PDE4B inhibitors and their uses

Abstract

The compounds of formula I, their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions containing them, and their use as PDE4B inhibitors in the manufacture of drugs for treating related diseases, wherein each group in formula (I) is as defined in the specification. [C1] TIFF2025528779000487.tif27156

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and in particular to a low molecular weight compound having selective inhibitory activity against PDE4B, its stereoisomer or pharmaceutically acceptable salt, and its use in the manufacture of a drug for treating related diseases. [Background technology]

[0002] PDE4 inhibitors exert antidepressant effects in humans and animals by enhancing cAMP signaling in the brain. PDE4 inhibitors also play an important role in the treatment of other central nervous system diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, stroke, and Huntington's disease. Research and development of PDE4 inhibitors has also made great progress. The rationale for their use in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease lies in the inhibition of the functions of a number of inflammatory cells and resident cells by PDE4, which is believed to be involved in the pathogenesis of these diseases. Extensive clinical studies have shown that cyclic adenosine monophosphate (cAMP) blocks the proliferation and chemotaxis of inflammatory cells and inhibits the release of inflammatory and cytotoxic mediators in the lungs. PDE4 is particularly abundant in immune cells, inflammatory cells, and smooth muscle cells.

[0003] PDE4 inhibitors exert their anti-inflammatory effects primarily by inhibiting the hydrolysis of PDE4, increasing cAMP levels in the body, inhibiting the release of inflammatory factors, and promoting the production of anti-inflammatory mediators. Roflumilast has been used clinically to treat COPD and has a pronounced anti-inflammatory effect, inhibiting the release of inflammatory mediators such as TNF-α, interleukins, and chemokines from monocytes, macrophages, and T cells. However, such inhibitors generally have serious side effects, such as nausea and vomiting, limiting their clinical application. Extensive research has shown that in humans, phosphodiesterase 4 subtype B (PDE4B) is involved in inflammatory responses and the release of various inflammatory mediators in the body, while subtype D is closely associated with side effects such as nausea and vomiting. This provides a new perspective for discovering PDE4 inhibitors with reduced side effects. Designing PDE4B inhibitors may reduce side effects and facilitate further clinical application.

[0004] Phosphodiesterase 4 has high selectivity for cAMP and exists in four subtypes, PDE4A, 4B, 4C, and 4D, with at least 25 splice variants. The catalytic domains of the four PDE4 subtypes share highly homologous protein sequences, meaning that inhibitors targeting the catalytic domain do not result in subtype selectivity. However, most reported classical PDE4 inhibitors target the catalytic domain. A new mode of action for PDE4 inhibitors reported in recent years involves simultaneous interaction between the catalytic domain and regulatory sequences, which stabilize the protein in a closed conformation, blocking cAMP entry and exerting their inhibitory effects. However, research has revealed that there are amino acid differences between PDE4B and 4D in these regulatory sequences, and inhibitor design based on these differences can lead to subtype selectivity. Therefore, it is expected that subtype B selectivity can be achieved by utilizing the two amino acid differences, PDE4B Leu674 and PDE4D Gln594, in the downstream regulatory sequence CR3 (Conserved Region 3), thereby reducing inhibitor side effects while maintaining activity.

[0005] A selective PDE4B inhibitor with good activity, high safety and minimal side effects has been discovered, which has good prospects for clinical development and may be used to treat COPD or cancer or other proliferative diseases or conditions. Summary of the Invention [Means for solving the problem]

[0006] The present invention provides a small molecule compound having PDE4B inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has high activity, low toxic side effects, excellent pharmacokinetic characteristics and bioavailability, as shown in formula (I), [ka] And, wherein when Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L1)n-(L2)m-; [ka] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; [ka] When Cy is selected from Cy7 and Cy9, L is -L4-; [ka] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-. In all embodiments of the present invention, unless otherwise specified, the linking position of L1 is arbitrary. For example, in the case of L1 linked to L2 (-CR2=N-), both the N atom and the C atom may be the linking positions to L2. L2 is [ka] C 1-4 Alkylene group, C 2-4Alkenylene group, C 2-4 Alkynylene groups, CO, O, NR L2 , a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; in some embodiments, each L is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene groups, CO, O, NR L2, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH2; and in some embodiments, each L2 is independently [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] In some embodiments, each L2 is independently selected from [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] In some embodiments, each L2 is independently selected from [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] In all aspects of the present invention, unless otherwise specified, the linking positions between L2 and the groups on both the left and right sides are arbitrary. For example, one terminal L2 [ka] wherein both the N atom and the C atom may be the moiety to be linked to Cy; R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, and in some embodiments, R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, and in some embodiments, R L2 is H, a methyl group, an ethyl group, a propyl group, or an isopropyl group, L3 is a heterocycloalkylene group or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally containing 1 to 3 R L3 In some embodiments, L3 is substituted with [ka] In some embodiments, L3 is selected from: [ka] is selected from Each R L3 are independently halogen, ═O, CN, C 1-4Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 Form a cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and in some embodiments, each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; In some embodiments, L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH2; in some embodiments, L4 is [ka] a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group and the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH2; in some embodiments, L4 is [ka] In some embodiments, L4 is selected from: [ka] In some embodiments, L4 is selected from: [ka] and in some embodiments, L4 is [ka] and in some embodiments, L4 is [ka] and in some embodiments, L4 is [ka] and A is —S(O)—, —C(O)—, —B(OH)—, —S—, —S(═N)—CN or —C(═N)—CN; in some embodiments, A is —S(O)—, —C(O)—, —B(OH)—, —S— or —S(═N)—CN; in some embodiments, A is —S(O)—; X1 and X2 are independent CR X1 , O, S, or N, and in some embodiments, X1, X2 are independently CR X1 , S, or N, and in some embodiments, X1, X2 are independently S or N, and in some embodiments, X1, X2 are independently CR X1 or N, and in some embodiments, X1, X2 are CR X1 In some embodiments, X1, X2 are independently N; X3, X4, and X5 are independently C or N, and in some embodiments, X3 and X4 are independently N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and in some embodiments, Cy5 is [ka] is selected from Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; and in some embodiments, each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 Alkoxy groups, OH, C 3-6 Cycloalkyl groups, C 2-6 alkynyl and NH, and in some embodiments, each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C3-6 A cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, wherein the cycloalkyl group or heterocycloalkyl group is optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 Alkoxy groups, OH, C 3-6 Cycloalkyl groups, C 2-6 alkynyl and NH, and in some embodiments, each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; and in some embodiments, each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 is a haloalkyl group, or R X1 R is independently a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; and in some embodiments, each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 A haloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group, a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, the heterocycloalkyl group optionally contains halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; and in some embodiments, each RX1 , R independently represents H, halogen, C 1-4 Alkyl groups, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 A haloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; and in some embodiments, each R X1 , R independently represents H, halogen, C 1-4 Alkyl groups, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 A haloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 Forming a cycloalkyl group, said cycloalkyl group optionally containing halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; and in some embodiments, each R X1, R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, wherein the cycloalkyl group or heterocycloalkyl group is optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; or R1 and R2 and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from alkoxy, OH, and NH; in some embodiments, R is C 1-4 Alkyl group or C 1-4or R1 and R2 and the atoms connected thereto together form a 5- to 7-membered monocyclic heterocycloalkyl group, a 6- to 8-membered tandem cyclic heterocycloalkyl group, a 7- to 9-membered spirocyclic heterocycloalkyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the monocyclic heterocycloalkyl group, tandem cyclic heterocycloalkyl group, spirocyclic heterocycloalkyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from alkoxy, OH, and NH; in some embodiments, R is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, or R1 and R2 and the atoms to which they are connected together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; Or R1 and R2 and the atoms connected to them together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; Or R1 and R2 and the atoms connected to them together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4or R1 and R2 and the atoms connected thereto may be taken together to form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 and substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH2, and in some embodiments, R1 and R2 and the atoms connected thereto together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 In some embodiments, R is H, C 1-4 Alkyl group or C 1-4 In some embodiments, R and R and the atoms to which they are connected are taken together to form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R3 is H, halogen, C 1-4 alkyl group, CN, OH, or absent, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms connected thereto together form C 3-8A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 alkoxy, OH, and NH; in some embodiments, R is H, halogen, C 1-4 R3 and R2 are alkyl groups, CN, OH or absent, or R3 and R2 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, and the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups are optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-7 A cycloalkyl group, a 5-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; In some embodiments, R3 is H, halogen, C 1-4 alkyl group, CN, OH or absent, or R3 and R2 and the atoms to which they are connected together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-6 Form a cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, R x4 and R5 or R x4 and R6 and the atoms connected to them together form C 3-8A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from alkoxy groups, OH, and NH; in some embodiments, R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, said heteroaryl group optionally containing halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from alkoxy groups, OH, and NH; in some embodiments, R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, and optionally a halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group, C 1-4 haloalkyl group or C 3-6 In some embodiments, R is H, C 1-4 Alkyl group or C 1-4In some embodiments, R4 is H, methyl, ethyl, propyl, isopropyl, or a halogenated methyl, ethyl, propyl, or isopropyl group, and halogens include F, Cl, Br, and I; R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl group or C 3-6 In some embodiments, R is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group or -NHC 1-4 is an alkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 In some embodiments, R6 is H, halogen, ═O, CN, methyl, ethyl, propyl, isopropyl, or methoxy, ethoxy, propoxy, or isopropoxy; R x5 is C 1-4 alkyl group, CN, OH, or absent, and in some embodiments, R x5 is a methyl group, an ethyl group, a propyl group, an isopropyl group, CN, OH, or is absent, R7 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 A cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or R7 and R9 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and the alkyl group, haloalkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; in some embodiments, R is C1-4 Alkyl group or C 1-4 or R7 and R9 and the atoms to which they are connected together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, said heterocycloalkyl group optionally containing halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; in some embodiments, R is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, or R7 and R9 and the atoms to which they are connected together form the following ring: [ka] and forming a ring selected from the group consisting of: 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; In the present invention, R 9’ and R7, or R 9’ and R x5 and the atoms connected thereto are taken together as C 3-8 a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, phenyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and in some embodiments, R 9’ and R7, or R 9’ and R x5and the atoms connected thereto together form a 5- to 7-membered monocyclic heterocycloalkyl group, a 7- to 10-membered spirocyclic heterocycloalkyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycloalkyl group, spirocyclic heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and in some embodiments, R 9’ and R7 and the atoms connected thereto together form the following ring: [ka] and optionally forming a ring selected from C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from or R 9’ and R x5 and the atoms connected to them together [ka] and optionally forming C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from R 9’ and R7, or R 9’ and R x5 At least one pair of these forms a ring, R8 is R 8’, -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; or -N=S(=O)(C 1-4 -N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from alkyl, ═O, OH, NH, CN, and in some embodiments, R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from alkyl, ═O, OH, NH, CN, and in some embodiments, R 8’ is C 3-6 a cycloalkyl group, said cycloalkyl group optionally being selected from the group consisting of C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H, C 1-4 Alkyl group or C 1-4In some embodiments, R is H or C 1-4 In some embodiments, R is H, a methyl group, an ethyl group, a propyl group, or an isopropyl group; Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 In some embodiments, the cycloalkyl group is optionally substituted with 1-3 of F, Cl, Br, I, CN, ═O, OH, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, halogenated methyl, ethyl, propyl, isopropyl, etc., where halogen includes F, Cl, Br, and I. R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, C 1-4 Alkyl-CN, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4and -C(O)-(4- to 6-membered heterocycloalkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra, or -C(O)-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3, -(CH2) t -OC 1-2 Haloalkyl groups, -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t-C(O)NRaRb, -(CH2) t substituted with the group -NRa-C(O)CH3, In some embodiments, R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 and -C(O)-(4- to 6-membered heterocycloalkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra, or -C(O)-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3, -(CH2) t -OC 1-2 Haloalkyl groups, -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t substituted with the group -NRa-C(O)CH3, In some embodiments, R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3)2-CH2-OC(O)NH2, -CH(CH3)-CH2-OC(O)NH2, -C(O)-Ra, -CH(CH3)-CH2-OC(O)NHCH3 or -C(CH3)2-CH2-OC(O)NHCH3, wherein the heterocycloalkylene group, cycloalkylene group, arylene group, heteroarylene group optionally further contains 1 to 3 halogen atoms, such as CN, ═O, OH, -SF5, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2)t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3, -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t In some embodiments, R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4-C(NRaRb)=CRa-NO2 or -C(CH3) t -CH2-OC(O)NHCH3, and the heterocycloalkylene group, cycloalkylene group, arylene group, and heteroarylene group may optionally further contain 1 to 3 halogen atoms, such as CN, ═O, OH, —SF5, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 In some embodiments, R 12 is selected from a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, or a 5- to 10-membered heteroarylene group, and the heterocycloalkylene group, cycloalkylene group, arylene group, and heteroarylene group optionally further comprise 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 In some embodiments, R is substituted with a haloalkyl group. 12is selected from a 4- to 10-membered heterocycloalkylene group and a 3- to 10-membered cycloalkylene group, and the heterocycloalkylene group and cycloalkylene group may optionally further contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 In some embodiments, R is substituted with a haloalkyl group. 12 is selected from a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 10-membered parallel heterocyclo ring, a 7- to 8-membered bridged heterocyclo ring, a 7- to 10-membered heterocyclospiro ring, a 3- to 6-membered monocycloalkyl group, a 6- to 10-membered parallel carbocyclic ring, a 7- to 8-membered bridged carbocyclic ring, and a 7- to 10-membered spiro carbocyclic ring, and the monocyclic heterocycloalkyl group, parallel heterocyclo ring, bridged heterocyclo ring, spiro carbocyclic ring, monocycloalkyl group, parallel carbocyclic ring, bridged carbocyclic ring, and spiro carbocyclic ring may optionally further contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 In some embodiments, R is substituted with a haloalkyl group. 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] C 1-4 Alkyl-CN, -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN, -C(NHC 1-2 alkyl)=CH-NO 2、-CH(CH3)-CH2-NH-C(O)O(CH3), -C(CH3)2-CH2-NH-C(O)O(CH3), -CH(CH3)-CH2-OC(O)NH2, -C(CH3)2-CH2-OC(O)NH2, -C(O)-Ra, -CH(CH3)-CH2-OC(O)NHCH3 or -C(CH3)2-CH2-OC(O)NHCH3, said rings optionally containing halogen, CN, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; and in some embodiments, R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN, -C(NHC 1-2 alkyl)=CH-NO 2、 -C(CH3)2-CH2-NH-C(O)O(CH3), -C(CH3)2-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(CH3), -CH(CH3)2-CH2-OC(O)NH2, -C(O)-Ra, -C(CH3)2-CH2-OC(O)NHCH3 or -CH(CH3)-CH2-OC(O)NHCH3, said rings optionally containing halogen, CN, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2)t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; and in some embodiments, R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN, -C(NHC 1-2 alkyl)=CH-NO 2、-C(CH3)2-CH2-NH-C(O)O(CH3), -C(CH3)2-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(CH3), -CH(CH3)-CH2-OC(O)NH2, -C(O)-Ra, -C(CH3)2-CH2-OC(O)NHCH3 or -CH(CH3)-CH2-OC(O)NHCH3, said rings optionally containing halogen, CN, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; and in some embodiments, R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN or -C(NHC 1-2 alkyl)=CH-NO2, said ring optionally being selected from halogen, CN, OH, -SF5, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C1-2 alkyl), =NOC 1-2 In some embodiments, R 12 represents a cycloalkyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, [ka] wherein the ring is optionally selected from halogen, CN, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 In some embodiments, R 12 is -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 alkyl), -CH(CH3)-CH2-OC(O)NHCH3; Ra and Rb are independently H, halogen, or C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, haloC 1-4 an alkoxy group or a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O; or Ra and Rb are each independently H, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy or haloC 1-4 alkoxy groups, Optionally, Ra, Rb and the atoms connected thereto together form C 3-6 forming a cycloalkyl group, R 13is selected from a 7- to 11-membered spiro ring, a 4- to 10-membered parallel ring, a 5- to 8-membered heterocyclobridged ring, a 4- to 6-membered monocyclic heterocycloalkyl group containing an S(O) group, a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and a 7-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the spiro ring, parallel ring, heterocyclobridged ring, and monocyclic heterocycloalkyl group may optionally contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 In some embodiments, R is substituted with a haloalkyl group. 13 teeth, [ka] wherein the ring is optionally selected from halogen, CN, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from haloalkyl groups, R 14 is -(CH2) t -OC(O)NH2, -(CH2) t -OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl groups containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl groups optionally contain 1-3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl groups and C 1-4 In some embodiments, R is substituted with a haloalkyl group. 14 is -(CH2) t -OC(O)NH, 5-6 membered monocyclic heterocycloalkyl groups containing 1-3 heteroatoms selected from N, S, and O; in some embodiments, R 14 is -(CH2) t -OC(O)NH2, [ka] wherein n and m are independently 0, 1, 2, or 3; in some embodiments, n is 0, 1, 2, or 3; and in some embodiments, m is 0, 1, or 2; r is 1, 2, 3, or 4; in some embodiments, r is 1 or 2; t is selected from 0, 1, 2, 3, or 4; in some embodiments, t is selected from 0, 1, or 2; p is selected from 0 or 1; As a condition, Cy1 is [ka] isn't it.

[0007] The present invention provides a more specific technical solution 1, which is a compound as shown in formula I, its stereoisomer or pharmaceutically acceptable salt: [ka] wherein when Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L1)n-(L2)m-; [ka] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; [ka] When Cy is selected from Cy7 and Cy9, L is -L4-; [ka] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; L2 is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C2-4 Alkynylene groups, CO, O, NR L2 , a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is a heterocycloalkylene group or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally containing 1 to 3 R L3 is replaced by Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; In some embodiments, L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN, or -C(=N)-CN; X1 and X2 are independent CR X1 , O, S or N; X3, X4, and X5 are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; Or each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 Alkoxy groups, OH, C 3-6 Cycloalkyl groups, C 2-6 substituted with 1 to 3 groups selected from an alkynyl group and NH2; Or each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; Or each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5, 3- to 5-membered cycloalkyl group or C 1-4 A haloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; or R1 and R2 and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R3 is H, halogen, C 1-4alkyl group, CN, OH, or absent, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms connected thereto together form C 3-8 A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, R x4 and R5 or R x4 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group, C 1-4 haloalkyl group or C 3-6 is a cycloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl group or C 3-6 is a cycloalkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C1-4 is an alkoxy group, R x5 is C 1-4 alkyl group, CN, OH or absent, R7 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 A cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or R7 and R9 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and the alkyl group, haloalkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 9’ and R7, or R 9’ and R x5 and the atoms connected thereto are taken together as C 3-8 a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, phenyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; -N=S(=O)(C 1-4 alkyl)2 or -N(C 3-6 cycloalkyl)C(O)NH(C 1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, C 1-4 Alkyl-CN, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C1-4 alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 and -C(O)-(4- to 6-membered heterocycloalkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra, or -C(O)-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3, -(CH2) t -OC 1-2 Haloalkyl groups, -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t substituted with the group -NRa-C(O)CH3, Or R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3) t -CH2-OC(O)NH2, -C(CH3) t -CH2-NH-C(O)O(C 1-4 alkyl), -C(CH3) t -CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t-C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3, -(CH2) t -OC 1-2 Haloalkyl groups, -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t substituted with the group -NRa-C(O)CH3, Ra and Rb are independently H, halogen, or C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, haloC 1-4 an alkoxy group or a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O; Optionally, Ra, Rb and the atoms connected thereto together form C 3-6 forming a cycloalkyl group, R 13is selected from a 7- to 11-membered spiro ring, a 4- to 10-membered parallel ring, a 5- to 8-membered heterocyclic bridged ring, a 4- to 6-membered monocyclic heterocycloalkyl group containing an S(O)2 group, a quaternary monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and a heptad monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the spiro ring, parallel ring, heterocyclic bridged ring, and monocyclic heterocycloalkyl group may optionally contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 14 is -(CH2) t -OC(O)NH2, -(CH2) t -OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl groups containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl groups optionally contain 1-3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; n and m are independently 0, 1, 2, or 3; r is selected from 1, 2, 3 or 4; t is selected from 0, 1, 2, 3 or 4; p is selected from 0 or 1; As a condition, Cy1 is [ka] isn't it.

[0008] The present invention provides a more specific technical solution 2, which is a compound of formula I, its stereoisomer or pharmaceutically acceptable salt, wherein Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, and L is -(L1)n-(L2)m-; [ka] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; [ka] When Cy is selected from Cy7 and Cy9, L is -L4-; [ka] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; L2 is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene groups, CO, O, NR L2 , a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is a heterocycloalkylene group or heterocycloalkylene-(CH2)r -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally containing 1 to 3 R L3 is replaced by Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independent CR X1, O, S or N; X3, X4, and X5 are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, C 1-4 A haloalkyl group or a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; or R1 and R2 and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R3 is H, halogen, C 1-4 alkyl group, CN, OH, or absent, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms connected thereto together form C 3-8 A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, R x4 and R5 or R x4 and R6 and the atoms connected to them together form C 3-8A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group, C 1-4 haloalkyl group or C 3-6 is a cycloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl group or C 3-6 is a cycloalkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R x5 is C 1-4 alkyl group, CN, OH or absent, R7 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 A cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or R7 and R9 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and the alkyl group, haloalkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 9’ and R7, or R 9’ and R x5and the atoms connected thereto are taken together as C 3-8 a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, phenyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; or -N=S(=O)(C 1-4 -N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3) t -CH2-OC(O)NH2, -C(O)-Ra or -C(CH3) t -CH2-OC(O)NHCH3, and the heterocycloalkylene group, cycloalkylene group, arylene group, and heteroarylene group may optionally further contain 1 to 3 halogen atoms, such as CN, ═O, OH, —SF5, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group or R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 and the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, —SF, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2)t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 substituted with an alkyl group or a 5- to 6-membered heteroaryl group; Ra and Rb are independently H, halogen, or C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, haloC 1-4 an alkoxy group or a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O; Optionally, Ra, Rb and the atoms connected thereto together form C 3-6 forming a cycloalkyl group, R 13 is selected from a 7- to 11-membered spiro ring, a 4- to 10-membered parallel ring, a 5- to 8-membered heterocyclobridged ring, a 4- to 6-membered monocyclic heterocycloalkyl group containing an S(O) group, a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and a 7-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the spiro ring, parallel ring, heterocyclobridged ring, and monocyclic heterocycloalkyl group may optionally contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 14 is -(CH2) t -OC(O)NH2, -(CH2) t-OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl groups containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl groups optionally contain 1-3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; n and m are independently 0, 1, 2, or 3; r is selected from 1, 2, 3 or 4; t is selected from 0, 1, 2, 3 or 4; P is selected from 0 or 1; As a condition, Cy1 is [ka] isn't it.

