerator at -80°C. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 with blood drug concentration data at different time points. Results This is shown in Table 4.

[0324] [Table 8]

[0325] Experimental results showed that the compound of the present invention has a low clearance rate, high plasma exposure, high oral availability, and excellent pharmacokinetic properties.

[0326] Although specific embodiments of the present invention have been described above, these are merely illustrative examples, and it will be understood by those skilled in the art that various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Accordingly, the scope of protection of the present invention is limited by the appended claims.

Claims

1. Compounds selected from those represented by general formula (I) 【Chemistry 1】 (In the formula, 【Chemistry 2】 This indicates the presence or absence of a connection. M １ is N or CR １ Selected from, M ２ is N, C or CR ２ Selected from, M ３ is N or CR ３ Selected from, M ４ is N or CR ４ Selected from, M ５ is selected from N or CR ５ and M ６ is N or CR ６ Selected from, R １ , R ２ , R ３ , R ４ , R ５ and R ６ Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, aminoalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. Ring B １ It is selected from aryl or heteroaryl compounds. Ring B ２ It is selected from aryl, heteroaryl, or heterocyclyl. R ａ These are, independently, hydrogen, deuterium, hydroxyl, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, and -P(O)RR. ’ Selected from cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclyl are further optionally substituted with one or more substituents from deuterium, halogen, hydroxy, cyano, or alkyl. R and R ’ Each is 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, and the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclyl are further optionally substituted with one or more substituents from deuterium, halogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, or haloalkoxy. Or, R ｅ and R ｆ These are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are further optionally substituted with one or more substituents from among deuterium, halogen, oxo, hydroxy, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl groups. Or, R ２ and R ｆ It binds to cycloalkyl, heterocyclyl, aryl, or hetero An aryl is formed, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with one or more substituents from among deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. Or, R ｆ M ２ A cycloalkyl, heterocyclyl, aryl, or heteroaryl is bonded to a C or N on the ring where it is located, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with one or more substituents from among deuterium, halogen, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. Or any two R ｂ These are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with one or more substituents from among deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. Or, L ２ and R ｅ These are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with one or more substituents from among deuterium, halogen, cyano, amino, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. L １ is a bond, -NH-, -S-, -O-, -CH ２ - , CH ２ CH ２ -, -C(O)NH-, -NHC(O)-, or -C(O)- are selected. L ２ is -Ak1-Cy1-Ak2-Cy2-Ak3-, Ak1, Ak2, and Ak3 are each independently - (CH ２ ) ｎ３ -, -O-, -C(O)-, -NH-, -NR ７ -ien-CH ２ NR ７ -, - (CR ８ R ９ ) ｎ４ -, selected from alkynylene or bond, Cy1 and Cy2 are each independently bonded, selected from cycloalkylidene, heterocyclylene, arylene, or heteroarylene, and the cycloalkylidene, heterocyclylene, arylene, and heteroarylene are further optionally substituted with 1 to 4 substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, alkyl, haloalkyl, alkoxy, hydroxyalkyl, or haloalkoxy. R ７ , R ８ and R ９ Each is independently selected from hydrogen, deuterium, halogen, alkyl, cyano, hydroxy, cycloalkyl, haloalkyl, deuterated alkyl, halocycloalkyl, hydroxyalkyl, or alkoxy, or R ８ and R ９ These are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents from among deuterium, halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, or hydroxyalkyl. Or, R ａ and L ２ These are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are further optionally substituted with one or more substituents from among deuterium, halogen, amino, cyano, hydroxy, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclyl. L ３ The bond is selected from -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. n1, n2, n3, and n4 are each independently selected from 0, 1, 2, or 3. The stereoisomer thereof or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound is further represented by general formula (II-A), 【Transformation 3】 During the ceremony, R ｄ These are, independently, hydrogen, deuterium, halogen, oxo, hydroxyl, and C. １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Preferably, R ｄ These are, independently, hydrogen, deuterium, fluorine, chlorine, oxo, hydroxyl, and C. １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R ｄ and L ２ are combined into C ３－６ Forming a cycloalkyl or 3-6 membered heterocycline, the C ３－６ Cycloalkyls and 3-6 membered heterocyclines are deuterium, halogen, cyano, oxo, and C １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ It is further optionally substituted with one or more substituents from cycloalkyl or 3- to 6-membered heterocyclines. Ring A is selected from a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl. The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that p is selected from 0, 1, 2, 3, or 4.