[0009] The present invention provides a more specific technical solution 3, which is a compound of formula I, its stereoisomer or pharmaceutically acceptable salt, When Cy is selected from Cy1, Cy2, Cy3 and Cy8, L is -(L1)n-(L2)m-; [ka] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; [ka] When Cy is selected from Cy7 and Cy9, L is -L4-; [ka] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; L2 is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C2-4 Alkynylene groups, CO, O, NR L2 , a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is a heterocycloalkylene group or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally containing 1 to 3 R L3 is replaced by Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independent CR X1 or N, X3, X4, and X5 are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 A haloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; or R1 and R2 and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R3 is H, halogen, C 1-4 alkyl group, CN, OH, or absent, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms connected thereto together form C 3-8A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, R x4 and R5 or R x4 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group, C 1-4 haloalkyl group or C 3-6 is a cycloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl group or C 3-6 is a cycloalkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R x5 is C 1-4 alkyl group, CN, OH or absent, R7 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 A cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or R7 and R9 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and the alkyl group, haloalkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 9’ and R7, or R 9’ and R x5 and the atoms connected thereto are taken together as C 3-8 a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, phenyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; or -N=S(=O)(C 1-4-N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy C 1-6 Alkyl group, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 and the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, —SF, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t-NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 substituted with an alkyl group or a 5- to 6-membered heteroaryl group; Ra and Rb are independently H, halogen, or C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy or haloC 1-4 alkoxy groups, Optionally, Ra, Rb and the atoms connected thereto together form C 3-6 forming a cycloalkyl group, R 13 is selected from a 7- to 11-membered spiro ring, a 4- to 10-membered parallel ring, a 5- to 8-membered heterocyclobridged ring, a 4- to 6-membered monocyclic heterocycloalkyl group containing an S(O) group, a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and a 7-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the spiro ring, parallel ring, heterocyclobridged ring, and monocyclic heterocycloalkyl group may optionally contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; n and m are independently 0, 1, 2, or 3; r is selected from 1, 2, 3 or 4; t is selected from 0, 1, 2, 3 or 4; As a condition, Cy1 is [ka] isn't it.

[0010] The present invention provides a more specific technical solution 4, which is a compound of formula I, its stereoisomer or pharmaceutically acceptable salt, When Cy is selected from Cy1, Cy2, Cy3 and Cy8, L is -(L1)n-(L2)m-; [ka] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; [ka] When Cy is selected from Cy7, L is -L4-; [ka] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; L2 is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene groups, CO, O, NR L2, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is a heterocycloalkylene group or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally containing 1 to 3 R L3 is replaced by Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independent CR X1 or N, X3, X4, and X5 are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 is a haloalkyl group, or R X1 R is independently a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; or R1 and R2 and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R3 is H, halogen, C 1-4 alkyl group, CN, OH, or absent, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms connected thereto together form C 3-8A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, R x4 and R5 or R x4 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group, C 1-4 haloalkyl group or C 3-6 is a cycloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl group or C 3-6 is a cycloalkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R x5 is C 1-4 alkyl group, CN, OH or absent, R7 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 A cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or R7 and R9 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and the alkyl group, haloalkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 9’ and R7, or R 9’ and R x5 and the atoms connected thereto are taken together as C 3-8 a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, phenyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, or R 8’is —N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally selected from the group consisting of C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 is selected from a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, or a 5- to 10-membered heteroarylene group, and the heterocycloalkylene group, cycloalkylene group, arylene group, and heteroarylene group optionally further comprise 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 13is selected from a 7- to 11-membered spiro ring, a 4- to 10-membered parallel ring, a 5- to 8-membered heterocyclic bridged ring, a 4- to 6-membered monocyclic heterocycloalkyl group containing an S(O)2 group, a quaternary monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and a heptad monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the spiro ring, parallel ring, heterocyclic bridged ring, and monocyclic heterocycloalkyl group may optionally contain 1 to 3 halogen atoms, such as CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; n and m are independently 0, 1, 2, or 3; r is 1, 2, 3 or 4; As a condition, Cy1 is [ka] isn't it.

[0011] The present invention provides a more specific technical solution 5, which is a compound of formula I, its stereoisomer or pharmaceutically acceptable salt, wherein Cy is selected from Cy1, Cy2 and Cy3, and L is -(L1)n-(L2)m-; [ka] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; [ka] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; L2 is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene groups, CO, O, NR L2, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH2, or L2 is [ka] C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene groups, CO, O, NR L2 , a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-linked heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-linked heterocycloalkyl group, bridged heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally substituted with halogen, ═O, CN, C1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is a heterocycloalkylene group or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally containing 1 to 3 R L3 is replaced by Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independent CR X1 or N, X3, X4, and X5 are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, Each R X1 , R independently represents H, halogen, C 1-4 Alkyl groups, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 is a haloalkyl group, or R X1 R is independently a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; or R1 and R2 and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R3 is H, halogen, C 1-4 alkyl group, CN, OH, or absent, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms connected thereto together form C 3-8A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, R x4 and R5 or R x4 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group, C 1-4 haloalkyl group or C 3-6 is a cycloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl group or C 3-6 is a cycloalkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R x5 is C 1-4 alkyl group, CN, OH or absent, R7 is C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 3-6 A cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or R7 and R9 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and the alkyl group, haloalkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 9’ and R7, or R 9’ and R x5 and the atoms connected thereto are taken together as C 3-8 a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, phenyl group, heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, or R 8’is —N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally selected from the group consisting of C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; n and m are independently 0, 1, 2, or 3; r is 1, 2, 3 or 4; As a condition, Cy1 is [ka] isn't it.

[0012] In a sixth aspect of the present invention, there is provided a compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to the first, second, third, fourth or fifth aspect of the present invention, wherein ring B is a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a tetrahydropyrrolopyrrolyl group, a tetrahydropyrroloiimidazolyl group or a thienopyrrolyl group; R1 is C 1-4 Alkyl group or C 1-4or R1 and R2 and the atoms connected thereto together form a 5- to 7-membered monocyclic heterocycloalkyl group, a 6- to 8-membered tandem cyclic heterocycloalkyl group, a 7- to 9-membered spirocyclic heterocycloalkyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, and O, and the monocyclic heterocycloalkyl group, tandem cyclic heterocycloalkyl group, spirocyclic heterocycloalkyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R2 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R3 is H, halogen, C 1-4 alkyl group, CN, OH or absent, or R3 and R2 and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl groups are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-7A cycloalkyl group, a 5-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, said heteroaryl group optionally containing halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R7 is C 1-4 Alkyl group or C 1-4 or R7 and R9 and the atoms to which they are connected together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, said heterocycloalkyl group optionally containing halogen, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 9’ and R7, or R 9’ and R x5 and the atoms connected thereto together form a 5- to 7-membered monocyclic heterocycloalkyl group, a 7- to 10-membered spirocyclic heterocycloalkyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycloalkyl group, spirocyclic heterocycloalkyl group, and heteroaryl group are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from r is 1 or 2.

[0013] In a seventh aspect of the present invention, there is provided a compound according to any one of the first to sixth aspects, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each L2 is independently [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] is selected from R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is [ka] is selected from Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] is selected from In some embodiments, L4 is [ka] is selected from A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN; Cy5 is [ka] is selected from Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, -N(CH3)2, -NH(CH3), C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, wherein the cycloalkyl group or heterocycloalkyl group is optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; Or each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, wherein the cycloalkyl group or heterocycloalkyl group is optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 Alkoxy groups, OH, C 3-6 Cycloalkyl groups, C 2-6 substituted with 1 to 3 groups selected from an alkynyl group and NH2; Or each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, wherein the cycloalkyl group or heterocycloalkyl group is optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; Or, each R X1, R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5, 3- to 5-membered cycloalkyl group or C 1-4 A haloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group, a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, the heterocycloalkyl group optionally contains halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Or R1 and R2 and the atoms connected to them together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R3 is H, halogen, C 1-4 alkyl group, CN, OH or absent, or R3 and R2 and the atoms to which they are connected together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-6 Form a cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, and optionally a halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group or -NHC 1-4 is an alkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R7 is C1-4 Alkyl group or C 1-4 is a haloalkyl group, or R7 and R9 and the atoms to which they are connected together form the following ring: [ka] and forming a ring selected from the group consisting of: 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R 9’ and R7 and the atoms connected thereto together form the following ring: [ka] and optionally forming a ring selected from C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from or R 9’ and R x5 and the atoms connected to them together [ka] and optionally forming C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from As a condition, R 9’ and R7, or R 9’ and R x5 At least one pair of these forms a ring, R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; -N=S(=O)(C 1-4 alkyl)2 or -N(C 3-6 cycloalkyl)C(O)NH(C 1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H or C 1-4 is an alkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN, -C(NHC 1-2alkyl)=CH-NO 2、 -C(CH3) t -CH2-NH-C(O)O(CH3), -C(CH3) t -CH2-OC(O)NH2, -C(O)-Ra or -C(CH3) t -CH2-OC(O)NHCH3, said rings being optionally selected from halogen, CN, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; In some embodiments, R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN, -C(NHC 1-2 alkyl)=CH-NO 2、 -C(CH3) t -CH2-NH-C(O)O(CH3), -C(CH3) t -CH2-OC(O)NH2, -C(O)-Ra or -C(CH3) t -CH2-OC(O)NHCH3, said rings being optionally selected from halogen, CN, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; R 13 teeth, [ka] wherein the ring is optionally selected from halogen, CN, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from haloalkyl groups; n is 0, 1, 2 or 3; m is 0, 1 or 2; r is 1 or 2; t is selected from 0, 1 or 2.

[0014] In an eighth aspect of the present invention, there is provided a compound according to any one of the first to sixth aspects, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each L2 is independently [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] is selected from R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is [ka] is selected from Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] is selected from A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN; Cy5 is [ka] is selected from Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-4Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 is a haloalkyl group, or R X1 R is independently a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group, a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, the heterocycloalkyl group optionally contains halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Or R1 and R2 and the atoms connected to them together form the following ring: [ka] or R1 and R2 and the atoms connected thereto together form a ring selected from: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R3 is H, halogen, C 1-4 alkyl group, CN, OH or absent, or R3 and R2 and the atoms to which they are connected together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-6 Form a cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, and optionally a halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group or -NHC 1-4 is an alkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R7 is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, or R7 and R9 and the atoms to which they are connected together form the following ring: [ka] and forming a ring selected from the group consisting of: 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R 9’ and R7 and the atoms connected thereto together form the following ring: [ka] and optionally forming a ring selected from C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from or R 9’ and R x5 and the atoms connected to them together [ka] and optionally forming C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from As a condition, R 9’ and R7, or R 9’ and R x5At least one pair of these forms a ring, R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; or -N=S(=O)(C 1-4 alkyl)2, or R 8’ is -N(C 3-6 cycloalkyl)C(O)NH(C 1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H or C 1-4 is an alkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] C 1-4 Alkyl-CN, -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN, -C(NHC 1-2 alkyl)=CH-NO 2、 -CH(CH3)-CH2-NH-C(O)O(CH3), -C(CH3)2-CH2-NH-C(O)O(CH3), -CH(CH3)-CH2-OC(O)NH2, -C(CH3)2-CH2-OC(O)NH2, -C(O)-Ra, -CH(CH3)-CH2-OC(O)NHCH3 or -C(CH3)2-CH2-OC(O)NHCH3, said rings optionally containing halogen, CN, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2)t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; or R 12 represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, [ka] -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 alkyl)=N-CN or -C(NHC 1-2 alkyl)=CH-NO2, or -C(CH3) t -CH2-OC(O)NH2, -C(O)-Ra, or -C(CH3) t -CH2-OC(O)NHCH3, said rings being optionally selected from halogen, CN, OH, -SF5, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NH-C(O)NH2, -(CH2) t -NH-C(=NH)NH2, -(CH2) t -NH-C(O)-O-(C 1-2 alkyl), -(CH2) t -NH-C(C 1-2alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=N-CN, -(CH2) t -NH-C(NHC 1-2 alkyl)=CH-NO2, -(CH2) t -C(NHC 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=N-CN, -(CH2) t -C(C 1-2 alkyl)=NO-(C 1-2 alkyl), =NOC 1-2 Alkyl group, 5-6 membered heteroaryl group or -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl groups 、 -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; R 13 teeth, [ka] wherein the ring is optionally selected from halogen, CN, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from haloalkyl groups; n is 0, 1, 2 or 3; m is 0, 1 or 2; r is 1 or 2; t is selected from 0, 1 or 2.

[0015] In a ninth aspect of the present invention, there is provided a compound according to any one of the first to sixth aspects, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each L2 is independently [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] or each L2 is independently selected from [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] or each L2 is independently selected from [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] or each L2 is independently selected from [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] is selected from R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is [ka] or L3 is selected from [ka] is selected from Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN; Cy5 is [ka] is selected from Each R X1 , R independently represents H, halogen, C 1-4 Alkyl groups, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 is a haloalkyl group, or R X1 R is independently a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or RX1 and R6 and the atoms connected to them together form C 3-6 Forming a cycloalkyl group, said cycloalkyl group optionally containing halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Or R1 and R2 and the atoms connected to them together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 or R1 and R2 and the atoms connected thereto may be taken together to form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R3 is H, halogen, C 1-4 alkyl group, CN, OH or absent, or R3 and R2 and the atoms to which they are connected together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-6 Form a cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, and optionally a halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group or -NHC 1-4 is an alkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, R7 is C 1-4 Alkyl group or C 1-4is a haloalkyl group, or R7 and R9 and the atoms to which they are connected together form the following ring: [ka] and forming a ring selected from the group consisting of: 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R 9’ and R7 and the atoms connected thereto together form the following ring: [ka] and optionally forming a ring selected from C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from or R 9’ and R x5 and the atoms connected to them together [ka] and optionally forming C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from As a condition, R 9’ and R7, or R 9’ and R x5 At least one pair of these forms a ring, R8 is R 8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C3-6 a cycloalkyl group, said cycloalkyl group optionally being selected from the group consisting of C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H or C 1-4 is an alkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; n is 0, 1, 2 or 3; m is 0, 1 or 2; r is 1 or 2.

[0016] In a tenth aspect of the present invention, there is provided a compound according to any one of the first to sixth aspects, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Each L2 is independently [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] or each L2 is independently selected from [ka] CO, O, NR L2 , C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 alkynylene groups, [ka] is selected from R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, L3 is [ka] is selected from Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl group or C 1-4 alkoxy groups, or R L3 and R X1 and the atoms connected to them together form C 3-6 forming a cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L4 is [ka] or L4 is selected from [ka] is selected from A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN; Cy5 is [ka] is selected from Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 2-4 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4 Alkyl group, SCF3, SF5 or C 1-4 is a haloalkyl group, or R X1 R is independently a 3- to 5-membered cycloalkyl group, or two R, R and R on adjacent ring atoms X1 , or R X1 and R6 and the atoms connected to them together form C 3-6 A cycloalkyl group, a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group, the heterocycloalkyl group optionally contains halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, Or R1 and R2 and the atoms connected to them together form the following ring: [ka] or R1 and R2 and the atoms connected thereto together form a ring selected from [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R3 is H, halogen, C 1-4 alkyl group, CN, OH or absent, or R3 and R2 and the atoms to which they are connected together form the following ring: [ka] and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R4, or R3 and R5 and the atoms connected thereto, together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group or a phenyl group containing 1 to 3 heteroatoms selected from N, S and O, wherein the heterocycloalkyl group, phenyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R3 and R6 and the atoms connected thereto together form C 5-6 Form a cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and optionally halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R x4 H, halogen, C 1-4 alkyl group, CN, OH or absent, or R x4 and R4, or R x4 and R5 and the atoms connected thereto together form an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, and optionally a halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R4 is H, C 1-4 Alkyl group or C 1-4 is a haloalkyl group, R5 is H, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group or -NHC 1-4 is an alkyl group, R6 is H, halogen, =O, CN, C1-4 Alkyl group or C 1-4 is an alkoxy group, R7 is C 1-4 Alkyl group or C 1-4 is a haloalkyl group, or R7 and R9 and the atoms to which they are connected together form the following ring: [ka] and forming a ring selected from the group consisting of: 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; or R 9’ and R7 and the atoms connected thereto together form the following ring: [ka] and optionally forming a ring selected from C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from or R 9’ and R x5 and the atoms connected to them together [ka] and optionally forming C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 Alkyl group, =O, OH, NH2, CN or R 8’ and substituted with 1 to 3 groups selected from As a condition, R 9’ and R7, or R 9’ and R x5 At least one pair of these forms a ring, R8 is R8’ , -OR 8’ or -(CH2) r R 8’ and R 8’ is C 3-6 a cycloalkyl group, said cycloalkyl group optionally being selected from the group consisting of C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, mercapto C 1-4 Alkyl groups, halogens, haloC 1-4 substituted with 1 to 3 groups selected from an alkyl group, ═O, OH, NH, and CN; R9 is H or C 1-4 is an alkyl group, Each R 10 is independently R 8’ , -OR 8’ , -NHR 8’ or -(CH2) r R 8’ and R 11 is C 3-6 a cycloalkyl group, wherein the cycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl groups and C 1-4 substituted with haloalkyl groups; R 12 represents a cycloalkyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, [ka] wherein the ring is optionally selected from halogen, CN, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from haloalkyl groups; R 13 teeth, [ka] wherein the ring is optionally selected from halogen, CN, OH, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from haloalkyl groups; n is 0, 1, 2 or 3; m is 0, 1 or 2; r is 1 or 2.

[0017] In an eleventh aspect of the present invention, there is provided a compound according to any one of the above aspects 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Cy1 is [ka] or [ka] or [ka] is selected from Cy2 is [ka] is selected from Cy4 is [ka] or [ka] or [ka] or [ka] or [ka] or [ka] is selected from Cy5 is [ka] is selected from Cy7 is [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] is selected from Cy9 is [ka] is selected from.

[0018] In a twelfth aspect of the present invention, there is provided a compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of the above aspects 1 to 7, wherein Cy1 is [ka] or Cy1 is selected from [ka] or Cy1 is selected from [ka] or Cy1 is selected from [ka] is selected from Cy5 is [ka] or Cy5 is selected from [ka] is selected from Cy7 is [ka] or Cy7 is selected from [ka] or Cy7 is selected from [ka] is selected from.

[0019] In a thirteenth aspect of the present invention, there is provided a compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of the above aspects 1 to 7, wherein -(L1)n-(L2)m- is [ka] and R6 is H; -L3- is [ka] is selected from -L4- is [ka] or [ka] is selected from [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R each independently represents F, Cl, Br, a methyl group, an isopropyl group, an ethoxy group, a methoxy group, an ethynyl group, a propynyl group, a cyclopropyl group, a cyclobutyl group, a dimethylamino group, [ka] and in some embodiments, [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R each independently represents F, Cl, Br, a methyl group, an ethynyl group, a propynyl group, a cyclopropyl group, [ka] Selected from R X1 is H, In some embodiments, [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R are each independently selected from F, Cl, Br, a methyl group, an ethynyl group, a propynyl group, or a cyclopropyl group; R X1 is H, In some embodiments, [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R are each independently selected from F, Cl, Br, a methyl group, an ethynyl group, a propynyl group, or a cyclopropyl group; R X1 is H, or R X1 and R6 and the atoms connected thereto together form a morpholino group, a furyl group, a pyrrolyl group, or a thienyl group, and in some embodiments, R X1 and R6 and the atoms to which they are connected together form a morpholino group, a furyl group, or a thienyl group.

[0020] In a fourteenth aspect of the present invention, there is provided a compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of the above aspects 1 to 7, wherein -(L1)n-(L2)m- is [ka] and R6 is H; -L3- is [ka] is selected from -L4- is [ka] is selected from [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R are each independently selected from F, Cl, Br, a methyl group, an ethynyl group, or a cyclopropyl group; R X1 is H, or R X1 and R6 and the atoms to which they are connected together form a morpholino group, a furyl group, or a thienyl group.

[0021] In a fifteenth aspect of the present invention, there is provided a compound according to any one of the first to fifth aspects, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] Here, L4 is [ka] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated. 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independent CR X1 , S or N, R L2 is H, C 1-4 Alkyl group or C 3-6 is a cycloalkyl group, R6 is H, halogen, =O, CN, C 1-4 Alkyl group or C 1-4 is an alkoxy group, Each R X1 , R independently represents H, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl group, CONHC 1-4 Alkyl group, NHSO2C 1-4 Alkyl group, SO2NHC 1-4 Alkyl groups, SO2C 1-4Alkyl groups, SCF3, SF5, 3- to 5-membered cycloalkyl groups, C 1-4 a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 and R6 and the atoms connected to them together form C 3-8 A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R1 and R2 and the atoms connected thereto together form a 5-10 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, B, and O, and the cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally selected from halogen, ═O, CN, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group, OH, and NH; R 12 is a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C 1-6 Alkyl group, C 1-4 Alkyl-CN, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 -C(NRaRb)=CRa-NO 2、 -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 and -C(O)-(4- to 6-membered heterocycloalkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra, or -C(O)-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, -SF5, C 1-4 Alkyl group, C 1-4 Alkyl-CN, Hydroxy-C 1-4 Alkyl group, C 1-4 Haloalkyl groups, -(CH2) t -OC(O)NH2, -(CH2) t -NRa-C(O)NH2, -(CH2) t -NRa-C(=NH)NH2, -(CH2) t -NRa-C(O)-O-(C 1-4 alkyl), -(CH2) t -NRa-C(C 1-4 alkyl)=N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN, -(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN, -(CH2) t -C(C 1-4 alkyl)=N-CN, -(CH2) t -C(C 1-4 alkyl)=NO-(C 1-4 alkyl), =NOC 1-4 Alkyl group, 5-6 membered heteroaryl group, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3, -(CH2) t -OC 1-2 Haloalkyl groups, -(CH2) t -OC 3-6 Cycloalkyl groups, -(CH2) t -OC 1-4 Alkyl-OC3-6 Cycloalkyl groups, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t substituted with the group -NRa-C(O)CH3, Ra and Rb are independently H, halogen, or C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, haloC 1-4 an alkoxy group or a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O; p is selected from 0 or 1.

[0022] In a sixteenth aspect of the present invention, there is provided a compound according to the fifteenth aspect, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, L4 is [ka] and R 12 is -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 alkyl), —CH(CH3)—CH2—OC(O)NHCH3.

[0023] In a seventeenth aspect of the present invention, there is provided a compound according to the above formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, L4 is [ka] or L4 is [ka] and R6 and RX1 and the atoms to which they are connected together form a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, Si; A is -S(O)-; R1 and R2 and the atoms connected to them together [ka] Forming R 12 is -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-2 alkyl), -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-2 alkyl), -CH(CH3)-CH2-OC(O)NHCH3; [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R are each independently selected from F, Cl, a methyl group, an ethyl group, an isopropyl group, an ethoxy group, a methoxy group, an ethynyl group, a propynyl group, a cyclopropyl group, a cyclobutyl group, and a dimethylamino group.

[0024] In an eighteenth aspect of the present invention, there is provided a compound according to formula (I) above, a stereoisomer or a pharmaceutically acceptable salt thereof, Cy is selected from Cy1, Cy2, Cy4, Cy5, Cy7 and Cy9; When Cy is selected from Cy1 and Cy2, L is -(L1)n-(L2)m-; when Cy is selected from Cy4 and Cy5, L is -L3-; when Cy is selected from Cy7 and Cy9, L is -L4-; Cy1 is [ka] is selected from Cy2 is [ka] is selected from Cy4 is [ka] is selected from Cy5 is [ka] is selected from Cy7 is [ka] is selected from Cy9 is [ka] is selected from -(L1)n-(L2)m- is [ka] and R6 is H; -L3- is [ka] is selected from -L4- is [ka] is selected from [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R each independently represents F, Cl, Br, a methyl group, an isopropyl group, an ethoxy group, a methoxy group, an ethynyl group, a propynyl group, a cyclopropyl group, a cyclobutyl group, a dimethylamino group, [ka] Selected from R X1 is H, or R X1 and R6 and the atoms to which they are connected together form a morpholino group, a furyl group, a pyrrolyl group, or a thienyl group.

[0025] In a nineteenth aspect of the present invention, there is provided a compound according to formula (I) above, a stereoisomer or a pharmaceutically acceptable salt thereof, Cy is selected from Cy1, Cy7; when Cy is selected from Cy1, L is -(L1)n-(L2)m-, and when Cy is selected from Cy7, L is -L4-; Cy1 is [ka] is selected from Cy7 is [ka] is selected from -(L1)n-(L2)m- is [ka] and R6 is H; -L4- is [ka] is selected from [ka] optionally, 1 to 3 R R The following structure is substituted with: [ka] R R each independently represents F, Cl, Br, a methyl group, an isopropyl group, an ethoxy group, a methoxy group, an ethynyl group, a propynyl group, a cyclopropyl group, a cyclobutyl group, a dimethylamino group, [ka] Selected from R X1 is H, or R X1 and R6 and the atoms to which they are connected together form a morpholino group, a furyl group, a pyrrolyl group, or a thienyl group.

[0026] In a twenty-first aspect of the present invention is a compound selected from one of the structures in Table 1, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0027] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24]

[0028] In a twenty-first aspect of the present invention is a compound selected from one of the structures in Table 2 below, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0029]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

[0030] The present invention further provides a composition or pharmaceutical formulation, comprising a compound according to any one of the preceding claims, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (a unit dosage form is also referred to as a "formulation specification").

[0031] The present invention also provides a composition or pharmaceutical formulation, which contains 1 to 1500 mg of a compound according to any one of the above methods, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0032] The present invention further provides a use of the compound, its stereoisomer or pharmaceutically acceptable salt according to any one of the above methods in the manufacture of a medicament for treating / preventing a PDE4B-mediated disease, wherein the PDE4B-mediated disease is cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0033] The present invention further provides a method for treating a disease in a mammal or human, the method comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the disease is preferably cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease, and the therapeutically effective amount is preferably 1 to 1500 mg. In some embodiments, the mammal described in the present invention does not include a human.

[0034] As used herein, an "effective amount" or "therapeutically effective amount" includes administering a sufficient amount of a compound disclosed herein that relieves to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a compound disclosed herein necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 1-50 mg, 1-1 ... 500mg, 5~1000mg, 5~900mg, 5~800mg, 5~700mg, 5~600mg, 5~500mg, 5~400mg, 5~300mg, 5~250mg, 5~200mg, 5~150mg, 5~1 25mg, 5~100mg, 5~90mg, 5~70mg, 5~80mg, 5~60mg, 5~50mg, 5~40mg, 5~30mg, 5~25mg, 5~20mg, 10~1500mg, 10~1000mg, 10 ~900mg, 10~800mg, 10~700mg, 10~600mg, 10~500mg, 10~450mg, 10~400mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 1 0~125mg, 10~100mg, 10~90mg, 10~80mg, 10~70mg, 10~60mg, 10~50mg, 10~40mg, 10~30mg, 10~20mg, 20~1500mg, 20~1000 mg, 20~900mg, 20~800mg, 20~700mg, 20~600mg, 20~500mg, 20~400mg, 20~350mg, 20~300mg, 20~250mg, 20~200mg, 20~15 0mg, 20~125mg, 20~100mg, 20~90mg, 20~80mg, 20~70mg, 20~60mg, 20~50mg, 20~40mg, 20~30mg, 50~1500mg, 50~1000mg,Examples of effective dosages include, but are not limited to, 50 to 900 mg, 50 to 800 mg, 50 to 700 mg, 50 to 600 mg, 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 125 mg, 50 to 100 mg, 100 to 1500 mg, 100 to 1000 mg, 100 to 900 mg, 100 to 800 mg, 100 to 700 mg, 100 to 600 mg, 100 to 500 mg, 100 to 400 mg, 100 to 300 mg, 100 to 250 mg, and 100 to 200 mg. In some embodiments, the pharmaceutical composition or formulation of the present invention comprises a therapeutically effective amount of a compound of the present invention or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition or pharmaceutical formulation, which comprises a therapeutically effective amount of a compound according to the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also called the "formulation specification"). In some embodiments, the pharmaceutical composition contains 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, The present invention may be administered in an amount of 0 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

[0035] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0036] A method for treating a disease in a mammal or human, the method comprising administering to a subject a daily dose of 1 to 1500 mg / day of a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, the daily dose may be a single dose or divided doses, and in some embodiments the daily dose is 10 to 1500 mg / day, 20 to 1500 mg / day, 25 to 1500 mg / day, 50 to 1500 mg / day, 75 to 1500 mg / day, 100 to 1500 mg / day, 200 to 1500 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1000 mg / day, In some embodiments, the daily dose is 1 to 400 mg / day, including, but not limited to, 100 to 1000 mg / day, 200 to 1000 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day, 25 to 400 mg / day, 50 to 400 mg / day, 100 to 400 mg / day, and 200 to 400 mg / day. mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0037] The present invention relates to a kit, which may contain a composition in the form of a single dose or multiple doses, and which comprises a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof is the same as that in the pharmaceutical composition.

[0038] In the present invention, the amounts of the compounds of the invention or their stereoisomers or pharmaceutically acceptable salts are in each case calculated in the form of the free base.

[0039] "Preparation specifications" refers to the weight of the active ingredient contained in one unit dosage form, one tablet, or each other unit dosage form.

[0040] Synthetic Route Patent documents such as WO2013026797A1 describe methods for preparing PDE4B inhibitors, and those skilled in the art can combine these documents with known organic synthesis techniques to prepare the compounds of the present invention, where the starting materials are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are those obtained from legitimate commercial sources, and suppliers include companies such as Taitan Technology, Ananji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, Yaoming Kangde and Bailingwei Technology.

[0041] Specific and similar reactants can be selectively identified through indexes of known chemicals produced by the American Chemical Society's Chemical Information Retrieval Service, which are available in many public and university libraries and online. Chemicals that are known but not commercially available in the catalogs may optionally be produced by custom chemical synthesis businesses, many of which offer custom synthesis services (e.g., the companies listed above).

[0042] term Unless otherwise specified in the present invention, the terms used in the present invention have the following meanings.

[0043] As used herein, "halogen" refers to F, Cl, Br, I, or an isotope thereof.

[0044] "Halogenated" or "halogen substituted" refers to the replacement of a hydrogen atom with one or more selected from F, Cl, Br, I, or isotopes thereof, and the upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogen atoms in the group to be substituted. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, they may be replaced with the same or different halogens.

[0045] The term "deuterated" or "deuteride" refers to a situation in which a hydrogen atom in a group such as an alkyl group, a cycloalkyl group, an alkylene group, an aryl group, a heteroaryl group, a mercapto group, a heterocycloalkyl group, an alkenyl group, or an alkynyl group is substituted with at least one deuterium isotope, and the upper limit of the number of deuteration is equal to the sum of the number of substitutable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuteration is any integer between 1 and the upper limit, and is preferably 1 to 20 deuterium atom substitutions, more preferably 1 to 10 deuterium atom substitutions, even more preferably 1 to 6 deuterium atom substitutions, and even more preferably 1 to 3 deuterium atom substitutions.

[0046] "Alkyl group" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl group of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, and even more preferably 1 to 2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof.

[0047] "Alkylene group" refers to divalent straight- and branched-chain saturated alkyl groups; examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0048] The term "cycloalkyl group" refers to a monovalent non-aromatic partially unsaturated or fully saturated substituted or unsubstituted carbocyclic hydrocarbon group, and unless otherwise specified, typically has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] or cycloheptyl, etc.

[0049] A "cycloalkylene group" is a divalent radical of a "cycloalkyl group", and non-limiting examples include cyclopropylene, cyclobutylene, and the like.

[0050] "Heterocyclo" or "heterocyclo group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 3 heteroatoms selected from N, O, or S, and includes monocyclic heterocyclos, bridged bicyclic heterocyclos, fused bicyclic heterocyclos, and spiro bicyclic heterocyclos. Unless otherwise specified, the heterocyclo is preferably 3 to 12-membered, more preferably 4 to 12-membered, more preferably 4 to 10-membered, and even more preferably 4 to 7-membered. This definition includes heterocycloalkyl groups and heteroaryl groups. N and S in the heterocyclo ring can be oxidized to various oxidation states. Heterocyclo groups may be attached at a heteroatom or a carbon atom, and non-limiting examples include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholino, thiomorpholino, 1,3-dithianyl, dihydrofuryl, and the like. azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group, and oxaspiro[3.3]heptyl group; [ka] Includes:

[0051] A "heterocyclylene group" is a divalent group corresponding to a "heterocyclo group", and non-limiting examples include imidazolyl, piperidinylene, aziridinyl, and the like.

[0052] "Carbocycle" or "carbocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridged rings, bicyclic parallel rings, and bicyclic spiro rings, which, unless otherwise specified, have 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. The definition includes cycloalkyl groups and aryl groups. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl groups; [ka] and the bicyclic bridged ring is [ka] and the like, and the bicyclic parallel ring is [ka] and the like, and bicyclic spiro rings include [ka] Includes:

[0053] An "aryl group" refers to a carbocyclic ring having aromatic character. Non-limiting examples include phenyl, naphthyl, and the like.

[0054] "Alkynyl group" refers to a straight- or branched-chain monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds; unless otherwise specified, an alkynyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms; non-limiting examples include ethynyl, propynyl, and propargyl groups.

[0055] "Alkenyl group" refers to a straight- or branched-chain monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds; unless otherwise specified, an alkynyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms; non-limiting examples include vinyl, propenyl, allyl, 2-butenyl, and 1-butenyl.

[0056] The term "alkoxy group" or "alkyloxy group" refers to an -O-alkyl group, and unless otherwise specified, is -OC 1-8 an alkyl group, preferably -OC 1-6 It is an alkyl group, more preferably -OC 1-4 alkyl group, more preferably -OC 1-2 alkyl groups. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy groups, etc. The term "haloalkoxy group" refers to an -O-haloalkyl group, and unless otherwise specified, is an -O-haloC 1-8 alkyl group, preferably -O-haloC 1-6 alkyl group, more preferably -O-haloC 1-4 alkyl group, more preferably -O-haloC 1-2 It is an alkyl group. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0057] "C 1-4 "Alkyl acyl group" is C 1-4 It refers to alkyl-C(O)-. Non-limiting examples include formyl, acetyl, and propionyl groups.

[0058] "C 1-4 The alkylsulfonyl group is C 1-4 It refers to alkyl-S(O)2-. Non-limiting examples include methanesulfonyl, ethylsulfonyl, and propylsulfonyl.

[0059] A "heteroaromatic ring" or "heteroaryl group" refers to a heterocyclic ring having aromatic character. Non-limiting examples include pyrazolyl, pyrimidine, thiazolyl, pyridine, furyl, and the like.

[0060] The term "heterocycloalkyl group" refers to a non-aromatic, partially unsaturated, or fully saturated heterocyclo, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably a 5- or 6-membered ring. In addition to carbon atoms, the heterocycloalkyl group further contains 1 to 3 heteroatoms selected from N, S, O, Si, and P as ring members. Non-limiting examples include azetidinyl, morpholino, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, and the like.

[0061] "Alkylamino" or "alkylamino" refers to an amino substituted with one or two alkyl groups, and is also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0062] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may, but is not necessarily, substituted with F, and includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0063] "Pharmaceutically acceptable salts" refers to salts in which the compounds of the present invention retain the biological effectiveness and properties of the free acids or free bases and which are obtained by reaction of said free acids with non-toxic inorganic or organic bases, or by reaction of said free bases with non-toxic inorganic or organic acids.

[0064] A "pharmaceutical composition" refers to a mixture of one or more of the compounds herein or their stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals, with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0065] The term "carrier" refers to a system that does not significantly stimulate the living body, does not eliminate the biological activity and properties of a given compound, and can change the drug's administration form and distribution in the body, control the drug's release rate, and deliver the drug to the target organ. Non-limiting examples include microcapsules, microspheres, nanoparticles, liposomes, etc.

[0066] "Excipient" refers to a substance that is not itself a therapeutic agent, but is added to a pharmaceutical composition as a diluent, excipient, adhesive, and / or vehicle to improve its processing or storage properties, or to allow or facilitate the compound or pharmaceutical composition to form a dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and may be described as wetting agents, buffers, suspending aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to, the following: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients; Excipients, such as cocoa butter, suppository wax, (9) oils, such as peanut oil, cottonseed oil, safflower oil, goa oil, olive oil, corn oil, and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) water for endotoxin testing, (17) isotonic saline, (18) Ringer's solution, (19) ethanol, (20) pH buffer solutions, (21) polyesters, polycarbonates, and / or polyanhydrides, and (22) other non-toxic, compatible substances used in drug formulations.

[0067] "Stereoisomer" refers to isomers that result from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0068] The term "solvate" refers to a substance formed by intermolecular non-covalent bonding of a compound of the present invention or a salt thereof with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0069] A "cocrystal" refers to a crystalline body formed by the association of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) through hydrogen bonding or other non-covalent bonds, where the API and CCF are both solids in their pure states at room temperature and there is a fixed stoichiometric ratio between the components. Cocrystals are multi-component crystalline bodies, and include not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate. [Brief explanation of the drawings]

[0070] [Figure 1] Compound 51 dose-dependently inhibits LPS-induced TNF-α expression in mouse lung tissue. [Figure 2] Compound 84 dose-dependently inhibits LPS-induced TNF-α expression in mouse lung tissue. DETAILED DESCRIPTION OF THE INVENTION

[0071] The present invention will be described in detail below with reference to examples. Unless specific conditions are specified in the examples, the experiments were carried out according to general conditions. The examples are provided to better explain the present invention, and it should be understood that the present invention is not limited to the examples provided. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention still fall within the scope of protection of the present invention.

[0072] Dess-Martin reagent, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIPEA: N,N-diisopropylethylamine NMP: N-methylpyrrolidine TBDMSCl: tert-butyldimethylchlorosilane DMAP: 4-dimethylaminopyridine HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate T3P: propylphosphoric tricycloanhydride Example 1 [ka]

[0073] Step 1: In a nitrogen atmosphere, compound 1A (21.6 mL, 155 mmol), compound 1B (15.6 mL, 142 mmol), and 2 mL of piperidine were added to a three-neck flask, heated to 45°C, and reacted for 48 hours. 1N hydrochloric acid was added to make the system acidic, and 200 mL of ethyl acetate was added three times for extraction. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain 36 g of crude compound 1C, which was used directly in the next step. LCMS m / z=249.1[M+H] + .

[0074] Step 2: Under a nitrogen atmosphere, 80 mL of dichloromethane was added to a three-neck flask and the mixture was cooled to -10 °C. Titanium tetrachloride (4.9 mL, 44.4 mmol) was added, followed by the slow addition of isopropyl alcohol (3.4 mL, 44.4 mmol) and the reaction mixture was allowed to react for 30 min. Crude compound 1C (10 g) was dissolved in 10 mL of DCM and slowly added to the mixture. Triethylamine (17 mL, 121 mmol) was then added and the reaction mixture was allowed to react for 2 h at -10 °C. After the starting material disappeared, 42 mL of 3N hydrochloric acid was added to quench the reaction. The mixture was then warmed to room temperature and extracted three times with 200 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 8 g of crude compound 1D, which was used directly in the next step. 1H NMR(400MHz,CDCl3)δ 4.36(s,1H),4.25 - 4.19(m,2H),2.80 - 2.73(m,1H),2.66 - 2.58(m,1H),1.58(s,3H),1.49(s,3H),1.32 - 1.27(m,3H).

[0075] Step 3: 8 g of crude compound 1D was dissolved in a mixed solvent of methanol: concentrated hydrochloric acid = 150 mL: 15 mL, urea (24 g, 400 mmol) was added, and the system was heated to 90 °C and reacted for 24 h. The solid produced in the system was collected, washed with water twice, and dried to obtain 6.4 g of crude compound 1E, which was directly used in the next step of the reaction. LCMS m / z=245.1[M+H] + .

[0076] Step 4: 6.4 g of crude compound 1E was added to a round-bottom flask, and 100 mL of water and sodium hydroxide (8 g, 200 mmol) were added. The mixture was heated to 85 °C and reacted for 24 h. Hydrochloric acid was added to adjust the system to acidic. The solid formed in the system was collected and dried to obtain 3 g of crude compound 1F, which was used directly in the next step of the reaction. LCMS m / z=196.9[MH] - .

[0077] Step 5: In a nitrogen gas atmosphere, 3 g of crude compound 1F was dissolved in 60 mL of acetonitrile, and phosphorus oxychloride (5.7 mL, 61 mmol) was added. The mixture was heated to 90°C and reacted for 48 hours. After cooling, the mixture was poured into 300 mL of water, and the resulting solid was collected and dried to give 1 g of crude compound 1G. LCMS m / z=235.0 and 237.0[M+H] + .

[0078] Step 6: In a nitrogen atmosphere, 1 g of crude compound 1G was dissolved in 30 mL of acetonitrile, and 1.5 g of crude compound 1H salt (see patent WO2013 / 026797A1 for the method) and triethylamine (5 mL, 36 mmol) were added. The mixture was heated to 80 °C and reacted for 18 hours. After cooling to room temperature, the mixture was concentrated and reacted. After the reaction, 50 mL of ethyl acetate was added three times for extraction. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain 740 mg of crude compound 1I, which was used directly in the next step. LCMS m / z=300.1[M+H] + .

[0079] Step 7: 740 mg of crude compound 1I was dissolved in 30 mL of acetic acid, 2 mL of 30% hydrogen peroxide was added, and the mixture was allowed to react at room temperature for 2 hours. After the starting material disappeared, the mixture was extracted three times with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated to give 540 mg of crude compound 1J, which was used directly in the next step. LCMS m / z=316.1[M+H] + .

[0080] Step 8: In a nitrogen atmosphere, 270 mg of crude compound 1J, 4-(4-chlorophenyl)piperidine (220 mg, 1.12 mmol), and DIPEA (0.86 mL, 5.2 mmol) were dissolved in 30 mL of 1,4-dioxane, and the mixture was heated to 100 °C and reacted for 18 h. After the reaction was concentrated, 246 mg of crude racemic compound 1 was obtained by thin-layer chromatography separation, and chiral separation gave compound 1-1 (77 mg, 19%) and compound 1-2 (70 mg, 17%).

[0081] LCMS m / z=475.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.35 - 7.25(m,5H),4.85 - 4.75(m,3H),3.75 - 3.70(m,2H),3.14 - 3.07(m,1H),2.96 - 2.78(m,3H),2.72 - 2.65(m,1H),2.42 - 2.29(m,2H),2.19 - 2.10(m,2H),1.85 - 1.68(m,4H),1.57 - 1.44(m,2H),1.36(s,3H),1.18(s,3H).

[0082] Chiral separation method: Instrument: Waters 150 SFC, Column: Chiralpak Column (250 x 30 mm, ID 30 mm, 10 μm particle size), Mobile phase: A for CO2 and B for MeOH, Gradient: 30% phase B isocratic elution, Flow rate: 80 mL / min, Back pressure: 100 bar, Column temperature: 25°C, Wavelength: 220 nm, Retention time: Compound 1-1: 1.160 min and Compound 1-1: 1.701 min. Example 2 [ka]

[0083] Step 1: In a nitrogen atmosphere, 270 mg of crude compound 1J, crude compound 2A (320 mg, see US20140228286A1), and DIPEA (0.86 mL, 5.2 mmol) were dissolved in 30 mL of 1,4-dioxane, heated to 100 °C, and reacted for 18 hours. After concentrating the mixture and reacting, 226 mg of crude racemic compound 2 was obtained by thin-layer chromatography separation, and chiral separation yielded compound 2-1 (54 mg, 13%) and compound 2-2 (40 mg, 10%). LCMS m / z=477.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.86(s,2H),7.31(s,1H),4.86 - 4.80(m,1H),4.73 - 4.64(m,2H),3.76 - 3.69(m,2H),3.23 - 3.00(m,4H),2.73 - 2.65(m,1H),2.41 - 2.28(m,2H),2.19 - 2.11(m,2H),2.02 - 1.92(m,2H),1.84 - 1.58(m,4H),1.35(s,3H),1.18(s,3H).

[0084] Chiral separation method: Instrument: Waters 150 SFC, Column: Chiralpak Column (250 x 30 mm, ID 30 mm, 10 μm particle size), Mobile phase: A for CO2 and B for MeOH, Gradient: 30% phase B isocratic elution, Flow rate: 70 mL / min, Back pressure: 100 bar, Column temperature: 25°C, Wavelength: 220 nm, Retention time: Compound 2-1: 1.063 min and Compound 2-2: 1.546 min. Example 3 [ka]

[0085] Compound 3 (35 mg, 22%) was obtained from compound 3A and 4-chlorobutyric acid methyl ester by following the procedure of Example 1.

[0086] 1 H NMR(400MHZ,DMSO-d6)δ 8.86(s,2H),6.48(s,1H),4.88(t,1H),4.67(d,2H),3.70(m,2H),3.17(s,1H) ,3.00-3.06(m,3H),2.92(m,1H),2.38(d,4H),2.13(s,2H),1.96(d,3H),1.87 - 1.71(m,2H),1.58-1.67(m,2H). LCMS(ESI):=463.2[M+H] + . Example 4

change

[0087] ステップ1: Compound 3 was divided into 3-1 (26.1 mg) and 3-2 (21.1 mg, 22%).

[0088] Chiral fragmentation method: Instrument: Waters 150 SFC, column: Chiralpak Column (250×30 mm, ID 30 mm, 10 μm particle size), mobile phase: A for CO2 and B for IPA+CAN (0.1% NH3·H2O), elution: 70% phase B isocratic elution, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25°C, wavelength: 220 nm.

[0089] Compound 3-1, retention time: 1.328 min. 1 H NMR(400MHZ,DMSO-d6)δ 8.86(s,2H),6.48(s,1H),4.88(t,1H),4.67(d,2H),3.70(m,2H),3.17(s,1H) ,3.00-3.06(m,3H),2.92(m,1H),2.38(d,4H),2.13(s,2H),1.96(d,3H),1.87 - 1.71(m,2H),1.58-1.67(m,2H). LCMS(ESI):=463.2[M+H] + . Compound 3-2, retention time: 2.125 min. 1 H NMR(400MHZ,DMSO-d6)δ 8.86(s,2H),6.48(s,1H),4.88(t,1H),4.67(d,2H),3.70(m,2H),3.17(s,1H) ,3.00-3.06(m,3H),2.92(m,1H),2.38(d,4H),2.13(s,2H),1.96(d,3H),1.87 - 1.71(m,2H),1.58-1.67(m,2H). LCMS(ESI):=463.2[M+H] + . Example 5 [ka]

[0090] Step 1: Raw material 4A (15 g, 78.50 mmol), methyl thioglycolate (8.33 g, 78.50 mmol), potassium carbonate (27.12 g, 196.25 mmol), and tetrabutylammonium hydrogen sulfate (8 g, 23.55 mmol) were added to 400 mL of N,N-dimethylformamide solvent, stirred at room temperature overnight, and then filtered. The filtrate was concentrated under reduced pressure to obtain the target compound, which was used directly in the next step. LCMS m / z=217.1[M+1] +

[0091] Step 2: Raw material 4B (2.9 g, 13.41 mmol) was added to thionyl chloride (30 mL), heated to 90°C, stirred for 4 hours, and then concentrated to remove excess thionyl chloride. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The filtrate was dried, filtered, and concentrated. The target compound 4C (3.1 g, 91% yield) was obtained by silica gel column chromatography (PE:EA (v / v) = 1:0 to 6:1). LCMS m / z=253.0[M+1] + 1 H NMR (400MHz, CDCl3) δ8.58(s,1H),3.72(s,3H),3.59(s,2H).