3. The aforementioned compound is further represented by general formula (II-B), 【Chemistry 4】 During the ceremony, R ｄ These are hydrogen, deuterium, halogen, oxo, and C, respectively, independently. １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Ring A is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl. R ｄ１ is independently selected from hydrogen, deuterium, halogen, oxo, C １－６ alkyl, C １－６ alkoxy, hydroxyC １－６ alkyl, C １－６ haloalkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, or 3- to 6-membered heterocyclyl, The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that p and j are each independently selected from 0, 1, 2, 3, or 4.

4. The aforementioned 【Transformation 5】 teeth, 【Transformation 6】 Selected from, Preferably, 【Transformation 7】 teeth, 【Transformation 8】 Selected from, M ７ is selected from O, CH ２ , C(O), S, S(O), S(O) ２ , or NR １０ , and R １０ is selected from hydrogen, deuterium, C １－３ alkyl, C １－３ alkoxy, C １－３ haloalkyl, C １－３ haloalkoxy, C ３－６ cycloalkyl, or 3- to 6-membered heterocyclyl, and the C １－３ alkyl, C １－３ alkoxy, C １－３ haloalkyl, C １－３ haloalkoxy, C ３－６ cycloalkyl, and 3- to 6-membered heterocyclyl are each independently substituted with one or more of deuterium, hydroxy, cyano, amino, oxo, fluorine, or chlorine The substituents are further optionally substituted, M ８ These are N, O, S, C(O), CH ２ CH, S(O), or S(O) ２ Selected from, R ｄ２ and R ｄ３ These are, independently, hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, and C. １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines are further optionally substituted with one or more substituents from deuterium, hydroxyl, cyano, amino, oxo, fluorine, or chlorine. p2 and p3 are each independently selected from 1, 2, 3, or 4. The compound according to claim 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that n9 is selected from 1, 2, or 3.

5. The aforementioned 【Chemistry 9】 teeth, 【Chemistry 10】 Selected from, Preferably, the above 【Chemistry 11】 teeth, 【Chemistry 12】 Selected from, M ９ and M １０ Each is independently CH ２ , C(O), NR １０ CH, O, S, S(O), or S(O) ２ Selected from, R １０ is hydrogen, deuterium, halogen, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines are further optionally substituted with one or more substituents from deuterium, hydroxyl, cyano, amino, oxo, fluorine, or chlorine. R ｄ４ These are, independently, hydrogen, deuterium, halogen, amino, cyano, oxo, and C. １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines are further optionally substituted with one or more substituents from deuterium, hydroxyl, cyano, amino, oxo, fluorine, or chlorine. p4 is independently selected from 1, 2, 3, or 4. The compound according to claim 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that n5 is selected from 1, 2, or 3.

6. Ring B １ These include indazolyl, pyrazolyl, benzimidazolyl, and pyridotriazolyl. Selected from pyridopyrazolyl, pyridinoimidazolyl, or pyrimidinoimidazolyl, Preferably, the above 【Chemistry 13】 teeth, 【Chemistry 14】 Selected from, Ring B ２ This is selected from pyridyl, phenyl, pyridonyl, pyridadinol, pyrimidopyrazolyl, pyrrolopyridinyl, pyrimidyl, pyrimidopyrrolyl, or pyridopyrazolyl. Preferably, the above 【Chemistry 15】 teeth, 【Chemistry 16】 Selected from, In the formula, R ｂ１ , R ｂ２ , R ｂ３ and R ｂ４ These are, independently, hydrogen, deuterium, halogen, cyano, hydroxyl, and C. １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R ｂ１ and R ｂ２ These combine to form a 5-6 member heterocycline, and the 5-6 member heterocycline is composed of deuterium, halogen, cyano, hydroxyl, and C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Cycloalkyl, A compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is further optionally substituted with one or more substituents from among 3 to 6-membered heterocyclines.