[0092] Step 3: Starting material 4C (3.9 g, 15.41 mmol), starting material 4D (3.32 g, 15.41 mmol), and triethylamine (3.12 g, 30.82 mmol) were added to acetonitrile (70 mL). The mixture was heated to 50°C and stirred for 16 hours. After cooling and concentration, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The target compound 4E (2.6 g, 39% yield) was obtained by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1). LCMS m / z=432.1[M+1] +

[0093] Step 4: 4E (1.3 g, 3.01 mmol) was added to dry tetrahydrofuran (20 mL), and sodium borohydride (0.68 g, 18.06 mmol) was added in an ice bath. The mixture was then slowly warmed to room temperature and stirred for 16 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography (PE:EA (v / v) = 1:0 to 2:3) to obtain the target compound 4F (0.7 g, 57% yield). LCMS m / z=404.2[M+1] +

[0094] Step 5: The raw material 4F (0.6 g, 1.49 mmol) was added to dry dichloromethane (10 mL), and triethylamine (0.45 g, 4.44 mmol) and methylsulfonyl chloride (0.34 g, 2.97 mmol) were added in an ice bath. The mixture was then slowly warmed to room temperature and stirred for 1 hour. Water was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound 4F (0.85 g, 100% yield). LCMS m / z=482.1[M+1] +

[0095] Step 6: Starting material 4G (0.85 g, 1.76 mmol) was added to dry N,N-dimethylformamide (10 mL) and sodium hydride reagent (0.28 g, 7.04 mmol, 60% in oil) was added in an ice bath. The mixture was then slowly warmed to room temperature and stirred for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated and then purified by silica gel column chromatography (PE:EA (v / v) = 1:0 to 8:1) to obtain the target compound 4H (0.45 g, 66% yield). LCMS m / z=386.1[M+1] + 1 H NMR(400MHz,CDCl3)δ7.77(s,1H),3.99(s,2H),3.77-3.80(m,2H),2.83-2 .85(m,2H),2.23-2.28(m,4H),1.67-1.74(m,2H),0.85(s,9H),0.0(s,6H).

[0096] Step 7: Starting material 4H (400 mg, 1.04 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphino) (29 mg, 0.1 mmol), water (19 mg, 1.04 mmol), and titanium tetraisopropoxide (14 mg, 0.051 mmol) were added sequentially to dichloromethane (10 mL) and stirred at room temperature for 0.5 hours. tert-Butanol peroxide (120 mg, 1.35 mmol) was then added and stirred for 3 hours. After dilution with water, the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate, dried, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE:EA (v / v) = 1:0 to 2:3) to obtain target compound 4I (0.40 g, 96% yield). LCMS m / z=402.1[M+1] +

[0097] Step 8: Starting material 4I (0.4 g, 0.99 mmol), starting material 2A (0.29 g, 1.48 mmol), and DIPEA (0.38 g, 2.94 mmol) were added to 1,4-dioxane solvent (20 mL). The mixture was heated to 95°C and stirred for 16 hours. After cooling and concentration, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The target compound 4J (0.5 g, 90% yield) was obtained by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1). LCMS m / z=563.2[M+1] +

[0098] Step 9: The raw material 4J (0.6 g, 1.07 mmol) was dissolved in tetrahydrofuran (20 mL) and tetrabutylammonium fluoride solution (1.6 mL, 1.60 mmol, 1 M) was added. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was purified and separated by silica gel column chromatography (DCM:anhydrous methanol (v / v) = 1:0 to 10:1) to give the title compound 4K (0.3 g, 62% yield). LCMS m / z=449.2[M+1] + 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.16(s,1H),4.93(t,1H),4.62-4.65(m,2H),3.84-3.92(m,2H),3.74-3.79(m,1H),3.56-3.62(m ,1H),3.16-3.22(m,1H),2.98-3.08(m,3H),2.62-2.68(m,1H),2.38-2.41(m,1H),2.24-2.30(m,3H),1.95(d,2H),1.59-1.73(m,4H).

[0099] Step 10: The raw material 4K (300 mg, 0.67 mmol) was purified by chiral HPLC resolution to give the target compound 4-1 (100 mg) and the target compound 4-2 (100 mg).

[0100] Instrument name: Waters 150 SFC, Chromatography column: Chiralcel OD Column (250 × 30 mm, ID 30 mm, 10 μm particle size), Mobile phase: A for CO₂ and B for EtOH + ACN (0.1% NH₃·H₂O), Gradient: 40% B phase isocratic elution, Flow rate: 100 mL / min, Column pressure: 100 bar, Column temperature: 25°C, Absorption wavelength: 220 nm, Cycle time: ~2.9 min, Sample preparation: Dissolve in acetonitrile.

[0101] Compound 4-1 Peak appearance time: 0.578 min LCMS m / z=449.2[M+1] + 1 H NMR(400MHz, DMSO-d6)δ8.85(s,1H),8.16(s,1H),4.93(t,1H),4.62-4.65(m,2H),3.84-3.92(m,2H),3.74-3.79(m,1H),3.56-3.62(m ,1H),3.16-3.22(m,1H),2.98-3.08(m,3H),2.62-2.68(m,1H),2.38-2.41(m,1H),2.24-2.30(m,3H),1.95(d,2H),1.59-1.73(m,4H). Compound 4-2 Pik appearance time: 0.812 min LCMS m / z=449.2[M+1] + 1 H NMR(400MHz, DMSO-d6)δ8.85(s,1H),8.16(s,1H),4.93(t,1H),4.62-4.65(m,2H),3.84-3.92(m,2H),3.74-3.79(m,1H),3.56-3.62(m ,1H),3.16-3.22(m,1H),2.98-3.08(m,3H),2.62-2.68(m,1H),2.38-2.41(m,1H),2.24-2.30(m,3H),1.95(d,2H),1.59-1.73(m,4H). Example 6

change

[0102] Step 1: To a 150 mL sealed tube containing (1-ethoxycyclopropoxy)trimethylsilane (7 g, 40.23 mmol) and acetic acid (1.21 g, 20.12 mol) dissolved in tetraethylene glycol dimethyl ether (30 mL), ethyl (triphenylphosphoranylidene)acetate (14 g, 40.23 mol) dissolved in dichloromethane (6 mL) was added and reacted in an oil bath at 100 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and directly concentrated to remove the dichloromethane. The residue was rapidly separated and purified by column chromatography (eluent ratio: EA / PE = 0% to 10%) to obtain the target compound 5B (4 g, 79%).

[0103] Compound 5B and ethyl thioglycolate were used as starting materials, and the procedure of Example 1 was followed to obtain compound 5 (50 mg, 33%).

[0104] Chiral resolution of compound 5: Compound 5 (50 mg) was taken and used for resolution, and after separation, compound 5-1 (retention time: 1.257 s, 15 mg, ee%=100%) and compound 5-2 (retention time: 1.553 s, 17 mg, ee%=100%) were obtained.

[0105] The division conditions are as follows:

[0106] Instrument: Waters 150 MGM, Column: DAICEL CHIRALPAK AD, Mobile phase: A for CO2 and B for EtOH(0.1%NH3·H2O)), gradient: B 40%, flow rate: 120mL / min, back pressure: 100 bar, Column temperature: 35°C, wavelength: 220 nm, cycle: 13 min, Compound 5-1: 1H NMR(400MHz,CDCl3)δ=8.62(s,2H),5.85(s,1H),4.79(d,2H),3.87(s,2H),3.67 (d,1H),3.17(tt,1H),3.07(t,2H),2.73(d,1H),2.29(t,4H),2.06(d,2H),1.92 - 1.80(m,3H),1.61 - 1.57(m,1H),1.39 - 1.30(m,2H),1.11(t,1H),1.08 - 1.04(m,1H),0.84(d,1H). Compound 5-2: 1 H NMR(400MHz,CDCl3)δ=8.62(s,2H),6.00(s,1H),4.80(d,2H),3.86(d,2H),3.68(d,1H),3.17(tt,3.8,1H),3.07(t,2H),2.72(d,1H),2.35 - 2.24(m,4H),2.06(d,2H),1.88 - 1.80(m,3H),1.62 - 1.56(m,1H),1.39 - 1.30(m,1H),1.17 - 1.09(m,1H),1.07 - 1.00(m,1H),0.92 - 0.79(m,1H). Example 7 [ka]

[0107] Compound 6C (35 g, 97%) was obtained using compound 3A and methyl acrylate as starting materials, following the procedures of Example 1 (reactions in steps 1 and 2). LC-MS(ESI): m / z=161.1[M+H] +

[0108] Step 3: Compound 6C (30 g, 187.5 mmol) was dissolved in methanol (300 mL) at room temperature. Malononitrile (18.56 g, 281.2 mmol) and imidazoline (38.25 g, 562.5 mmol) were added at room temperature and the mixture was stirred for 3 h. After the reaction was complete, most of the methanol was removed by shaking. Water (50 mL) was added and the mixture was extracted twice with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent ratio: EA:PE = 0% to 50%) to give the title compound 6D (26.7 g, 69%). LC-MS(ESI): m / z=209.1[M+H] +

[0109] Step 4: In a nitrogen atmosphere, compound 6D (12 g, 61.86 mmol) was dissolved in hydrogen chloride-dioxane solution (4 M, 100 mL) at room temperature, and the temperature was raised to 100 ° C. and the reaction was continued overnight. A large amount of solid precipitated. After the reaction was completed, the solid was filtered and spin-dried to obtain crude compound 6E (9 g, 80%), which was used directly in the next step without further purification. LC-MS(ESI): m / z=195.1[M+H] +

[0110] Step 5: Compound 6E (2 g, 10.31 mmol) was added to a 120 mL sealed tube containing phosphorus oxychloride (20 mL) at room temperature. Trimethylbenzylammonium chloride (3.83 g, 20.62 mmol) was added at room temperature, and the mixture was heated to 150 °C and reacted for 7 h. After the reaction was completed, the reaction mixture was slowly added to saturated sodium bicarbonate solution (100 mL) in an ice bath and extracted twice with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent ratio: EA:PE = 0% to 50%) to give the title compound 6F (1.1 g, 46%).

[0111] Step 6: Compound 6F (1.1 g, 4.78 mmol) was dissolved in 1,4-dioxane (12 mL) at room temperature, and N,N-diisopropylethylamine (1.23 g, 9.56 mmol) and (1-aminocyclobutyl)methanol hydrochloride (0.65 g, 4.78 mmol) were added at room temperature. The mixture was then heated to 100 °C and reacted overnight. After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent ratio: MeOH:DCM = 0% to 10%) to give the title compound 6G (600 mg, 43%). LC-MS(ESI): m / z=296.3[M+H] +

[0112] Step 7: Compound 6G (600 mg, 2.03 mmol) was dissolved in acetic acid (30 mL) at room temperature, and 30% hydrogen peroxide (1.0 mL) was added at room temperature and reacted for 2 h. After the reaction was completed, saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted twice with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent ratio: MeOH:DCM = 0% to 10%) to give the title compound 6H (300 mg, 47%). LC-MS(ESI): m / z=312.3[M+H] +

[0113] Step 8: Compound 6H (150 mg, 0.48 mmol) was dissolved in 1,4-dioxane (2.0 mL) at room temperature. N,N-diisopropylethylamine (124 mg, 0.96 mmol) and 4-(4-chlorophenyl)piperidine (94 mg, 0.48 mmol) were added at room temperature, and the mixture was heated to 100 °C and reacted overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was separated by preparative HPLC to obtain racemic compound 6 (70 mg, 31%). The separation method was as follows: 1. Equipment: Waters 2767 Preparative Liquid Chromatography, Chromatography Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, with the content of mobile phase A ranging from 10% to 55%. c. Flow rate: 12 mL / min.

[0114] Chiral preparative separation of the racemic compound. Preparative chromatography conditions: 1. Instrument: Waters 150 SFC, 2. Chromatographic column: Chiralpak IC-Column (250 × 30 mm, ID 30 mm, 10 μm particle size), 3. Mobile phase system: A for CO₂ and B for MeOH (0.1% NH₃·H₂O), 4. Gradient: B 35%, 5. Flow rate: 100 mL / min. After preparation, title compound 6-1 (30 mg, 13.3%, retention time: 1.092 min, absolute configuration not determined) and title compound 6-2 (31 mg, 13.7%, retention time: 1.761 min, absolute configuration not determined) were obtained.

[0115] Compound 6-1 1H NMR(400MHz,Methanol-d4)δ 7.22 - 7.16(m,2H),7.16 - 7.10(m,2H),4.66 - 4.57(m,2H),3.82(q,2H),3.71 - 3.61(m,1H),3.40 - 3.26(m,2H),3.17 - 3.02(m,3H),2.79(tt,1H),2.35 - 2.08(m,4H),1.90 - 1.70(m,4H),1.70 - 1.57(m,2H). LC-MS(ESI): m / z=471.1[M+H] + Compound 6-2 1 H NMR(400MHz,Methanol-d4)δ 7.33 - 7.27(m,2H),7.26 - 7.21(m,2H),4.77 - 4.67(m,2H),3.92(q,2H),3.81 - 3.70(m,1H),3.49 - 3.36(m,2H),3.27 - 3.12(m,3H),2.89(tt,1H),2.43 - 2.24(m,4H),1.98 - 1.82(m,4H),1.80 - 1.68(m,2H). LC-MS(ESI): m / z=471.1[M+H] + Example 8 [ka]

[0116] Using compounds 6H and 2A as starting materials, racemic compound 7 (80 mg, 35%) was obtained by following the procedure in Example 2. The separation method was as follows: 1. Equipment: Waters 2767 preparative liquid chromatography, chromatography column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, with the content of mobile phase A ranging from 10% to 55%. c. Flow rate: 12 mL / min.

[0117] Chiral preparative separation of the racemic compound. Preparative chromatography conditions: 1. Instrument: Waters 150 SFC, 2. Chromatographic column: Chiralpak IC-Column (250 × 30 mm, ID 30 mm, 10 μm particle size), 3. Mobile phase system: A for CO₂ and B for MeOH (0.1% NH₃·H₂O), 4. Gradient: B 35%, 5. Flow rate: 100 mL / min. After preparation, title compound 7-1 (31 mg, 13.6%, retention time: 1.400 min, absolute configuration not determined) and title compound 7-2 (33 mg, 14.5%, retention time: 1.681 min, absolute configuration not determined) were obtained.

[0118] Compound 7-1 1 H NMR(400MHz,Methanol-d4)δ 8.75(s,2H),4.66(dt,2H),3.92(q,2H),3.81 - 3.71(m,1H),3.50 - 3.36(m,2H),3.30 - 3.19(m,4H),2.42 - 2.24(m,4H),2.10(dd,2H),1.99 - 1.83(m,4H). LC-MS(ESI): m / z=473.2[M+H] + Compound 7-2 1 H NMR(400MHz,Methanol-d4)δ 8.75(s,2H),4.67(dd,2H),4.55(s,1H),3.92(q,2H),3.82 - 3.70(m,1H),3.50 - 3.36(m,2H),3.27 - 3.21(m,3H),2.42 - 2.24(m,4H),2.10(dd,2H),2.01 - 1.79(m,4H). LC-MS(ESI): m / z=473.2[M+H] + Example 9 [ka]

[0119] Step 1: Compound 3H (3.7 g, 12.3 mmol) was separated using a chiral column to obtain compounds 8A-P1 (1.1 g, 30%) and 8A-P2 (0.9 g, 24%). The chiral separation method was as follows: Instrument: Waters 150 SFC; Column: Chiralpak IC Column (250 × 30 mm, ID 30 mm, 10 μm particle size); Mobile phase: A for CO₂ and B for IPA + ACN (0.1% NH₃·H₂O); Gradient: 45% phase B isocratic elution; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25 °C; Wavelength: 220 nm.

[0120] Compound 8A-P1, retention time: 0.614min. 1 H NMR(400MHZ,DMSO-d6)δ 7.58(s,1H),4.91(t,1H),3.68(d,2H),3.25-3.18(m,1H),3.11-3.03(m,1H),2.86 - 2.76(m,1H),2.73 - 2.61(m,1H),2.37 - 2.23(m,3H),2.17(m,2H),2.09 - 1.93(m,1H),1.87 - 1.68(m,2H). LCMS(ESI):=302.1[M+H] + . Compound 8A-P2, retention time: 1.148min. 1 H NMR(400MHZ,DMSO-d6)δ 7.58(s,1H),4.91(t,1H),3.68(d,2H),3.25-3.18(m,1H),3.11-3.03(m,1H),2.86 - 2.76(m,1H),2.73 - 2.61(m,1H),2.37 - 2.23(m,3H),2.17(m,2H),2.09 - 1.93(m,1H),1.87 - 1.68(m,2H). LCMS(ESI):=302.1[M+H] + .

[0121] Step 2: Compound 8A-P1 (0.10 g, 0.33 mmol), 8B (77 mg, 0.40 mmol, see CN103145607 for synthetic method), and DIPEA (0.13 mg, 0.99 mmol) were dissolved in dioxane (10 mL) and stirred at 85 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by HPLC to give compound 8-1 (60 mg, 40%).

[0122] Preparative method: Instrument: Abilene 1290 Infinity II Preparative Liquid Chromatography; Chromatography column: XSelect@Prep C18 (19 mm x 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: 5 mmol ammonium acetate; Mobile phase B: methanol; Gradient elution; Mobile phase B content: 50% to 85%; Flow rate: 15 mL / min; Elution time: 18 min; Retention time: 16.8 min.

[0123] Compound 8-1, 1 H NMR(400MHZ,DMSO-d6)δ 7.48(d,2H),7.40(d,2H),6.53(s,1H),6.31(s,1H),4.91(t,1H),4.33(s, 2H),3.94(t,2H),3.73(d,2H),3.10-3.05(m,1H),2.95-2.88(m,1H),2.74 - 2.51(m,4H),2.46-2.33(m,3H),2.17(brs,2H),2.02-1.91(m,1H),1.87-1.77(m,2H). The synthesis, preparation and separation of compound 8-2 (45 mg, 36%) was the same as that of compound 8-1.

[0124] compound 8-2, 1H NMR(400MHZ,DMSO-d6)δ 7.48(d,2H),7.40(d,2H),6.53(s,1H),6.31(s,1H),4.91(t,1H),4.33(s, 2H),3.94(t,2H),3.73(d,2H),3.10-3.05(m,1H),2.95-2.88(m,1H),2.74 - 2.51(m,4H),2.46-2.33(m,3H),2.17(brs,2H),2.02-1.91(m,1H),1.87-1.77(m,2H). LCMS(ESI):=459.50[M+H] + . Example 10 [ka]

[0125] Step 1: Substrate 9A (5.0 g, 20.77 mmol), dioxane (100 mL), and water (20 mL) were dissolved in a 250 mL single-neck flask. Sodium carbonate (6.6 g, 62.31 mmol), 9B (7.1 g, 22.85 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.5 g, 2.08 mmol) were added and stirred overnight at 100 °C under nitrogen gas protection. The reaction mixture was diluted with water (50 mL), filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to give the title compound 9C (5.0 g, 81%). LC-MS(ESI): m / z=240.1[M-56+H]+.

[0126] Step 2: Substrate 9C (1.0 g, 3.38 mmol), methanol (5 mL), and HCl-dioxane (4 M, 5 mL) were added to a 50 mL single-neck flask to dissolve the compound, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to give the title compound 9D (0.79 g, 100%). LC-MS(ESI): m / z=196.2[M+H] + .

[0127] Step 3: Compound 8A-P1 (0.10 g, 0.33 mmol), 9D (77 mg, 0.40 mmol), and DIPEA (0.13 mg, 0.99 mmol) were dissolved in dioxane (10 mL) and stirred at 85 °C for 16 h. After the reaction was completed, the solvent was removed and compound 9-1 (70 mg, 46%) was obtained by HPLC preparative analysis.

[0128] Preparative method: Instrument: Abilene 1290 Infinity II Preparative Liquid Chromatography; Chromatography column: XSelect@Prep C18 (19 mm x 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: 5 mmol ammonium acetate; Mobile phase B: methanol; Gradient elution; Mobile phase B content: 50% to 85%; Flow rate: 15 mL / min; Elution time: 18 min; Retention time: 16.5 min.

[0129] The synthesis and isolation conditions for compound 9-2 (60 mg, 48%) were the same as those for compound 9-1.

[0130] Compound 9-1, 1 H NMR(400MHZ,DMSO-d6)δ 8.89(s,2H),7.32 - 7.24(m,1H),6.54(s,1H),4.90(t,1H),4.43(s,2H),3.94(t,2H),3.73(d,2H),3.10-3.04(m,1H),2.95-2.88(m,1H),2.71 - 2.53(m,4H),2.45 - 2.27(m,3H),2.22 - 2.09(m,2H),2.02 - 1.91(m,1H),1.88 - 1.69(m,2H). compound 9-2, 1H NMR(400MHZ,DMSO-d6)δ 8.89(s,2H),7.32 - 7.24(m,1H),6.54(s,1H),4.90(t,1H),4.43(s,2H),3.94(t,2H),3.73(d,2H),3.10-3.04(m,1H),2.95-2.88(m,1H),2.71 - 2.53(m,4H),2.45 - 2.27(m,3H),2.22 - 2.09(m,2H),2.02 - 1.91(m,1H),1.88 - 1.69(m,2H). LCMS(ESI):=461.50[M+H] + . Example 11 [ka]

[0131] Step 1: Compound 3H (150 mg, 0.50 mmol), 4-(4-chlorophenyl)piperidine hydrochloride (131 mg, 0.55 mmol), and DIPEA (260 mg, 2.00 mmol) were dissolved in dioxane and reacted at 90 °C for 16 h. After the reaction was completed, the solvent was removed, and compound 10-1 (44.3 mg, 19%) and 10-2 (26.5 mg, 11%) were obtained by SFC preparative separation.

[0132] Chiral separation method: Instrument: Waters 150 SFC, Column: Chiralcel OX Column (250 x 30 mm, ID 30 mm, 10 μm particle size), Mobile phase: A for CO2 and B for EtOH + ACN, Gradient: 45% phase B isocratic elution, Flow rate: 120 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm.

[0133] Compound 10-1, retention time: 1.128min. 1H NMR(400MHZ,DMSO-d6)δ 7.38 - 7.29(m,2H),7.30 - 7.20(m,2H),6.47(s,1H),4.90(t,1H),4.77(d,2H),3.70(d,,2H),3.10-3.03(m,1H),2.54-2.51(m,1H),2.98 - 2.79(m,4H),2.72 - 2.61(m,1H),2.45-2.30(m,3H),2.18 - 2.08(m,2H),2.03 - 1.89(m,1H),1.83-1.71(m,4H),1.55 - 1.41(m,2H). LCMS(ESI):=461.2[M+H] + . Compound 10-2, retention time: 1.609min. 1 H NMR(400MHZ,DMSO-d6)δ 7.38 - 7.29(m,2H),7.30 - 7.20(m,2H),6.47(s,1H),4.90(t,1H),4.77(d,2H),3.70(d,2H),3.10-3.03(m,1H),2.54-2.51(m,1H),2.98 - 2.79(m,4H),2.72 - 2.61(m,1H),2.45-2.30(m,3H),2.18 - 2.08(m,2H),2.03 - 1.89(m,1H),1.83-1.71(m,4H),1.55 - 1.41(m,2H). LCMS(ESI):=461.2[M+H] + . Example 12 [ka]

[0134] Step 1: Compound 3H (150 mg, 0.50 mmol), 4-(4-chlorophenyl)piperazine hydrochloride (131 mg, 0.55 mmol), and DIPEA (260 mg, 2.00 mmol) were dissolved in dioxane and reacted at 90 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure and fractionated by SFC to give compounds 11-1 (29.2 mg, 13%) and 11-2 (39.9 mg, 17%).

[0135] Chiral fractionation method: Instrument: Waters 150 SFC, cartridge: Chiralcel OX Column (250×30 mm, ID 30 mm, 10 μm particle size), mobile phase: A for CO2 and B for EtOH+ACN (0.1% NH3·H2O), elution: 45% phase B isocratic elution, flow rate: 120 mL / min, back pressure: 100 bar, cartridge temperature: 25°C, wavelength: 220 nm.

[0136] Compound 11-1, retention time: 1.192 min. 1 H NMR(400MHZ,DMSO-d6)δ 7.42 - 7.17(m,2H),7.12 - 6.84(m,2H),6.55(s,1H),4.89(t,1H),3.84(t,4H),3.71(d,2H),3.18-3.13(m,4H),3.10-3.04(m,1H),2.95-2.87(m,1H),2.74 - 2.63(m,1H),2.61-2.51(m,1H),2.46 - 2.23(m,3H),2.23 - 2.10(m,2H),2.00-1.94(m,1H),1.91 - 1.67(m,2H). LCMS(ESI):=462.2[M+H] + . Compound 11-2, retention time: 1.766 min. 1 H NMR(400MHZ,DMSO-d6)δ 7.42 - 7.17(m,2H),7.12 - 6.84(m,2H),6.55(s,1H),4.89(t,1H),3.84(t,4H),3.71(d,2H),3.18-3.13(m,4H),3.10-3.04(m,1H),2.95-2.87(m,1H),2.74 - 2.63(m,1H),2.61-2.51(m,1H),2.46 - 2.23(m,3H),2.23 - 2.10(m,2H),2.00-1.94(m,1H),1.91 - 1.67(m,2H). LCMS(ESI):=462.2[M+H] + . Example 13

change

[0137] Step 1: Compound 12A (3.00 g, 20.10 mmol) and compound 12B (3.74 g, 20.10 mmol) were weighed and placed in a 100 mL one-neck flask. 1,4-Dioxane (30 mL) was added to dissolve the compound. N,N-Diisopropylethylamine (7.79 g, 60.30 mmol) was added to the reaction mixture. After the addition was complete, the mixture was stirred at 80 °C for 16 h. TLC spot plate (petroleum ether: ethyl acetate = 5:1) showed a complete reaction. Water (20 mL) was added to the reaction mixture, the mixture was stirred for 5 min, and ethyl acetate (20 mL) was added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 12C (3.0 g, yield: 50%). LCMS m / z=299.1[M+1] +

[0138] Step 2: Compound 12C (1.0 g, 3.35 mmol) was weighed and placed in a 100 mL single-neck flask. Then, methanol (10 mL) was added to dissolve the compound. A 4N solution of hydrochloric acid in dioxane (10 mL) was added. After the addition was complete, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure until no droplets remained, yielding the target compound 12D (0.80 g, crude). LCMS m / z=199.1[M+1] +

[0139] Step 3: Compound 8A-P1 (80 mg, 0.27 mmol), compound 12D (65 mg, 0.33 mmol), and N,N-diisopropylethylamine (0.10 g, 0.77 mmol) were added to a 100 mL single-neck flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude target compound, which was then purified by preparative HPLC to give the title compound 12-1 (60 mg, 48%).

[0140] Preparative method: Instrument: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm), Sample: Dissolve in DMF and filter through a 0.45 μm filter to prepare the sample solution. Preparative Chromatography Conditions: a) Mobile Phase A and B: Acetonitrile, B: Water (containing 5 mM aqueous ammonia), b) Gradient elution, Mobile Phase A content: 35% to 80%, c) Flow rate: 15 mL / min, d) Elution time: 20 min, Retention time: 13.50 min.

[0141] The synthesis, preparation and separation of compound 12-2 (58 mg, 47%) was the same as that of compound 12-1.

[0142] LCMS m / z=464.2[M+1] + Compound 12-1, 1 H NMR(400MHZ,DMSO-d6)δ 8.44(d,2H),6.55(s,1H),4.88(t,1H),3.73-3.82(m,8H),3.70(d,2H),3.04-3.10(m,1H),2.88-2.95( m,1H),2.54-2.70(m,2H),2.29-2.44(m,3H),2.10-2.19(m,2H),1.90-2.00(m,1H),1.72-1.85(m,2H). Compound 12-2, 1 H NMR(400MHZ,DMSO-d6)δ 8.44(d,2H),6.55(s,1H),4.88(t,1H),3.73-3.82(m,8H),3.70(d,2H),3.04-3.10(m,1H),2.88-2.95( m,1H),2.54-2.70(m,2H),2.29-2.44(m,3H),2.10-2.19(m,2H),1.90-2.00(m,1H),1.73-1.87(m,2H). Example 14 [ka]

[0143] Step 1: Compound 13A (1.00 g, 5.45 mmol) and compound 13B (1.16 g, 5.45 mmol) were weighed and placed in a 100 mL one-neck flask. 1,4-Dioxane (30 mL) was added to dissolve the compounds. The reaction mixture was then diluted with sodium tert-butanol (1.57 g, 16.34 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.27 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphino (0.34 g, 0 0.55 mmol) was added, and after the addition was complete, the mixture was stirred at 90 degrees for 16 hours. The TLC spot plate (petroleum ether: ethyl acetate = 5:1) was checked for complete reaction. Water (20 mL) was added to the reaction mixture, stirred for 5 minutes, and ethyl acetate (20 mL) was added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 13C (1.0 g, yield: 58%). LCMS m / z=315.1[M+1] +

[0144] Step 2: Compound 13C (0.30 g, 0.95 mmol) was weighed into a 100 mL single-neck flask, and then methanol (10 mL) was added to dissolve the compound. A 4N solution of hydrochloric acid in dioxane (10 mL) was added, and the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure until no droplets remained, yielding the target compound 13D (0.20 g, crude). LCMS m / z=215.1[M+1] +

[0145] Step 3: Compound 8A-P1 (80 mg, 0.27 mmol), compound 13D (69 mg, 0.32 mmol), and N,N-diisopropylethylamine (0.10 g, 0.77 mmol) were added to a 100 mL single-neck flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude target compound, which was then purified by preparative HPLC to give the title compound 13-1 (12 mg, 9%).

[0146] Preparative method: Instrument: Water 2767 preparative liquid. Chromatography column: SunFire@Prep C18 (19 mm x 250 mm). Samples were dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: a. Mobile phases A and B: acetonitrile, B: water (containing 5 mM aqueous ammonia). b. Gradient elution: Mobile phase A content: 45% to 85%. c. Flow rate: 15 mL / min. d. Elution time: 20 min, retention time: 12.80 min.

[0147] The synthesis, preparation and separation of compound 13-2 (40 mg, 30%) was the same as that of compound 13-1. LCMS m / z=480.2[M+1] +

[0148] Compound 13-1, 1 H NMR(400MHz,DMSO-d6)δ 6.84(d,1H),6.45(s,1H),6.33-6.37(m,2H),4.88(t,1H),3.67-3.79(m,4H),3.36-3. 46(m,4H),3.11(d,2H),2.97-3.01(m,7H),2.85-2.92(m,1H),2.53-2.67(m,2H),2.25 -2.46(m,3H),2.05 -2.15(m,2H),1.89-1.98(m,1H),1.69 -1.85(m,2H). Compound 13-2, 1 H NMR(400MHz,DMSO-d6)δ 6.84(d,1H),6.45(s,1H),6.33-6.37(m,2H),4.88(t,1H),3.67-3.79(m,4H),3.36-3. 46(m,4H),3.11(d,2H),2.97-3.01(m,7H),2.85-2.91(m,1H),2.53-2.67(m,2H),2.25 -2.46(m,3H),2.05 -2.15(m,2H),1.89-1.98(m,1H),1.69 -1.84(m,2H). Example 15 [ka]

[0149] Compound 14-1 (76 mg, 59.6%) was obtained using compound (3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester and 9A as starting materials, following the procedure of Example 13.

[0150] The synthesis and purification of compound 14-2 (83 mg, 65.1%) was the same as that of compound 14-1.

[0151] Compound 14-1: 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,2H),6.46(s,1H),4.95 - 4.81(m,1H),3.81 - 3.64(m,6H),3.46 - 3.34(m,4H),3.12 - 3.00(m,3H),2.95 - 2.82(m,1H),2.71 - 2.54(m,2H),2.45 - 2.25(m,3H),2.18 - 2.05(m,2H),2.00 - 1.88(m,1H),1.88 - 1.64(m,2H). Compound 14-2: 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,2H),6.46(s,1H),4.91 - 4.83(m,1H),3.82 - 3.62(m,6H),3.47 - 3.36(m,4H),3.15 - 3.02(m,3H),2.94 - 2.81(m,1H),2.70 - 2.52(m,2H),2.47 - 2.24(m,3H),2.18 - 2.05(m,2H),2.03 - 1.89(m,1H),1.88 - 1.63(m,2H). LC-MS(ESI): m / z=490.6[M+H] + . Example 16 [ka]

[0152] Step 1: 8A-P1 (80 mg, 0.26 mmol) and 6B (120 mg, see WO2020099886 for synthetic methods) were dissolved in 1,4-dioxane (10 mL), DIPEA (0.5 mL) was added, and the mixture was heated at 90 °C overnight. Complete reaction of the raw materials was confirmed by LCMS, and the mixture was concentrated, water (100 mL) was added, and the mixture was extracted with a mixture of DCM:MeOH = 20:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Compound 15-1 (84 mg, 66.2%) was obtained by column chromatography (DCM:MeOH = 1:0 to 0:1).

[0153] The synthesis and purification of compound 15-2 (88 mg, 69.8%) was the same as that of compound 15-1.

[0154] Compound 15-1: 1 H NMR(400MHz,DMSO-d6)δ 7.21 - 7.10(m,2H),6.58 - 6.50(m,2H),6.46(s,1H),4.92 - 4.85(m,1H),3.84 - 3.73(m,2H),3.73 - 3.65(m,2H),3.51 - 3.43(m,2H),3.43 - 3.35(m,2H),3.20 - 3.12(m,2H),3.11 - 3.00(m,3H),2.93 - 2.81(m,1H),2.69 - 2.59(m,1H),2.58 - 2.51(m,1H),2.47 - 2.25(m,3H),2.16 - 2.04(m,2H),1.99 - 1.88(m,1H),1.87 - 1.64(m,2H). Compound 15-2: 1H NMR(400MHz,DMSO-d6)δ 7.20 - 7.11(m,2H),6.58 - 6.50(m,2H),6.46(s,1H),4.93 - 4.84(m,1H),3.81 - 3.72(m,2H),3.72 - 3.64(m,2H),3.52 - 3.43(m,2H),3.43 - 3.34(m,2H),3.22 - 3.11(m,2H),3.11 - 3.02(m,3H),2.91 - 2.80(m,1H),2.68 - 2.59(m,1H),2.58 - 2.52(m,1H),2.48 - 2.29(m,3H),2.16 - 2.03(m,2H),1.99 - 1.87(m,1H),1.87 - 1.64(m,2H). LC-MS(ESI): m / z=488.6[M+H] + . Example 17 [ka]

[0155] Compound 16-1 (50 mg, 20%) was obtained from compounds 16A and 16B by following the procedure of Example 10.

[0156] The synthesis of compound 16-2 (50 mg, 20%) was carried out using 8A-P2 as the starting material, and the preparation and separation procedures were the same as those for compound 16-1.

[0157] Preparative method: Instrument: SHIMADZU LC-20AP, Chromatography column: Phenomenex C18. The sample was dissolved in acetonitrile and water and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: 10 mmol ammonium bicarbonate, Mobile phase B: acetonitrile. Gradient elution was performed, with the content of mobile phase B ranging from 30% to 60%, the flow rate was 25 ml / min, the elution time was 15 min, and the retention time was 3.3 min.

[0158] Compound 16-1, 1H NMR(400MHz,DMSO-d6)δ 7.34(s,4H),6.45(s,1H),6.03(t,1H),4.88(t,1H),3.92(brs,2H),3.83(brs,2H),3.70(d,2H),3 .09-3.03(m,1H),2.94-2.87(m,1H),2.72-2.63(m,3H),2.59-2.52(m,1H),2.51-2.45(m,2H),2.43 - 2.26(m,3H),2.14-2.10(m,2H),1.97-1.92(m,1H),1.83-1.74(m,2H). compound 16-2, 1 H NMR(400MHz,DMSO-d6)δ 7.34(s,4H),6.45(s,1H),6.03(t,1H),4.88(t,1H),3.92(brs,2H),3.83(brs,2H),3.70(d,2H),3 .09-3.03(m,1H),2.94-2.87(m,1H),2.72-2.63(m,3H),2.59-2.52(m,1H),2.51-2.45(m,2H),2.43 - 2.26(m,3H),2.14-2.10(m,2H),1.97-1.92(m,1H),1.83-1.74(m,2H). LCMS(ESI):=473.2[M+H] + . Example 18 [ka]

[0159] Compound 17-1 (30 mg, 12%) was obtained from compounds 17A and 16B by following the procedure of Example 10.

[0160] The synthesis of compound 17-2 (48 mg, 19%) was carried out using 8A-P2 as the starting material, and the preparation and separation procedures were the same as those for compound 17-1.

[0161] Preparative method: Instrument: Waters 150 SFC, Chromatography column: Chiralpak IG Column (250 × 30 mm, ID 30 mm, 10 μm particle size), Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: EtOH + ACN (0.1% NH3 · H2O), b. Isocratic elution, content of mobile phase B is 65%, c. Flow rate 100 mL / min, d. Elution time 15 min, e. Back pressure 100 bar, f. Column temperature: 25 degrees Celsius.

[0162] Compound 17-1, 1 H NMR(400MHz,DMSO-d6)δ 8.84(s,2H),7.38(s,1H),6.45(s,1H),4.91(t,1H),3.88-3.86(m,4H),3.71(d,2H),3.09-3.00(m,3H),2.91-2.87(m,1H),2.71 - 2.52(m,4H),2.46 - 2.24(m,3H),2.16-2.07(m,2H),2.02 - 1.91(m,1H),1.86 - 1.68(m,2H). Compound 17-2, 1 H NMR(400MHz,DMSO-d6)δ 8.84(s,2H),7.38(s,1H),6.45(s,1H),4.91(t,1H),3.88-3.86(m,4H),3.71(d,2H),3.09-3.00(m,3H),2.91-2.87(m,1H),2.71 - 2.52(m,4H),2.46 - 2.24(m,3H),2.16-2.07(m,2H),2.02 - 1.91(m,1H),1.86 - 1.68(m,2H). LCMS(ESI):=475.1[M+H] + . Example 19 [ka]

[0163] Step 1: Compound 18A (1.50 g, 13.62 mmol) and di-tert-butyl dicarbonate (5.95 g, 27.24 mmol) were weighed and placed in a 100 mL one-neck flask. Water (30 mL) was added to dissolve the mixture. Sodium bicarbonate (3.43 g, 40.86 mmol) was added to the reaction mixture. After the addition was complete, the mixture was stirred for 16 h. TLC spot plate (petroleum ether:ethyl acetate = 5:1) showed a complete reaction. The solid precipitated from the reaction mixture was directly filtered to obtain the target compound 18B (1.5 g, yield: 35%). 1 H NMR(400MHZ,DMSO-d6)δ 3.96-4.06(m,8H),1.42(s,18H).

[0164] Step 2: Compound 18B (1.50 g, 4.83 mmol) and p-toluenesulfonic acid (0.83 g, 4.83 mmol) were weighed and placed in a 100 mL single-neck flask. Isopropyl acetate (30 mL) was added to dissolve the compound, and the mixture was stirred at 60 °C for 4 h. The TLC spot plate (petroleum ether: ethyl acetate = 3:1) was then screened for complete reaction. The solid precipitated from the reaction solution was directly filtered to obtain the target compound 18C (1.5 g, yield: 100%). 1 H NMR(400MHZ,DMSO-d6)δ 3.96-4.03(m,8H),1.42(s,9H).

[0165] Step 3: Compound 18C (0.30 g, 1.43 mmol) and 2-chloro-5-chloropyrimidine (0.21 g, 1.43 mmol) were weighed and placed in a 100 mL one-neck flask. 1,4-Dioxane (20 mL) was added to dissolve the compound. N,N-Diisopropylethylamine (0.55 g, 4.26 mmol) was added to the reaction mixture. After the addition was complete, the mixture was stirred at 80 °C for 16 h. TLC spot plate (petroleum ether: ethyl acetate = 5:1) showed a complete reaction. Water (20 mL) was added to the reaction mixture, the mixture was stirred for 5 min, and ethyl acetate (20 mL) was added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 18D (0.2 g, yield: 43%). LCMS m / z=323.1[M+1] +

[0166] Step 4: Compound 18D (0.2 g, 0.62 mmol) was weighed into a 100 mL single-neck flask, and then methanol (10 mL) was added to dissolve the compound. A 4N solution of hydrochloric acid in dioxane (10 mL) was added, and the mixture was stirred for 2 h after the addition. The organic phase was concentrated under reduced pressure until no droplets remained, yielding the target compound 18E (0.15 g, crude). LCMS m / z=223.1[M+1] +

[0167] Step 5: Compound 8A-P2 (single configuration, configuration not determined) (150 mg, 0.50 mmol), compound 18E (110 mg, 0.50 mmol), and N,N-diisopropylethylamine (0.20 g, 1.51 mmol) were added to a 100 mL single-neck flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude target compound, which was then purified by preparative HPLC to give the title compound 18 (single configuration, configuration not determined) (30 mg, 12%).

[0168] Preparative method: Instrument: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm), Sample: Dissolve in DMF and filter through a 0.45 μm filter to prepare the sample solution. Preparative Chromatography Conditions: a) Mobile Phase A and B: Acetonitrile, Mobile Phase B: Water (containing 5 mM aqueous ammonia), b) Gradient elution, Mobile Phase A content: 30% to 70%, c) Flow rate: 15 mL / min, d) Elution time: 20 min, Retention time: 10.80 min.

[0169] LCMS m / z=488.1[M+1] + 1 H NMR(400MHZ,DMSO-d6)δ 8.45(d,2H),6.54(s,1H),4.90(t,1H),4.30(m,8H),3.73(d,2H),3.04-3.11(m,1H),2.88-2.95( m,1H),2.58-2.72(m,2H),2.32-2.44(m,3H),2.15(s,2H),1.91-2.00(m,1H),1.71-1.88(m,2H). Example 20 [ka]

[0170] Step 1: Compound 19A (1 g, 4.44 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), purged with nitrogen gas three times, cooled to -78 °C, and lithium bis(trimethylsilyl)amide (8.88 mmol) was added dropwise. The mixture was maintained at -78 °C for 30 min, followed by N-phenylbis(trifluoromethanesulfonimide) (2.59 g, 6.66 mmol) dissolved in anhydrous tetrahydrofuran (5 ml). The mixture was maintained at -78 °C for 30 min, then cooled to room temperature and reacted for 2 h. Upon completion of the reaction, saturated ammonium chloride solution (30 ml) was added to quench the reaction. The organic phase was extracted with ethyl acetate (3 × 40 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and rapidly separated and purified by column chromatography (eluent ratio: EA / PE = 0% to 10%) to give compound 19B (1.3 g, 82%). LCMS(ESI): m / z=302.2[M+H-56] +

[0171] Step 2: Compound 19B (1.3 g, 3.64 mmol) was dissolved in 1,4-dioxane (20 mL) under nitrogen gas. Bistriphenylphosphinepalladium dichloride (260 mg, 0.37 mmol), bis(pinacolato)diboron (1.11 g, 4.37 mmol), and potassium acetate (1.07 g, 10.92 mmol) were added and reacted in an oil bath at 90 °C for 18 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was concentrated and directly purified by column chromatography (eluent ratio: EA / PE = 0% to 10%) to give the desired compound 19C (0.89 g, 73%). LCMS(ESI): m / z=280.2[M+H-56] +

[0172] Step 3: Compound 19C (0.89 g, 2.65 mmol) was dissolved in 1,4-dioxane / water (10 mL / 2 mL) under nitrogen gas. 5-Chloro-2-iodobenzene (574 mg, 2.41 mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (176 mg, 0.24 mmol), and sodium carbonate (766 mg, 7.32 mmol) were added and reacted in an oil bath at 90 °C for 18 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was concentrated and directly purified by column chromatography (eluent ratio: EA / PE = 0% to 10%) to give compound 19D (0.44 g, 52%). LCMS(ESI): m / z=264.2[M+H-56] +

[0173] Step 4: Compound 19D (220 mg, 0.69 mmol) was dissolved in 1,4-dioxane (2 mL) of hydrochloric acid, stirred at room temperature for 1 h, and then directly spun to dryness to give the hydrochloride salt of compound 19E (170 mg). LCMS(ESI): m / z=220.1[M+H] +

[0174] Step 5: Intermediate 8A-P2 (single configuration, configuration not determined) (100 mg, 0.33 mmol) was dissolved in 1,4-dioxane (5 mL), and the hydrochloride salt of 19E (85 mg, 0.33 mmol) and diisopropylethylamine (128 mg, 0.99 mmol) were added. The reaction mixture was incubated in an oil bath at 100 °C for 15 h. After completion of the reaction, the mixture was cooled to room temperature and monitored by LCMS. The product was then spin-dried and sent to the production line. The separation method by preparative HPLC was as follows: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, with a mobile phase A content of 10% to 55%. c. Flow rate: 12 mL / min. Retention time: 7.0 min. Compound 19 (130 mg, 81%) was obtained. LCMS(ESI): m / z=485.3[M+H] +

[0175] Resolution of Compound 19: Compound 19 (130 mg) was taken and used for resolution, and after separation, compound 19-1 (retention time: 1.134 min, 37 mg, ee%=100%) and compound 19-2 (retention time: 1.421 min, 32 mg, ee%=100%) were obtained.