7. The aforementioned R ａ These are, independently, hydrogen, deuterium, halogen, cyano, and C. １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, -P(O)RR ’ , C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines are composed of deuterium, halogens, hydroxyl, cyano, or C １－３ The alkyl group is further optionally substituted with one or more substituents. Preferably, R ａ These are, independently, hydrogen, deuterium, halogen, cyano, and C. １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Haloalkoxy, -P(O)RR ’ , C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines are composed of deuterium, halogens, hydroxyl, cyano, or C １－３ The alkyl group is further optionally substituted with one or more substituents. Or, the R ｂ , R ｃ , R ｅ and R ｆ These are, independently, hydrogen, deuterium, halogen, cyano, oxo, and C. １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－６ Alkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines contain deuterium, halogens, hydroxyl, and C. １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, or C １－３ The haloalkoxy is further optionally substituted with one or more substituents. Preferably, the R ｂ , R ｃ , R ｅ and R ｆ These are, independently, hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, and C. １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Haloalkoxy, C3 －６ Selected from cycloalkyl or 3-6 membered heterocyclyl, the C １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines contain deuterium, fluorine, chlorine, hydroxyl, and C. １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, or C １－３ The haloalkoxy is further optionally substituted with one or more substituents. Or, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are, independently, hydrogen, deuterium, halogen, cyano, oxo, and C. １－６ Alkyl, C １－６ Alkoxy, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Preferably, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are hydrogen, deuterium, fluorine, chlorine, cyano, oxo, and C, respectively, independently. １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, C １－３ Haloalkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R and R ’ These are hydrogen, deuterium, halogen, and C, respectively, independently. １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, or C １－６ Selected from haloalkoxys, Preferably, R and R ’ These are hydrogen, deuterium, fluorine, chlorine, and C, respectively, independently. １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, or C １－３ A compound according to any one of claims 1 to 6, characterized in that it is selected from haloalkoxys, the stereochemical compound thereof. Isomers or pharmaceutically acceptable salts thereof.

8. Said L ２ is -Ak1-Cy1-Ak2-Cy2-Ak3-, Ak1, Ak2, and Ak3 are each independently - (CH ２ ) ｎ３ -, -O-, -C(O)-, -NH-, -NR ７ -ien-CH ２ NR ７ -, - (CR ８ R ９ ) ｎ４ - or selected from combination, Cy1 and Cy2 are each independently bonded, selected from cyclohexylidene, piperidine, or piperazinerene, and cyclohexylidene, piperidine, and piperazinerene are deuterium, halogen, hydroxyl, cyano, oxo, C １－３ Alkyl, hydroxy C １－３ Alkyl, C １－３ Alkoxy, C ３－４ Cycloalkyl, 3-4 membered heterocyclyl, C １－３ Haloalkyl, or C １－３ It is further optionally substituted with 1 to 4 substituents selected from haloalkoxys. The aforementioned R ７ , R ８ and R ９ These are hydrogen, deuterium, halogen, and C, respectively, independently. １－３ Alkyl, cyano, hydroxy, C ３－４ Cycloalkyl, C １－３ Haloalkyl, C １－３ Alkyl deuterated, C １－３ Halocycloalkyl, hydroxyC １－３ Alkyl, or C １－３ Selected from alkoxy, Preferably, L ２ teeth 【Chemistry 17】 Selected from, in the formula, M and M ０ Each of them is independently CR １１ Or selected from N, R １１ is hydrogen, deuterium, halogen, hydroxyl, C １－３ Alkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ Selected from haloalkoxys, The compound according to any one of claims 1 to 7, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n6 and n7 are each independently selected from 0, 1, 2, 3, or 4.