[0176] The division conditions are as follows:

[0177] Instrument: Waters 150 MGM, Column: DAICEL CHIRALPAK AD, Mobile phase: A for CO2and B for EtOH(0.1%NH3·H2O)), gradient: B 40%, flow rate: 120mL / min, back pressure: 100 bar, Column temperature: 35°C, wavelength: 220 nm, cycle: 13 min, Compound 19-1: 1 H NMR(400MHz, CDCl3)δ=7.33(d,2H),7.27(d,2H),6.19(s,1H),6.03(s,1H),3.94(s,1H),3.87(s,2H),3.80 - 3.65(m,2H),3.60(s,1H),3.21-3.16(m,2H),3.11(s,1H),3.00 - 2.74(m,3H),2.67 - 2.46(m,3H),2.45 - 2.26(m,2H),2.24 - 2.11(m,2H),2.10 - 2.02(m,1H),2.01 - 1.87(m,2H). Compound 19-2: 1 H NMR(400MHz, CDCl3)δ=7.32(d,2H),7.27(d,2H),6.18(s,1H),6.03(s,1H),4.00(s,1H),3.87(s,2H),3.74-3.66(m,2H),3.60(s,1H),3.29 - 3.15(m,2H),3.15 - 3.03(m,1H),3.02 - 2.73(m,3H),2.68 - 2.47(m,3H),2.40(s,1H),2.36 - 2.26(m,1H),2.23 - 2.10(m,2H),2.10 - 2.01(m,1H),2.02 - 1.84(m,2H). Example 21

change

[0178] Step 1: Compound 20A (1.4 g, 5.0 mmol) was dissolved in 1,4-dioxane (30 mL). 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (360.0 mg, 0.5 mmol), potassium carbonate (1.4 g, 10.0 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.8 g, 6.0 mmol), and water (6.0 mL) were added. The mixture was purged with nitrogen gas three times and heated to 45°C for 14 h. The mixture was then passed through a silica gel short column, rinsed with ethyl acetate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 20B (1.7 g, 99%). LC-MS(ESI): m / z=284.1[M-56] +

[0179] Step 2: Compound 20B (340.0 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL). Bis(triphenylphosphine)dichloropalladium (70.0 mg, 0.1 mmol), triethylamine (202.0 mg, 2.0 mmol), trimethylsilylacetylene (130.0 mg, 1.3 mmol), and cuprous iodide (8.0 mg, 0.05 mmol) were added. The mixture was purged with nitrogen gas three times, heated to 50 °C, and reacted for 14 h. The mixture was then passed through a silica gel short column, rinsed with ethyl acetate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 20C (240.0 mg, 72%). LC-MS(ESI): m / z=302.1[M-56] +

[0180] Step 3: Compound 20C (240.0 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was allowed to react at room temperature for half an hour, and then concentrated to give compound 20D (150.0 mg, 87%), which was used directly in the next step. LC-MS(ESI): m / z=258.1[M+H] +

[0181] Step 4: Compound 20D (150.0 mg, 0.58 mmol) was dissolved in methanol (10.0 mL), and potassium carbonate (150.0 mg, 1.1 mmol) was added. The mixture was allowed to react at room temperature for 2 h, then concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound 20E (70.0 mg, 65%). LC-MS(ESI): m / z=186.1[M+H] +

[0182] Step 5: Compound 20E (140.0 mg, 0.74 mmol) was dissolved in 1,4-dioxane (15.0 mL), and compound 8A-P2 (single configuration, configuration not determined) (230.0 mg, 0.8 mmol) was added. The mixture was heated to 90°C and reacted for 12 hours. The mixture was then cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 20 (120.0 mg, 62%).

[0183] LC-MS(ESI): m / z=451.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.34(s,1H),6.53(s,1H),4.89(s,1H),4.68(s,1H),4.45(s,2H),3.95 - 3.92(m,2H),3.73(d,2H),3.09 - 3.05(m,1H),2.95 - 2.88(m,1H),2.66(d,4H),2.44 - 2.31(m,3H),2.20 - 2.14(m,2H),1.98 - 1.93(m,1H),1.87 - 1.77(m,2H). Example 22 [ka]

[0184] Step 1: Compound 18C (0.50 g, 2.38 mmol) and 1-chloro-4-iodobenzene (0.68 g, 2.68 mmol) were weighed and placed in a 100 mL one-neck flask. 1,4-Dioxane (30 mL) was added to dissolve the compound. The reaction mixture was then mixed with 1,1'-binaphthyl-2,2'-bisdiphenylphosphino (0.15 g, 0.24 mmol), sodium tert-butanol (0.69 g, 7.14 mmol), tris(dibenzylideneacetone)dipalladium (0.14 g, 0.24 mmol) was added, and after the addition was complete, the mixture was stirred at 85°C for 16 h. The TLC spot plate (petroleum ether: ethyl acetate = 5:1) was checked for complete reaction. Water (20 mL) was added to the reaction mixture, and the mixture was stirred for 5 min. Ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 21A (0.28 g, yield: 37%). LCMS m / z=321.1[M+1] +

[0185] Step 2: Compound 21A (0.2 g, 0.62 mmol) was weighed into a 100 mL single-neck flask, dissolved in methanol (10 mL), and then a 4 N solution of hydrochloric acid in dioxane (10 mL) was added. After the addition was complete, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure to give the target compound 21B (0.15 g, crude). LCMS m / z=221.1[M+1] +

[0186] Step 3: Compound 8A-P2 (150 mg, 0.50 mmol), compound 21B (110 mg, 0.50 mmol), and N,N-diisopropylethylamine (0.20 g, 1.51 mmol) were added to a 100 mL single-neck flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude target compound, which was then purified by preparative HPLC to give the title compound 21 (50 mg, 20%).

[0187] Preparative method: Instrument: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm), Sample: Dissolve in DMF and filter through a 0.45 μm filter to prepare the sample solution. Preparative Chromatography Conditions: a) Mobile Phase A and B: Acetonitrile, Mobile Phase B: Water (containing 5 mM aqueous ammonia), b) Gradient elution, Mobile Phase A content: 40% to 80%, c) Flow rate: 15 mL / min, d) Elution time: 20 min, Retention time: 12.20 min.

[0188] LCMS(ESI): m / z=486.1[M+1] + 1 H NMR(400MHZ,DMSO-d6)δ 7.21(d,2H),6.53(d,2H),4.90(t,1H),4.31(s,4H),4.10(s,4H),3.73(d,2H),3.05-3.10(m,1H),2.89 -2.95(m,1H),2.55-2.72(m,2H),2.32-2.46(m,4H),2.16(s,2H),1.92-2.00(m,1H),1.71-1.87(m,2H). Example 23 [ka]

[0189] Step 1: 22A (5.0 g, 33.6 mmol), 1,4-dioxo-8-azaspira[4.5]decane (5.3 g, 36.9 mmol), and DIPEA (13.0 g, 100.8 mmol) were dissolved in 100 mL of dioxane. The mixture was heated to 80 °C and reacted for 2 h. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The organic phases were combined, dried, and the solvent was removed by rotary evaporation. Purification by silica gel column chromatography (PE:EA = 20:1) gave the desired compound 22B (8.5 g, 99% yield). LCMS(ESI): m / z=256.2[M+H] +

[0190] Step 2: Starting material 22B (8.5 g, 33.2 mmol) was dissolved in 30 mL of tetrahydrofuran, 120 mL of 10% sulfuric acid was added, and the mixture was heated to 90 °C and refluxed for 12 h. After confirming complete reaction by TLC spot plate, the mixture was cooled to room temperature and the pH was adjusted to neutral with saturated sodium bicarbonate. The organic phase was washed with ethyl acetate (100 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give target compound 22C (6.2 g, 88% yield), which was used directly in the next step. LCMS(ESI): m / z=212.3[M+H] +

[0191] Step 3: Starting material 22C (6.2 g, 29.2 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl ether (10.6 g, 35.0 mmol) were dissolved in 62 mL of tetrahydrofuran, and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 g, 35.0 mmol) was added. The mixture was stirred at room temperature for 4 h. After monitoring the complete reaction by TLC, the mixture was concentrated and purified by silica gel column chromatography (PE:EA = 50:1) to give the target compound 22D (10.6 g, 73% yield). LCMS(ESI):m / z=494.0[M+H] +

[0192] Step 4: Starting material 22D (6.50 g, 13.2 mmol), bis(pinacolato)diboron (4.02 g, 15.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (190 mg, 0.26 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (144 mg, 0.26 mmol) were suspended in dioxane (65 mL) and stirred at room temperature for 15 min. Potassium acetate (2.58 g, 26.4 mmol) was added and the reaction mixture was heated at 90 °C for 16 h. The completion of the reaction was monitored by TLC and LCMS. The product was purified by silica gel column chromatography (PE:EA = 20:1) to give the title compound 22E (3.37 g, 79% yield). LCMS(ESI): m / z=322.4[M+H] +

[0193] Step 5: Compound 22E (500 mg, 1.55 mmol), 8A-P2 (422 mg, 1.40 mmol), tetrakis(triphenylphosphine)palladium (33 mg, 0.03 mmol), and sodium carbonate (493 mg, 4.65 mmol) were suspended in 10 mL of a 4:1 dioxane:water mixture and reacted at 90 °C for 4 h. After the reaction was complete, the reaction mixture was added dropwise to ice water and filtered. The filtrate was extracted three times with dichloromethane, and the organic phase and the residue were combined, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to give the target compound 22 (142 mg, 23%).

[0194] 1 H NMR(400MHz,DMSO-d6)δ 8.45(s,2H),7.18(t,1H),6.93(s,1H),4.92(s,1H),4.41-4.35(m,2H),3.97-3.90(2H),3.73(s,2H),3.23 - 3.03(m,2H),2.88 - 2.77(m,1H),2.75 - 2.64(m,1H),2.61(t,2H),2.46 - 2.26(m,3H),2.25-2.15(m,2H),2.11 - 1.96(m,1H),1.94 - 1.73(m,2H). LCMS(ESI): m / z=461.19[M+H] + Example 24 [ka]

[0195] Step 1: Under nitrogen gas protection, sodium hydride (3.56 g, 88.98 mmol) was slowly added to a solution of diethyl cyanomethyl phosphate (12.61 g, 71.18 mmol) and tetrahydrofuran (100 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to -78 °C and 23A (10.00 g, 59.32 mmol) was added. The reaction mixture was stirred for 2 h, then quenched by adding water (200 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to give the target compound 23B (6.50 g, yield: 57.18%). 1 H NMR(400MHz,CDCl3)δ 7.66 - 7.65(m,1H),7.53 - 7.52(m,1H),7.51 - 7.48(m,1H),7.31 - 7.28(m,1H),3.74(s,2H).

[0196] Step 2: Compound 23B (6.00 g, 31.31 mmol) was dissolved in methanol (120 mL), and Raney nickel (1 g) was added. The reaction mixture was purged with hydrogen and stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (eluent: DCM:MEOH = 10:1) to give the target compound 23C (1.60 g, yield: 26.12%). 1 H NMR(400MHz,CDCl3)δ 7.47 - 7.46(m,1H),7.42(s,1H),7.40 - 7.38(m,1H),7.20 - 7.18(m,1H),2.98 - 2.92(m,2H),2.85 - 2.81(m,2H).

[0197] Step 3: Compound 23C (1.60 g, 8.18 mmol) was dissolved in 30 mL of formic acid, and paraformaldehyde (3.20 g) was added. The mixture was then heated to 70 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, concentrated, washed with aqueous sodium hydroxide, extracted with ethyl acetate, and the organic phase was dried and concentrated to give the crude product. The crude product was purified by column chromatography (eluent: DCM:MEOH = 20:1-10:1) to give compound 23D (250 mg, yield: 14.72%). LCMS m / z=208.1[M+H] +

[0198] Step 4: Compound 8A-P2 (200 mg, 0.66 mmol) and compound 23D (250 mg, 1.20 mmol) were dissolved in 1,4-dioxane (6 mL), and DIPEA (235 mg, 1.82 mmol) was added. After the addition was complete, the mixture was heated to 85°C under nitrogen gas protection and stirred for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1) and then further purified by prep HPLC (preparation method: instrument: Waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm x 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Prep chromatographic conditions: a. Mobile phases A and B: acetonitrile, mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, mobile phase A content: 25% to 85%; c. Flow rate: 15 mL / min; d. Elution time: 15 min; retention time: 7.0 min) to obtain the target compound 23 (82.5 mg, 26.32%).

[0199] LCMS m / z=473.2[M+H] + 1H NMR(400MHz,CDCl3)δ 7.45 - 7.44(m,1H),7.34 - 7.32(m,1H),7.22 - 7.19(m,1H),6.23(br s,1H),4.90(s,2H),4.11(s,2H),3.94(s,2H),3.23 - 3.18(m,1H),2.93 - 2.85(m,2H),2.75(s,2H),2.64 - 2.49(m,2H),2.42 - 2.33(m,2H),2.30 - 2.22(m,2H),2.11 - 1.90(m,4H). Example 25 [ka]

[0200] Step 1: 24A (5 g, 24.18 mmol), 1-tert-butoxycarbonyl-3-azetidinamine (5 g, 29.02 mmol), and N,N-diisopropylethylamine (9.38 g, 72.54 mmol) were added to acetonitrile (50 mL) and heated to 60 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the acetonitrile. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound 24B (7 g, 84.44%) was obtained by silica gel column chromatography (eluent EA / PE = 0-60%). LC-MS(ESI): m / z=343.1[M+H] + .

[0201] Step 2: 24B (7 g, 20.42 mmol), titanium tetraisopropoxide (0.58 g, 2.04 mmol), and water (0.37 g, 20.42 mmol) were added to dichloromethane (100 mL) and stirred for 10 min. tert-Butyl hydroperoxide (7.89 g, 61.26 mmol, 70% concentration) was added and the mixture was allowed to react at room temperature for 5 h. The reaction was monitored for completion by TLC. Water (50 mL) was added to the reaction mixture, and the layers were separated. The organic phase was washed with aqueous sodium thiosulfate (50 mL), then with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 24C (6 g, 82.6%) was purified by silica gel column chromatography (eluent EA / PE = 0-100%) to give compound 24C.

[0202] 24C (5 g) was taken and sent for chiral separation. Chiral separation gave the title compound 24C-1 (2.2 g, 44%, retention time: 0.853 min) and the title compound 24C-2 (1.6 g, 32%, retention time: 1.070 min). Chiral separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralpak AS Column, Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), Isocratic elution: 30% mobile phase B, Flow rate: 120 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Elution time: 2.5 min. LC-MS(ESI): m / z=359.1[M+H] + .

[0203] Step 3: 24C-1 (1 g, 2.79 mmol), 13C (1.12 g, 3.35 mmol), and N,N-diisopropylethylamine (1.80 g, 13.92 mmol) were added to 1,4-dioxane (15 mL), and the mixture was heated to 100 °C and reacted for 4 h. After monitoring the complete reaction by LC-MS, the mixture was cooled to room temperature and directly concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent MeOH / DCM = 0-10%) to give the title compound 24D-1 (1.2 g, 79.34%).

[0204] Referring to the above procedure, 24C-2 (1 g, 2.79 mmol) was used as the starting material to obtain 24D-2 (1.2 g, 79.34%). LC-MS(ESI): m / z=542.2[M+H] + .

[0205] Step 4: 24D-1 (1.2 g, 2.21 mmol) was added to dichloromethane (15 mL), and trifluoroacetic acid (4 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure to give crude product 24E-1 (1.7 g).

[0206] Referring to the above procedure, 24D-2 (1.2 g, 2.21 mmol) was used as the starting material to obtain 24E-2 (1.7 g). LC-MS(ESI): m / z=442.2[M+H] + .

[0207] Step 5: Crude 24E-1 (1.7 g) and 1-iodo-3-fluoropropane (0.61 g, 3.25 mmol) were added to tetrahydrofuran (20 mL), and a 5 mol / L solution of sodium hydroxide (0.52 g, 13 mmol) was added. The mixture was allowed to react at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the tetrahydrofuran, and water (20 mL) was added. The mixture was extracted with MeOH / DCM (1 / 10) (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (MeOH / DCM = 0-15%) to give the product (0.6 g, 55%).

[0208] Chiral separation afforded the title compound 24-1 (200 mg, 18.36%, retention time: 1.525 min) and the title compound 24-2 (230 mg, 21.11%, retention time: 2.022 min). Chiral separation method: Instrument: Waters 150 preparative SFC (SFC-26), Chromatography column: ChiralPak AD, 250 × 30 mm ID, 10 μm, Mobile phase: A: carbon dioxide and B: isopropyl alcohol (0.1% aqueous ammonia), Isocratic elution: 30% mobile phase B, Flow rate: 150 mL / min, Back pressure: 100 bar, Column temperature: 38 °C, Wavelength: 220 nm, Elution time: 15 min.

[0209] Referring to the above procedure, compounds (0.7 g, 64%) were obtained from 24E-2 (1.7 g) as a starting material, and chiral separation was carried out to give 24-3 and 24-4.

[0210] Chiral separation afforded the title compound 24-3 (310 mg, 28.45%, retention time: 0.698 min) and the title compound 24-4 (280 mg, 25.7%, retention time: 1.514 min). Chiral separation method: Instrument: Waters 150 preparative SFC (SFC-26), Chromatography column: ChiralPak AD, 250 × 30 mm ID, 10 μm, Mobile phase: A: carbon dioxide and B: ethanol (0.1% aqueous ammonia), Isocratic elution: 65% mobile phase B, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 38 °C, Wavelength: 220 nm, Elution time: 5 min.

[0211] (Compound 24-1) 1H NMR(400MHz,DMSO-d6)δ 8.01(s,1H),7.51-7.47(m,2H),7.41-7.37(m,2H),6.26(s,1H),4.57-4.50(m,2H),4.42-4.38(m,1H),3.88(dd,1H),3.80-3.72(m,1H),3.69 - 3.52(m,4H),3.46-3.38(m,1H),3.25 - 3.15(m,2H),3.12-3.06(m,1H),3.02-2.82(m,5H),2.69-2.62(m,1H),2.56-2.50(m,2H),1.72-1.60(m,2H). LC-MS(ESI): m / z=502.2[M+H] + . (Compound 24-2) 1 H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.51-7.47(m,2H),7.41-7.37(m,2H),6.26(s,1H),4.56-4.49(m,2 H),4.42-4.37(m,1H),3.88(dd,1H),3.80-3.71(m,1H),3.68-3.52(m,4H),3.47 - 3.35(m,1H),3.24-3.14(m,2H),3.12-3.04(m,1H),3.00 - 2.81(m,5H),2.71-2.59(m,1H),2.49-2.43(m,2H),1.72-1.58(m,2H). LC-MS(ESI): m / z=502.2[M+H] + . (Compound 24-3) 1H NMR(400MHz, CDCl3)δ 7.38-7.26(m,4H),6.58-6.52(m,1H),6.05(s,1H),4.77-4.68(m,1H),4.55 -4.47(m,1H),4.43-4.36(m,1H),4.03-3.93(m,1H),3.83-3.69(m,3H),3.68 - 3.52(m,3H),3.38-3.21(m,2H),3.19-3.08(m,1H),3.08 - 2.94(m,3H),2.93-2.87(m,1H),2.82-2.69(m,1H),2.66-2.57(m,1H),2.56-2.40(m,2H),1.78-1.62(m,2H). LC-MS(ESI): m / z=502.2[M+H] + . (Compound 24-4) 1 H NMR(400MHz, CDCl3)δ 7.38-7.26(m,4H),6.65-6.32(m,1H),6.05(s,1H),4.83-4.70(m,1H),4.55 -4.46(m,1H),4.43-4.34(m,1H),4.03-3.92(m,1H),3.87-3.66(m,4H),3.66 - 3.52(m,2H),3.39-3.23(m,2H),3.18-3.08(m,1H),3.07 - 2.74(m,5H),2.68-2.59(m,1H),2.58-2.44(m,2H),1.84-1.71(m,2H). LC-MS(ESI): m / z=502.2[M+H] + . Example 26

change

[0212] Step 1: Compound 25A (15 g, 96.03 mmol) was dissolved in carbon tetrachloride (600 mL), and N-bromosuccinimide (17.09 g, 96.03 mmol) and azobisisobutyronitrile (1.58 g, 9.60 mmol) were added thereto. The mixture was protected with nitrogen gas, heated to 70 °C, and stirred overnight. The mixture was then cooled to room temperature, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was spin-dried to give compound 25B (24 g, crude), which was used directly in the next step without isolation or purification. LCMS(ESI):=235.1, 237.1[M+H] + .

[0213] Step 2: Crude product 25B (17 g, 63.8 mmol) was dissolved in ammonia methanol solution (7.0 M, 20 mL) and methanol (20 mL), stirred at room temperature for 2 h, and the solvent was evaporated under reduced pressure. After that, compound 25B was separated by silica gel chromatography (DCM:MeOH, v / v=10:1) to give compound 25C (8 g, 48.7% yield for two steps). LCMS(ESI):=172.1[M+H] + .

[0214] Step 3: Compound 25C (8 g, 46.73 mmol) was dissolved in a mixed solvent of methanol / ethanol (120 mL, v / v=1:1), potassium carbonate (12.92 g, 93.45 mmol) was added, stirred, heated to 90 °C, and reacted for 3 hours. The mixture was then cooled to room temperature, and the solvent was evaporated under reduced pressure. 150 ml of ethyl acetate was added, and the solid was dissolved and removed by filtration. The solvent was then spin-dried to obtain compound 25D (3.25 g, 36%). LCMS(ESI):=140.0[M+H] + .

[0215] Step 4: 25D (3.25 g, 23.35 mmol) was dissolved in dichloromethane (50 mL), triethylamine (7.09 g, 70.06 mmol) and a catalytic amount of 4-dimethylaminopyridine (285 mg, 2.34 mmol) were added thereto, and the mixture was cooled in an ice bath. Di-tert-butyl dicarbonate (10.2 g, 46.71 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The mixture was then directly spin-dried and separated by silica gel chromatography (EA:PE=1:3) to obtain compound 25E (4.45 g, 79.6%). LCMS(ESI):=184.1[M+H] + .

[0216] Step 5: 25E (4.45 g, 18.60 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled with ice water under nitrogen gas protection. Borane tetrahydrofuran complex (55.8 mL, 1.0 mol / L) was added dropwise thereto. After the addition was completed, the mixture was allowed to react at room temperature for 3 hours. After cooling with ice water, the reaction was quenched with a small amount of methanol. The solvent was evaporated under reduced pressure to obtain the crude product, which was separated by silica gel chromatography (EA:PE = 1:3) to obtain compound 25F (2.26 g, 53.9%). LCMS(ESI):=170.1[M+H] + .

[0217] Step 6: 25F (2.26 g, 10.03 mmol) was dissolved in chloroform (25 mL), a catalytic amount of glacial acetic acid was added, and liquid bromine (1.6 g, 10.03 mmol) was added dropwise while cooling with ice water. The mixture was stirred at room temperature overnight, and triethylamine (3.04 g, 30.09 mmol) and a catalytic amount of DMAP (123 mg, 1.00 mmol) were added thereto. The mixture was cooled in an ice bath, and di-tert-butyl dicarbonate (4.38 g, 20.06 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and then directly spun dry. The mixture was separated by silica gel chromatography (EA:PE = 1:3) to obtain compound 25G (2.26 g, 74.1%). LCMS(ESI):=248.1, 250.1[M+H] + .

[0218] Step 7: 25G (1 g, 3.29 mmol), 4-chlorophenylboronic acid (616.8 mg, 3.94 mmol), sodium carbonate (697 mg, 6.57 mmol), and tetrakis(triphenylphosphine)palladium (380 mg, 0.33 mmol) were added to a mixture of 1,4-dioxane and water (27.5 mL, v / v=10:1), and the mixture was purged with nitrogen gas. The mixture was reacted at 80 °C for 3 hours, quenched by adding water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel chromatography to give compound 25H (640 mg, 58.0%). LCMS(ESI):=280.1, 282.1[M+H] + .

[0219] Step 8: 25H (300 mg) was added to hydrochloric acid dioxane (5 mL, 4N) and reacted at room temperature for 2 hours, and the system was spun dry to give compound 25I (300 mg, crude), which was used directly in the next step reaction. LCMS(ESI):=236.1, 238.1[M+H] + .

[0220] Step 9: 8A-P2 (150 mg, 0.50 mmol), 25I (200 mg, crude), and DIPEA (321 mg, 2.49 mmol) were added to 1,4-dioxane (5 mL) and reacted at 80 °C for 3 hours. The solvent was spin-dried and sent to HPLC for fractionation. The resulting solution was added with sodium bicarbonate to adjust the pH to 7-8, extracted with dichloromethane, and concentrated to give compound 25 (65 mg, 26.1%).

[0221] Preparative HPLC Separation Method: 1. Equipment: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: Acetonitrile, Mobile Phase B: Water (containing 0.1% TFA). b. Gradient elution, with the content of Mobile Phase A ranging from 5% to 50%. c. Flow rate: 12 mL / min. d. Elution time: 20 min.

[0222] LCMS(ESI):=502.1[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 7.52 - 7.45(m,2H),7.37 - 7.32(m,2H),7.07(s,1H),6.27(s,1H),5.18(s,1H),4.95 - 4.61(m,4H),4.00 - 3.87(m,2H),3.28 - 3.17(m,1H),3.02 - 2.83(m,2H),2.72 - 2.49(m,2H),2.47 - 2.31(m,2H),2.30 - 2.16(m,2H),2.16 - 2.06(m,1H),2.05 - 1.88(m,2H). Example 27 [ka]

[0223] Step 1: Compound 26A (3.00 g, 16.92 mmol) and compound 12B (3.78 g, 20.30 mmol) were weighed and placed in a 100 mL one-neck flask. 1,4-Dioxane (30 mL) was added to dissolve the compound. N,N-Diisopropylethylamine (6.56 g, 50.76 mmol) was added to the reaction mixture. After the addition was complete, the mixture was stirred at 80 °C for 16 h. TLC spot plate (petroleum ether: ethyl acetate = 5:1) showed a complete reaction. Water (20 mL) was added to the reaction mixture, the mixture was stirred for 5 min, and ethyl acetate (20 mL) was added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 26B (2.8 g, yield: 48%). LCMS m / z=343.1[M+1] +

[0224] Compound 26B and trimethylethynylsilane were used as starting materials, and the procedure of Example 21 was followed to obtain compound 26 (80 mg, 27%).

[0225] Preparative method: Instrument: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm), Sample: Dissolve in DMF and filter through a 0.45 μm filter to prepare the sample solution. Preparative Chromatography Conditions: a) Mobile Phase A and B: Acetonitrile, Mobile Phase B: Water (containing 5 mM aqueous ammonia), b) Gradient elution, Mobile Phase A content: 35% to 80%, c) Flow rate: 15 mL / min, d) Elution time: 20 min, Retention time: 12.50 min.

[0226] LCMS m / z=454.2[M+1] + 1H NMR(400MHZ,DMSO-d6)δ 8.50(s,2H),6.56(s,1H),4.89(t,1H),4.28(s,1H),3.81(s,8H),3.70(d,2H),3.03-3.11(m,1H),2.88 -2.95(m,1H),2.53-2.70(m,2H),2.31-2.45(m,3H),2.15(s,2H),1.91-2.00(m,1H),1.73-1.87(m,2H). Example 28 [ka]

[0227] Step 1: Raw material 27A (3 g, 14.49 mmol) was added to 60 mL of dry tetrahydrofuran solvent, and lithium tetrahydroaluminum (270 mg, 7.25 mmol) reagent was added in an ice bath. The mixture was stirred in an ice bath for half an hour, then warmed to room temperature and stirred for 3 hours. Water was added to quench the mixture, and a small amount of dilute hydrochloric acid was added. The mixture was extracted three times with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then used directly in the next step of the reaction.

[0228] Step 2: Raw material 27B (2 g, 12.12 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (2.45 g, 24.24 mmol), imidazolyl (1.65 g, 24.24 mmol), and tert-butyldimethylchlorosilane (2.74 g, 18.18 mmol) were added. The mixture was stirred overnight at room temperature, diluted with water, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was purified and separated by silica gel column chromatography (PE:EA (v / v) = 1:0 to 20:1) to give 27C (1.8 g, 53% yield). 1 H NMR(400MHz,CDCl3)δ3.68(s,2H),2.45-2.50(m,4H),2.01-2.06(m,1H),1.72-1.79(m,1H),0.83(s,9H),0.0(s,6H).

[0229] Step 3: The starting material, 3-thiophenone (8 g, 78.28 mmol) and diethyl oxalate (11.44 g, 78.28 mmol) were added to anhydrous ethanol (70 mL). Sodium tert-butanol (7.9 g, 82.21 mmol) was added in an ice bath and stirred for 2 h. Glacial acetic acid (5.17 g, 86.11 mmol) was then added, followed by 4-hydrazinopiperidine-1-carboxylic acid tert-butyl ester hydrochloride (16.85 g, 78.28 mmol). The mixture was stirred for 20 h. The mixture was quenched with water, extracted with EA, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EA (v / v) = 1:0 to 10:1) to give 27E (8 g, 27% yield). LCMS m / z=382.2[M+1] +

[0230] Step 4: The raw material 27E (6 g, 15.73 mmol) was added to a mixed solvent of tetrahydrofuran (30 mL) and methanol (30 mL), and then lithium hydroxide (0.76 g, 31.65 mmol) dissolved in 15 mL of water was added. The mixture was stirred at room temperature for 2 hours, and the complete reaction of the raw material was monitored by TLC. After concentration, the mixture was diluted with water and the pH was adjusted to 2-3 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and used directly in the next step. LCMS m / z=354.1[M+1] +

[0231] Step 5: Starting material 27F (4 g, 11.32 mmol) and diphenylphosphoryl azide (5.67 g, 14.72 mmol) were added to tert-butanol (100 mL), and triethylamine (1.72 g, 16.98 mmol) was added. The mixture was protected with nitrogen gas, heated to 85°C, and stirred for 4 hours. The mixture was cooled and concentrated, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The target compound 27G (4 g, 83% yield) was purified and separated by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1).

[0232] LCMS m / z=425.2[M+1] + 1 H NMR(400MHz,CDCl3)δ5.99(s,1H),4.24-4.26(m,2H),4.04-4.06(m,1H),3.94-3.95(m,2H),3.82-3.83(m, 2H),2.77-2.81(m,2H),2.07-2.08(m,1H),2.01-2.02(m,1H),1.86-1.89(m,2H),1.54(s,9H),1.48(s,9H).

[0233] Step 6: Starting material 27G (4 g, 9.42 mmol) was added to anhydrous methanol (5 mL), and 20 mL of hydrochloric acid in 1,4-dioxane (4 M) was added, stirred at room temperature for 4 hours, and the complete reaction of the starting material was monitored by LCMS, and the mixture was directly concentrated to dryness and used in the next step reaction. LCMS m / z=225.1[M+1] +

[0234] Step 7: Starting material 27H (2.2 g, 9.81 mmol), 4-chloroiodobenzene (2.34 g, 9.81 mmol), tris(dibenzylideneacetone)palladium (0.45 g, 0.49 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.57 g, 0.98 mmol), and sodium tert-butanol (1.89 g, 19.62 mmol) were added to 1,4-dioxane (100 mL), protected with nitrogen, heated to 85 °C, and stirred for 16 h. The mixture was cooled, filtered, and the filtrate was diluted with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The filtrate was purified and separated by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1) to obtain the target compound 27I (0.8 g, 24% yield). LCMS m / z=335.1[M+1] +

[0235] Step 8: Starting material 27I (0.7 g, 2.09 mmol) was dissolved in N,N-dimethylacetamide (20 mL), sodium hydride (0.42 g, 10.45 mmol, 40% in oil) was added in an ice bath, and the mixture was stirred in an ice bath for 1 h. 27C (1.17 g, 4.18 mmol) was added and the mixture was stirred in an ice bath for 0.5 h, then warmed to room temperature and stirred for 3 h. The complete reaction of the starting material was monitored by LCMS. Water was added to quench the reaction, and the solvent was removed by evaporation under reduced pressure using an oil pump. The mixture was then purified by silica gel column chromatography (DCM:MeOH (v / v) = 1:0 to 5:1) to give target compound 27J (0.8 g, 91% yield). LCMS m / z=419.2[M+1] +

[0236] Step 9: Starting material 27J (200 mg, 0.48 mmol), 1,1'-bi-2-naphthol (69 mg, 0.24 mmol), water (9 mg, 0.48 mmol), and titanium tetraisopropoxide (68 mg, 0.24 mmol) were added to dichloromethane (10 mL) in order and stirred at room temperature for half an hour. Then, tert-butanol peroxide (65 mg, 0.72 mmol) was added and stirred for 3 hours. After dilution with water, the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate, dried, and filtered. The filtrate was concentrated and purified by TLC (DCM:MeOH=5:1) to obtain the target compound 27 (0.01 g, 5% yield).

[0237] LCMS m / z=435.2[M+1] + 1 H NMR(400MHz,CD3OD-d4)δ 7.14-7.17(m,2H),6.76-6.80(m,2H),4.29-4.39(m,2H),4.15-4.18(m,1H),3.65-3.78(m,4H), 3.12-3.15(m,2H),2.52-2.61(m,2H),1.91-2.03(m,6H),1.74-1.81(m,3H),1.60-1.66(m,1H). Example 29 [ka]

[0238] Step 1: Compound 28A (3.9 g, 20.0 mmol) and 1-aminocyclobutylmethanol hydrochloride (3.5 g, 25.0 mmol) were dissolved in acetonitrile (50.0 mL), triethylamine (6.1 g, 60.0 mmol) was added, and the mixture was heated to 70 °C and reacted for 14 h. The mixture was then concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 28B (5.2 g, 98%). LC-MS(ESI): m / z=260.0[M+H] +

[0239] Step 2: Compound 28B (2.0 g, 7.7 mmol) was dissolved in dichloromethane (40 mL), metachloroperoxybenzoic acid (1.5 g, 8.5 mmol) was added in an ice bath, and the mixture was allowed to warm slowly to room temperature overnight and then concentrated to give compound 28C (1.7 g, 80%), which was used directly in the next step. LC-MS(ESI): m / z=276.0[M+H] +

[0240] Step 3: Compound 28C (0.7 g, 2.4 mmol) was dissolved in 1,4-dioxane (40 mL), and then compound 9D (461 mg, 2.4 mmol) and diisopropylethylamine (1.3 g, 9.4 mmol) were added. The mixture was heated to 90° C. and reacted for 12 hours. The mixture was then cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol=9 / 1) to give compound 28D (380 mg, 37%). LC-MS(ESI): m / z=435.1[M+H] +

[0241] Step 4: Compound 28D (380 mg) was subjected to chiral resolution to give compound 28-1 (100 mg) and compound 28-2 (101 mg).

[0242] Preparation method: Instrument: MGII preparative SFC (SFC-14), Column: ChiralPak AD, 250 × 30 mm I.D., 5 μm, Mobile phase: (A for CO₂ and B for MeOH (0.1% NH₃·H₂O), Gradient: 50% phase B elution, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Cycle time: 3.3 min, Sample preparation: Sample concentration 10 mg / mL, acetonitrile solution, Sample loading: 3.5 mL at a time. After separation, the fraction was dried using a rotary evaporator at a bath temperature of 35 °C to obtain P1 (retention time: 1.334 min, set to compound 28-1) and P2 (retention time: 1.840 min, set to compound 28-2).

[0243] LC-MS(ESI): m / z=435.6[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.96(s,1H),7.37(s,1H),7.29(s,1H),4.92 - 4.89(m,1H),4.43(s,2H),3.95(s,2H),3.83 - 3.79(m,1H),3.74 - 3.70(m,1H),2.85(s,3H),2.65(s,2H),2.37 - 2.11(m,4H),1.96 - 1.69(m,2H). LC-MS(ESI): m / z=435.6[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.96(s,1H),7.37(s,1H),7.29(s,1H),4.92 - 4.89(m,1H),4.43(s,2H),3.95(s,2H),3.83 - 3.79(m,1H),3.74 - 3.70(m,1H),2.85(s,3H),2.65(s,2H),2.34 - 2.17(m,4H),1.87 - 1.80(m,2H). Example 30

change

[0244] Step 1: Under nitrogen gas protection in an ice bath, methanol (1 mL, 23.00 mmol) was slowly added dropwise to a mixture of 29A (1.50 g, 7.70 mmol, synthesized with reference to Patent WO 2010078348A1) and 4 M hydrochloric acid in dioxane (6 mL, 23.00 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was cooled to 5°C, and sodium methanol (830 mg, 15.4 mmol) and 7 N ammonia in methanol (1.6 mL) were added. The mixture was stirred at room temperature for 16 h. A solution of sodium methanol (1.10 g dissolved in 4.5 mL of methanol) was added to the reaction mixture at room temperature and stirred for 30 min. (2-chloro-3-dimethylamino-ylidene-2-propenyl)-dimethylammonium hexafluorophosphate (2.00 g) was then added and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to a small volume, and then 2-methyltetrahydrofuran (100 mL) was added and washed twice with water (80 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum to give a crude product. The crude product was purified three times by column chromatography (eluent: DCM:MeOH = 100:1 to 10:1) to give the target compound 29B (120 mg, yield: 8.52%). LC-MS(ESI): m / z=196.2[M+H] +

[0245] Step 2: Compound 8A-P2 (100 mg, 0.33 mmol) and compound 29B (100 mg, 0.51 mmol) were dissolved in 1,4-dioxane (6 mL), and DIPEA (130 mg, 1.00 mmol) was added. The mixture was heated to 85 °C under nitrogen gas protection and stirred for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: dichloromethane:methanol = 100:1 to 10:1) and then further purified by prep HPLC (preparation method: instrument: Waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm x 250 mm). The sample was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter to prepare the sample solution. The preparative chromatography conditions were: a. The composition of mobile phases A and B was mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonia water); b. Gradient elution, with a mobile phase A content of 20% to 80%; c. The flow rate was 15 mL / min. d. The elution time was 15 min, and the retention time was 7.0 min. Purification using the eluate gave the target compound 29 (3.5 mg, 2.29%). LCMS m / z=462.1[M+H] + 1 H NMR(400MHz,CDCl3)δ 8.61(s,2H),5.86(s,1H),4.88(s,1H),4.11 - 4.04(m,1H),3.97 - 3.91(m,1H),3.86(s,2H),3.68 - 3.59(m,3H),3.45 - 3.38(m,1H),3.07 - 2.98(m,2H),2.64 - 2.49(m,2H),2.37 - 2.25(m,4H),1.99 - 1.85(m,4H),1.69 - 1.62(m,1H). Example 31 [ka]

[0246] Step 1: Compound 30A (1.0 g, 4.83 mmol) was dissolved in acetonitrile (10 mL), and (1-aminocyclopentyl)methanol (610.0 mg, 5.31 mmol) and triethylamine (1.47 g, 14.49 mmol) were added. The mixture was heated to 70 °C and reacted for 14 h. The mixture was then concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 30B (500 mg, 36%). LC-MS(ESI): m / z=286.1[M+1] +

[0247] Step 2: Compound 30B (600.0 mg, 1.75 mmol), (S)-(-)-1,1'-bi-2-naphthol (50.0 mg, 0.18 mmol), tetraisopropyl titanium oxide (25.0 mg, 0.088 mmol), and water (32.0 mg, 1.75 mmol) were dissolved in dichloromethane (10 mL). The mixture was purged with nitrogen three times and stirred at room temperature for 1 h. After stirring for 1.5 h, tert-butanol peroxide (170.0 mg, 1.93 mmol) was added. The mixture was quenched with saturated aqueous sodium thiosulfate. The aqueous phase was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 30C (430.0 mg, 81%). LC-MS(ESI): m / z=302.1[M+H] +

[0248] Step 3: Compound 30C (430.0 mg, 1.42 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 9D (280.0 mg, 1.42 mmol) and triethylamine (550 mg, 4.26 mmol) were added. The mixture was heated to 90°C and reacted for 12 hours. The mixture was then cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 30 (290.0 mg, 44%). LC-MS(ESI): m / z=461.1[M+H] + 1H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.35 - 7.21(m,1H),6.58(s,1H),4.91(t,1H),4.48(s,2H),3.99(t,2H),3.74 - 3.60(m,2H),3.48 - 3.36(m,1H),3.32 - 3.22(m,1H),3.00 - 2.91(m,1H),2.90 - 2.82(m,1H),2.66(s,2H),2.20 - 2.05(m,2H),1.88 - 1.78(m,2H),1.74 - 1.63(m,2H),1.62 - 1.52(m,2H). Example 32 [ka]

[0249] Step 1: Compound 31A (2.0 g, 9.64 mmol) was dissolved in acetonitrile (20 mL), and 2-amino-2-methylpropan-1-ol (950.0 mg, 10.64 mmol) and triethylamine (2.93 g, 28.92 mmol) were added. The mixture was heated to 70 °C and reacted for 14 h. The mixture was then concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 31B (600 mg, 24%). LC-MS(ESI): m / z=260.1[M+1] +

[0250] Step 2: Compound 31B (600.0 mg, 2.31 mmol) was dissolved in dichloromethane (10 mL), metachloroperoxybenzoic acid (600.0 mg, 3.49 mmol) was added, and the mixture was stirred for 16 hours. The mixture was quenched with saturated aqueous sodium thiosulfate solution, and the aqueous phase was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 31C (632.0 mg, 99%). LC-MS(ESI): m / z=276.1[M+H] +

[0251] Step 3: Compound 31C (632.0 mg, 2.29 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 9D (540.0 mg, 2.75 mmol) and N,N-diisopropylethylamine (890 mg, 6.87 mmol) were added. The mixture was heated to 90°C and reacted for 12 hours. The mixture was then cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 31 (440.0 mg, 44%).

[0252] LC-MS(ESI): m / z=435.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.38 - 7.16(m,1H),6.23(s,1H),5.15(t,1H),4.49(s,2H),4.00(t,2H),3.51(d,2H),3.48 - 3.33(m,2H),3.01 - 2.91(m,1H),2.91 - 2.82(m,1H),2.67(s,2H),1.43(s,6H). Example 33 [ka]

[0253] Step 1: Compound 31 (380 mg) was subjected to chiral resolution to give compound 32-1 (165 mg) and compound 32-2 (180 mg).

[0254] Preparation method: Instrument: Waters 150 SFC, Column: Chiralpak AS, Mobile phase: (A for CO2 and B for MeOH (0.1% NH3·H2O), Gradient: 40% phase B elution, Flow rate: 120 mL / min, Back pressure: 100 bar, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 2.8 min, Sample preparation: Sample concentration 5 mg / mL, acetonitrile solution, Sample loading: 1.0 mL each time. After separation, the fraction was dried using a rotary evaporator at a bath temperature of 35°C to obtain P1 (retention time: 1.730 min, set to compound 32-1) and P2 (retention time: 1.948 min, set to compound 32-2).

[0255] LC-MS(ESI): m / z=435.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,2H),7.34 - 7.26(m,1H),6.21(s,1H),5.13(t,1H),4.49(d,2H),4.00(t,2H),3.51(d,2H),3.46 - 3.33(m,2H),3.01 - 2.81(m,2H),2.68(d,2H),1.43(s,6H). LC-MS(ESI): m / z=435.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,2H),7.34-7.26(m,1H),6.21(s,1H),5.13(t,1H),4.49(d,2H),4.00(t,2H),3.51(d,2H),3.47 - 3.32(m,2H),3.02 - 2.81(m,2H),2.67(d,2H),1.43(s,6H). Example 34 [ka]

[0256] Compound 33A and 4,4-dimethyl-[1,4]azasiline hydrochloride were used as starting materials, and the procedure of Example 31 was followed to obtain compound 33 (0.6 g, 45%). LC-MS(ESI): m / z=474.1[M+H] +

[0257] Compound 33 (600 mg) was subjected to chiral resolution to give compound 33-1 (200 mg) and compound 33-2 (202 mg).

[0258] Preparation method: Instrument: Waters 150 SFC, Column: Chiralcel column (250 × 30 mm × 10 μm), Mobile phase: (A for CO₂; B for 0.1% NH₃·H₂O in MEOH), Gradient: 35% phase B elution, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 3.0 min, Sample preparation: Sample concentration 10 mg / mL, acetonitrile solution, Sample loading: 3.0 mL each time. After separation, the fraction was dried using a rotary evaporator at a bath temperature of 35°C to obtain P1 (retention time: 1.592 min, assigned to compound 33-1) and P2 (retention time: 2.079 min, assigned to compound 33-2).

[0259] LC-MS(ESI): m / z=474.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.78(s,2H),7.18(s,1H),4.37(s,2H),4.05(d,2H),3.90 - 3.87(m,4H),3.41 - 3.36(m,1H),3.13 - 3.10(m,1H),2.98 - 2.79(m,2H),2.56(s,2H),0.90 - 0.64(m,4H),0.00(s,6H). LC-MS(ESI): m / z=474.1[M+H] + 1H NMR(400MHz,DMSO-d6)δ 8.78(s,2H),7.19(s,1H),4.37(s,2H),4.05(d,2H),3.90 - 3.87(m,4H),3.46 - 3.31(m,1H),3.16 - 3.08(m,1H),2.97 - 2.78(m,2H),2.56(s,2H),0.88 - 0.63(m,4H),0.00(s,6H). Example 35 [ka]

[0260] Compound 34 (160 mg, 53%) was obtained from compounds 13A and 12B by following the procedure of Example 14.

[0261] Preparative method: Instrument: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm), Sample: Dissolve in DMF and filter through a 0.45 μm filter to prepare the sample solution. Preparative Chromatography Conditions: a) Mobile Phase A and B: Acetonitrile, Mobile Phase B: Water (containing 5 mM aqueous ammonia), b) Gradient elution, Mobile Phase A content: 40% to 80%, c) Flow rate: 15 mL / min, d) Elution time: 20 min, Retention time: 12.60 min.

[0262] LCMS m / z=454.2[M+1] + 1 H NMR(400MHZ,DMSO-d6)δ 6.92(d,1H),6.78-6.81(m,1H),6.75(s,1H),6.53(s,1H),4.88(t,1H),3.82(t,4H),3.71(d,2H),3.01-3.09(m,9H) ,2.88-2.94(m,1H),2.52-2.70(m,2H),2.29-2.43(m,3H),2.09-2.19(m,2H),1.90-2.00(m,1H),1.72-1.86(m,2H). Example 36 [ka]

[0263] Step 1: Compound 20E (210.0 mg, 1.14 mmol) was dissolved in 1,4-dioxane (20.0 mL), and compound 35H (345.0 mg, 1.2 mmol, synthesized with reference to patent WO2014124860A1) was added. The mixture was heated to 90°C and reacted for 12 hours. The mixture was then cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 35F (360.0 mg, 72%). LC-MS(ESI): m / z=437.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.36(s,1H),7.34(s,1H),4.84(t,1H),4.68(s,1H),4.48(s,2H),3.97(t,2H),3.75(d,2H),3.51 - 3.36(m,1H),3.28 - 3.18(m,1H),2.98 - 2.84(m,2H),2.66(s,2H),2.43 - 2.30(m,2H),2.24 - 2.17(m,2H),1.86 - 1.71(m,2H).

[0264] Step 2: Compound 35F (0.8 g, 2.0 mmol) was dissolved in dichloromethane (15 mL), and trichloroacetyl isocyanate (452.0 mg, 2.4 mmol) was added in an ice bath. The reaction was continued for 1 h, and then concentrated to give 35G (1.2 g, 99%), which was used directly in the next step. LC-MS(ESI): m / z=624.0[M+1] +

[0265] Step 3: Compound 35G (1.2 g, 2.0 mmol) was dissolved in methanol (15 mL), and water (15 mL) and potassium carbonate (1.0 g, 8.0 mmol) were added. The mixture was reacted at room temperature for 2.5 hours, concentrated, extracted with dichloromethane, dried, and concentrated to give compound 35 (0.6 g, 62%).