9. The compound of general formula (II-A) is further represented by general formula (IV), general formula (IV-1), or general formula (IV-2), as described in any one of claims 2, 4, 6 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Chemistry 18]

10. The compound according to claim 9, a stereoisomer thereof, 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). 【Chemistry 19】

11. The compound according to any one of claims 3, 5 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound of the general formula (II-B) is further represented by the general formula (V). 【Chemistry 20】

12. (1) The R ａ C １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, or C １－３ Selected from haloalkoxys, preferably C １－３ Alkoxy or hydroxy C １－３ The conditions include being alkyl, and more preferably methoxy, ethoxy, propyroxy, hydroxymethyl, hydroxyethyl, or hydroxypropyl, (2) The above R ｂ C １－３ Alkyl, C １－３ Alkoxy, hydroxy C １－３ Alkyl, C １－３ Haloalkyl, or C １－３ Selected from haloalkoxys, preferably C １－３ Haloalkyl, or C １－３ The condition is that it is a haloalkoxy, more preferably difluoromethyl, trifluoromethyl, or trifluoromethoxy, (3) Said L ３ The conditions are selected from bond, -NH-C(O)-, or -C(O)-NH-, (4) The above R ３ These are hydrogen, deuterium, fluorine, chlorine, cyano, and C. １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ Selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, and C １－３ Alkyl, C １－３ Alkoxy, or C １－３ The conditions include being a haloalkyl, more preferably hydrogen, deuterium, fluorine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, or propyloxy, (5) Said M ０ The conditions are selected from N or CH, (6) Said M ４ is N or CR ４ And R ４ These are hydrogen, deuterium, fluorine, chlorine, and C １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ The conditions include being selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl, (7) Said M ５ is N or CR ５ And R ５ These are hydrogen, deuterium, fluorine, chlorine, and C １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ The conditions include being selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl, (8) Said M ６ is N or CR ６ And R ６ These are hydrogen, deuterium, fluorine, chlorine, and C １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ The conditions include being selected from haloalkoxys, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl, (9) Said M ７ is O, CH ２ , C(O), S, S(O), or S(O) ２ And, Mashiku is O, CH ２ Or the condition that S, (10) Said M ９ CH ２ The conditions are C(O), O or S, (11) M １０ CH ２ , C(O), NR １０ , O or S, R １０ is hydrogen, deuterium, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl, or C １－３ A compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by satisfying one or more of the conditions that the compound is selected from haloalkoxys, preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl, or trifluoromethyl.

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

14. The compound represented by formula (A-a-a). 【Chemistry 21】 (In the formula, M ４ is N or CR ４ And M ５ is N or CR ５ And M ６ is N or CR ６ And M ７ is O, S, or CH ２ And R ３ Deuterium, halogens, C １－３ Alkyl, C １－３ Alkoxy, or C １－３ Selected from haloalkyl, R ４ is hydrogen, deuterium, halogen, C １－３ Alkyl, C ３－５ Cycloalkyl, C １－３ Alkoxy, or C １－３ Selected from haloalkyl, R ５ These are hydrogen, deuterium, fluorine, chlorine, and C １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ Selected from haloalkoxys, R ６ These are hydrogen, deuterium, fluorine, chlorine, and C １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, or C １－３ Selected from haloalkoxys, R １２ and R １３ Each of these is independently selected from either a hydrogen or an amino protecting group.

15. The compound of formula (A-a-a) is further represented by formulas (A-a-a-1) and (A-a-a-2), 【Chemistry 22】 Preferably, the compound of formula (A-a-a) according to claim 14 is selected from intermediate E, intermediate E-a, intermediate E-b, intermediate F, intermediate G, intermediate I, intermediate M, intermediate O, intermediate P, intermediate Q, intermediate R, or intermediate S.

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

17. A compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a drug for treating or preventing an IRAK4-mediated disease, or Applications of the pharmaceutical composition described in item 16.

18. The application according to claim 17, characterized in that the disease is selected from autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related diseases, or cardiovascular diseases.

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