[0266] LC-MS(ESI): m / z=480.2[M+1] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.61(s,1H),7.34(s,1H),6.48(s,2H),4.68(s,1H),4.48(s,2H),4.44 - 4.32(m,2H),3.99 - 3.96(m,2H),3.52 - 3.36(m,1H),3.27 - 3.11(m,1H),2.99 - 2.85(m,2H),2.66(s,2H),2.41 - 2.24(m,4H),1.95 - 1.74(m,2H). Example 37 [ka]

[0267] Step 1: 36A (360 mg, 1.21 mmol, synthesized with reference to Patent WO2011124524A1) was dissolved in 1,4-dioxane (8 mL), and 20D (515 mg, 1.45 mmol) and N,N-diisopropylethylamine (780 mg, 6.05 mmol) were added sequentially. The mixture was heated to 85 °C under nitrogen gas protection and stirred for 16 h. The reaction mixture was allowed to return to room temperature, diluted with water (50 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. This was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 15:1) to obtain the target compound 36B (590 mg, yield: 94.07%). LC-MS(ESI): m / z=519.2[M+H] +

[0268] Step 2: Compound 36B (550 mg, 1.06 mmol) was dissolved in methanol (15 mL), potassium carbonate (150 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 2 h. The disappearance of the starting material was monitored by TLC spot plate (eluent: DCM:MeOH = 15:1). The mixture was diluted with water (50 mL) and extracted three times with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 10:1) to give the target compound 36C (350 mg, yield: 73.92%). LC-MS(ESI): m / z=447.2[M+H] +

[0269] Step 3: Compound 36C (350 mg, 0.78 mmol) was subjected to chiral resolution to give compound 36-1 (13.0 mg) and compound 36-2 (3.2 mg).

[0270] Analytical method: Instrument: SHIMADZU LC-20AD, Column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm, Mobile phase: A: heptane (0.05% N,N-diethylaniline), B: ethanol (0.05% N,N-diethylaniline), Gradient: 20% B in A, Flow rate: 1 mL / min, Column temperature: 35 °C, Wavelength: 254 nm. Preparation method: Instrument: SHIMADZU LC-20AP, Column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm), Mobile phase: An-hexane, B ethanol (0.1% NH₃·H₂O), Gradient: 8% B gradient elution, Flow rate: 110 mL / min, Column temperature: 25°C, Wavelength: 254 nm, Cycle time: 16 min, Sample preparation: Sample concentration 1.5 mg / mL, Sample loading: 2 mL per ethanol solution. After separation, the fraction was dried using a rotary evaporator at a bath temperature of 40°C to obtain compound 36-1 (retention time: 5.716 min) and compound 36-2 (retention time: 6.890 min).

[0271] Compound 36-1:LCMS m / z=447.2[M+H] + 1 H NMR(400MHz,CDCl3)δ 8.77(s,2H),8.09(s,1H),7.64 - 7.61(m,1H),7.37(s,1H),7.23 - 7.18(m,2H),6.76 - 6.72(m,1H),4.56 - 4.47(m,2H),4.10 - 4.00(m,2H),3.67 - 3.59(m,1H),3.45 - 3.39(m,2H),3.17 - 3.03(m,2H),2.86 - 2.77(m,2H). Compound 36-2: LCMS m / z=447.2[M+H] + 1 H NMR(400MHz,CDCl3)δ 8.77(s,2H),8.09(s,1H),7.64 - 7.61(m,1H),7.37(s,1H),7.23 - 7.17(m,2H),6.76 - 6.72(m,1H),4.54 - 4.49(m,2H),4.10 - 4.01(m,2H),3.67 - 3.59(m,1H),3.45 - 3.39(m,2H),3.17 - 3.03(m,2H),2.86 - 2.77(m,2H). Example 38 [ka]

[0272] Step 1: Compound 35F (2.0 g, 4.58 mmol) was dissolved in dichloromethane (100 mL), Dess-Martin periodinane (2.92 g, 6.88 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium thiosulfate, and the aqueous phase was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 37B (1.2 g, 60%). LC-MS(ESI): m / z=435.2[M+H] +

[0273] Step 2: Compound 37B (220 mg, 0.51 mmol) was dissolved in ammonia-methanol solution (5 mL, 7.0 M) and stirred at room temperature for 0.5 hours. Glyoxal (1 mL, 40 wt.% in water) was added and stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 130 mg of a pale yellow solid. Compound 37 (100 mg, 40%) was obtained by reverse-phase preparative separation (acetonitrile:water = 1:99 to 99:1).

[0274] LC-MS(ESI): m / z=473.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 11.38(s,1H),8.89(s,2H),8.20(s,1H),7.24(s,1H),6.90(s,1H),6.79(s,1H),4.68(s,1H),4.60-3.95(m,2H),3.94 - 3.58(m,2H),3.49-3.37(m,1H),3.25-3.15(m,1H),3.01 - 2.76(m,3H),2.65-2.51(m,5H),2.02 - 1.88(m,2H). Example 39 [ka]

[0275] Step 1: Compound 37B (1.2 g, 2.76 mmol) was dissolved in 1,2-dichloroethane (100 mL), ammonium acetate (21.3 g, 275.94 mmol) was added, and the mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (5.85 g, 27.60 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Then, saturated sodium bicarbonate solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol:ammonia water=10:1:0.1) to give compound 38B (180 mg, 15%). LC-MS(ESI): m / z=436.2[M+H] +.

[0276] Step 2: Compound 38B (100 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), triethylamine (35 mg, 0.35 mmol) was added in an ice bath, and the mixture was stirred for 5 minutes. After that, methyl chloroformate (24 mg, 0.25 mmol) was added and the mixture was allowed to react at 0 °C for 1 hour. Water was added to quench the reaction, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, filtered, concentrated, and purified by reverse-phase preparative separation (acetonitrile:water = 1 / 99 to 99 / 1) to give compound 38 (50 mg, 44%).

[0277] LC-MS(ESI): m / z=494.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),7.49(s,1H),7.40 - 7.31(m,1H),7.18(t,1H),4.68(s,1H),4.49(s,2H),3.99(t,2H),3.57 - 3.38(m,6H),3.27 - 3.16(m,1H),3.01 - 2.82(m,2H),2.67(s,2H),2.42 - 2.18(m,4H),1.88 - 1.68(m,2H). Example 40 [ka]

[0278] Step 1: Compound 38B (100 mg, 0.23 mmol) was dissolved in methanol (5 mL), N-cyanoacetimidamidomethyl ester (25 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by reverse-phase preparative separation (acetonitrile:water = 1 / 99 to 99 / 1) to give compound 39 (50 mg, 43%).

[0279] LC-MS(ESI): m / z=502.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ 8.90(s,2H),8.72(s,1H),7.53(s,1H),7.35(s,1H),4.69(s,1H),4.49(s,2H),3.98(t,2H),3.89-3.81(m,1H),3.78-3.68(m,1H) ,3.50-3.39(m,1H),3.25-3.18(m,1H),3.03-2.79(m,2H),2.72-2.64(m,2H),2.41-2.23(m,4H),2.21(s,3H),1.86-1.74(m,2H). Example 41 [ka]

[0280] Step 1: Compound 24A (3.00 g, 14.46 mmol) and imidazolyl (1.18 g, 17.35 mmol) were weighed and placed in a 100 mL one-neck flask. The mixture was dissolved in acetonitrile (30 mL). N,N-diisopropylethylamine (5.61 g, 43.38 mmol) was added and stirred at 70 °C for 16 h. The reaction was monitored for completeness by TLC spot plate (petroleum ether:ethyl acetate = 2:1). Water (50 mL) was added, stirred for 5 min, and extracted with ethyl acetate (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to give compound 40E (1.0 g, yield: 29%). LCMS m / z=239.1[M+1] +

[0281] Step 2: Compound 40E (1.0 g, 4.19 mmol) was weighed into a 100 mL single-neck flask and dissolved in dichloromethane (10 mL). tert-Butyl hydroperoxide (0.65 g, 5.03 mmol) was added and stirred at room temperature for 12 h. The reaction was monitored by TLC spot plate (petroleum ether:ethyl acetate = 2:1). Water (50 mL) was added, stirred for 5 min, and extracted with dichloromethane (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane:methanol = 20:1) to give the target compound 40F (0.63 g, 59% yield). LCMS m / z=255.1[M+1] +

[0282] Step 3: Compound 40F (300 mg, 1.18 mmol) was dissolved in dioxane (10 mL) in a 100 mL single-neck flask. Compound 40C (300 mg, 1.42 mmol) and N,N-diisopropylethylamine (0.46 g, 3.54 mmol) were added. After the addition was complete, the system was protected with nitrogen and stirred at 85 °C for 16 h. The reaction was monitored for completeness by TLC (dichloromethane:methanol = 10:1). Water (50 mL) was added, the mixture was stirred for 5 min, and the mixture was extracted with dichloromethane (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to give compound 40G. After chiral separation, compound 40-1 (200 mg) and compound 40-2 (120 mg) were obtained.

[0283] Chiral fragmentation method: Instrument: Waters 150 SFC, column: Chiralpak IC Column (250×30 mm, ID 30 mm, 10 μm particle size), mobile phase: A for CO2 and B for IPA+ACN (0.1% NH3·H2O), elution: 45% phase B isocratic elution, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25°C, wavelength: 220 nm.

[0284] LCMS m / z=433.2[M+1] + Compound 40-1, 1 H NMR(400MHZ,DMSO-d6)δ 8.59(s,1H),8.00(s,1H),7.23(s,1H),6.85(d,1H),6.34-6.37(m,2H),3.88-3.98( m,2H),3.58-3.77(m,3H),3.40-3.48(m,3H),3.12-3.37(m,6H),2.98-3.05(m,4H). Compound 40-2 1 H NMR(400MHZ,DMSO-d6)δ 8.59(s,1H),8.00(s,1H),7.23(s,1H),6.85(d,1H),6.34-6.37(m,2H),3.88-3.99( m,2H),3.58-3.77(m,3H),3.40-3.48(m,3H),3.12-3.37(m,6H),2.97-3.05(m,4H). Example 42

change

[0285] Step 1: Compound 41A (1.0 g, 3.95 mmol) and piperazine (0.41 g, 4.7 mmol) were weighed and placed in a 100 mL flask. Dioxane (20 mL) was added to dissolve the compound. Sodium tert-butanol (0.76 g, 7.9 mmol), tris(dibenzylideneacetone)dipalladium (0.11 g, 0.20 mmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (250 mg, 0.40 mmol) were added in that order. After the addition was complete, the mixture was stirred at 80 °C for 12 h. The complete reaction was monitored by TLC monitoring (petroleum ether:ethyl acetate=5:1), water (20 mL) was added, stirred for 5 min, extracted with ethyl acetate (20 mL), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate=5:1) to obtain the target compound 41B (0.50 g, 47%). LCMS m / z=259.1[M+1] +

[0286] Step 2: Compound 8A-P2 (350 mg, 1.16 mmol) and compound 41B (300 mg, 1.16 mmol) were added to a 100 mL single-neck flask and dissolved in dioxane (10 mL). Finally, N,N-diisopropylethylamine (0.45 g, 3.48 mmol) was added. After the addition was complete, the mixture was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction was monitored for completeness by TLC (dichloromethane:methanol = 10:1). Water (20 mL) was added, stirred for 5 min, and extracted with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to give compound 41C (0.40 g, 66%). LCMS m / z=524.2[M+1] +

[0287] Step 3: Compound 41C (0.35 g, 0.67 mmol) was weighed into a 100 mL single-neck flask and dissolved in methanol (10 mL). Potassium carbonate (0.27 g, 1.94 mmol) was added and stirred for 2 h after the addition was complete. The reaction was monitored for completeness by TLC (dichloromethane:methanol = 10:1). The reaction mixture was filtered under reduced pressure and concentrated to give the target compound. The crude product was purified by preparative HPLC to give the title compound 41 (200 mg, 66%).

[0288] Preparative method: Instrument: Water 2767 Preparative Liquid, Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm), Sample: Dissolve in DMF and filter through a 0.45 μm filter to prepare the sample solution. Preparative Chromatography Conditions: a) Mobile Phase A and B: Acetonitrile, Mobile Phase B: Water (containing 5 mM aqueous ammonia), b) Gradient elution, Mobile Phase A content: 40% to 80%, c) Flow rate: 15 mL / min, d) Elution time: 20 min, Retention time: 12.50 min.

[0289] LCMS m / z=452.2[M+1] + 1 H NMR(400MHZ,DMSO-d6)δ 7.31(d,2H),6.94(d,2H),6.55(s,1H),4.89(s,1H),3.92(s,1H),3.83(t, 4H),3.71(s,2H),3.25(t,4H),3.05-3.09(m,1H),2.88-2.95(m,1H),2.53 -2.71(m,2H),2.28-2.45(m,3H),2.09-2.21(m,2H),1.91-2.00(m,1H),1.73-1.88(m,2H). Example 43 [ka]

[0290] Compounds 42-1 and 42-2 were obtained from compound 24A and 1,2,4-triazole by following the procedure of Example 41.

[0291] Chiral separation method: Instrument: Waters 150 Prep-SFC F, SFC column: Chiralcel OJ-Column, Mobile phase: A for CO2, B for 0.1% NH3·H2O in IPA and ACN, Gradient: B 40% isocratic elution, Flow rate: 120mL / min, Back pressure: 100 bar, Column temperature: 25℃, Wavelength: 220nm.

[0292] Compound 42-1: Retention time: 1.217min. 1 H NMR(400MHz,DMSO-d6)δ 9.60(s,1H),8.48(s,1H),6.85(d,1H),6.41 - 6.34(m,2H),4.03 - 3.87(m,2H),3.74 - 3.56(m,2H),3.53 - 3.41(m,3H),3.28 - 3.13(m,5H),3.11 - 2.96(m,6H). LCMS(ESI): m / z=434.2[M+H] + Compound 42-2: Retention time: 1.570min. 1 H NMR(400MHz,DMSO-d6)δ 9.60(s,1H),8.48(s,1H),6.85(d,1H),6.41 - 6.34(m,2H),4.03 - 3.87(m,2H),3.74 - 3.56(m,2H),3.53 - 3.41(m,3H),3.28 - 3.13(m,5H),3.11 - 2.96(m,6H). LCMS(ESI): m / z=434.2[M+H] + Example 44 [ka]

[0293] Step 1: 43A (10.0 g, 46.3 mmol), 1,2-difluoro-4-nitrobenzene (7.3 g, 46.3 mmol), potassium hydroxide (7.8 g, 138.9 mmol), and N,N-dimethylformamide (100 mL) were added to a 250 mL single-neck flask in this order. After 6 h at room temperature, the mixture was heated to 60 °C and reacted for 24 h. After filtration, ethyl acetate (500 mL) was added to the filtrate, which was washed with water (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 43B (10.0 g, 64.5% yield) was obtained by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100). LC-MS(ESI): m / z=336.2[M+H] + .

[0294] Step 2: 43B (10.0 g, 29.9 mmol), ethyl acetate (100 mL), and palladium on carbon (2 g) were added to a 250 mL single-neck flask in this order, and the mixture was hydrogenated and reacted at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to give 43C (7.0 g, 76.9% yield). LC-MS(ESI): m / z=306.2[M+H] + .

[0295] Step 3: Acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), and cuprous iodide (2.24 g, 11.8 mmol) were added sequentially to a 100 mL single-neck flask and heated to 65 °C. A solution of 43C (3.0 g, 9.8 mmol) in acetonitrile (10 mL) was added dropwise. After the addition was complete, the mixture was reacted at 65 °C for 4 hours. After turning off the heater, the mixture was reacted for 12 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to give 43D (0.4 g, 12.6% yield). LC-MS(ESI): m / z=361.2[M-56+H] + .

[0296] Step 4: Methanol (10 mL), 43D (0.5 g, 1.20 mmol), and palladium on carbon (100 mg) were added to a 50 mL single-neck flask in this order, and the mixture was hydrogenated at room temperature for 16 hours. The filtrate was filtered and concentrated under reduced pressure to give 43E (0.3 g, 86.1% yield). LC-MS(ESI): m / z=235.2[M-56+H] + .

[0297] Step 5: 43E (0.3 g, 1.03 mmol) and hydrogen chloride-dioxane solution (4N, 15 mL) were added sequentially to a 50 mL single-neck flask, and the mixture was reacted at room temperature for 1 h. After concentration under reduced pressure, 43F (0.27 g, 99.6% yield) was obtained. LC-MS(ESI): m / z=191.2[M+H] + .

[0298] Step 6: 35H (287 mg, 1.0 mmol), 43F (270 mg, 1.03 mmol), dioxane (10 mL), and DIPEA (774 mg, 6.0 mmol) were added to a 50 mL single-neck flask in this order, and the mixture was reacted at 100 °C for 12 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to give 400 mg of the mixture.

[0299] Chiral separation gave the title compound 43G-1 (62 mg, 14.1%, retention time: 1.733 min) and the title compound 43G-2 (51 mg, 11.5%, retention time: 1.884 min). Chiral separation method: Instrument: Waters 150 MGM, Chromatography column: Chiralpak Column, Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), Isocratic elution: 30% mobile phase B, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Elution time: 3.0 min.

[0300] (Compound 43G-1) 1H NMR(400MHz,DMSO-d6)δ 7.43(s,1H),6.98 - 6.86(m,1H),6.86 - 6.75(m,1H),6.76 - 6.59(m,2H),4.90 - 4.79(m,1H),4.78 - 4.59(m,2H),4.37 - 4.28(m,1H),4.00 - 3.92(m,1H),3.90 - 3.78(m,1H),3.78 - 3.68(m,2H),3.49 - 3.36(m,1H),3.27 - 2.81(m,5H),2.76 - 2.55(m,2H),2.41 - 2.12(m,4H),1.87 - 1.70(m,2H). LC-MS(ESI): m / z=442.2[M+H] + . (Compound 43G-2) 1 H NMR(400MHz,DMSO-d6)δ 7.44(s,1H),6.95 - 6.89(m,1H),6.84 - 6.77(m,1H),6.75 - 6.62(m,2H),4.89 - 4.78(m,1H),4.79 - 4.59(m,2H),4.39 - 4.28(m,1H),4.02 - 3.81(m,2H),3.79 - 3.68(m,2H),3.51 - 3.39(m,1H),3.26 - 3.16(m,1H),3.14 - 2.83(m,4H),2.76 - 2.55(m,2H),2.43 - 2.25(m,2H),2.26 - 2.13(m,2H),1.89 - 1.69(m,2H). LC-MS(ESI): m / z=442.2[M+H] + .

[0301] Step 7: Dichloromethane (5 mL) and 43G-1 (60 mg, 0.14 mmol) were added sequentially to a 50 mL single-neck flask, and trichloroacetyl isocyanate (52 mg, 0.28 mmol) was added dropwise at 0 °C. The mixture was reacted at room temperature for 1 h and concentrated under reduced pressure to give crude 43H, which was used directly in the next step. LC-MS(ESI): m / z=629.1[M+H] + .

[0302] Step 8: Crude 43H, methanol (2 mL), water (2 mL), and potassium carbonate (38 mg, 0.28 mmol) were added to a 50 mL one-neck flask in this order and reacted overnight at room temperature. The reaction mixture was directly concentrated under reduced pressure and then purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to give the title compound 43 (40 mg, 60.6% yield over two steps).

[0303] 1 H NMR(400MHz,DMSO-d6)δ 7.69(s,1H),7.00 - 6.86(m,1H),6.88 - 6.75(m,1H),6.74 - 6.59(m,2H),6.49(s,2H),4.79 - 4.61(m,2H),4.49 - 4.14(m,3H),4.03 - 3.76(m,2H),3.50 - 3.37(m,1H),3.27 - 3.15(m,1H),3.14 - 2.84(m,4H),2.76 - 2.54(m,2H),2.43 - 2.18(m,4H),1.90 - 1.73(m,2H). LC-MS(ESI): m / z=485.2[M+H] + . Example 45 [ka]

[0304] Step 1: p-Chloriodobenzene (5.82 g, 24.41 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a 250 mL three-neck flask, purged with nitrogen, and n-butyllithium (39 mmol, 11.5 mL) was added dropwise at -78 °C. The mixture was reacted for 2 h at -78 °C. A solution of 19A (5 g, 22.19 mmol) in tetrahydrofuran (20 mL) was then added dropwise and the mixture was reacted for 1 h at -78 °C. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and ...

Claims

1. A compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein when Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L １ ) n-(L ２ ) m-, 【Chemistry 2】 When Cy is selected from Cy4, Cy5 and Cy6, L is -L ３ - and 【Chemistry 3】 When Cy is selected from Cy7 and Cy9, L is -L ４ - and 【Chemistry 4】 L １ is -NR ４ -, -CR ５ =N-, -CR ５ =CR ５ - or -CR ５ R ５ - and L ２ teeth, 【Chemistry 5】 C １－４ Alkylene group, C ２－４ Alkenylene group, C ２－４ Alkynylene group, CO, O, NR Ｌ２ , a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 10-membered parallel-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 6- to 10-membered bridged-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkylene group, alkenylene group, alkynylene group, monocyclic heterocycloalkyl group, parallel-ring heterocycloalkyl group, bridged-ring heterocycloalkyl group, and spirocyclic heterocycloalkyl group are optionally selected from halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R Ｌ２ is H, C １－４ Alkyl group or C ３－６ is a cycloalkyl group, L ３ is a heterocycloalkylene group or heterocycloalkylene-(CH ２ ) ｒ -, wherein the heterocycloalkylene group is a 4- to 10-membered heterocyclo containing 1 to 3 heteroatoms selected from N, S, and O, and optionally 1 to 3 R Ｌ３ is replaced by Each R Ｌ３ are independently halogen, ═O, CN, C １－４ Alkyl group or C １－４ alkoxy groups, or R Ｌ３ and R Ｘ１ and the atoms connected thereto together form C ３－６ forming a cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L ４ teeth, 【Chemistry 6】 a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from A is —S(O)—, —C(O)—, —B(OH)—, —S—, —S(═N)—CN, or —C(═N)—CN, X １ , X ２ is an independent CR Ｘ１ , O, S or N; X ３ , X ４ , X ５ are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl group-fused heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; Each R Ｘ１ , R independently represents H, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, —N(CH ３ ) ２ , -NH(CH ３ ), C ２－６ Alkynyl group, NHSO ２ NH ２ , NHCONH ２ , NHCOC １－４ Alkyl group, CONHC １－４ Alkyl group, NHSO ２ C １－４ Alkyl group, SO ２ NHC １－４ Alkyl group, SO ２ C １－４ Alkyl group, SCF ３ , SF ５ , 3- to 5-membered cycloalkyl group, C １－４ a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; Ｘ１ , or R Ｘ１ and R ６ and the atoms connected thereto together form C ３－８ A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R １ is C １－４ Alkyl group, C １－４ Haloalkyl group, C ３－６ a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or R １ and R ２ and the atoms to which they are connected together form a 5-10 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, O, and said cycloalkyl, heterocycloalkyl and heteroaryl groups optionally contain halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R ２ is H, C １－４ Alkyl group or C １－４ is a haloalkyl group, R ３ is H, halogen, C １－４ alkyl group, CN, OH or absent, or R ３ and R ２ , R ３ and R ６ , R ３ and R ４ , or R ３ and R ５ and the atoms connected thereto together form C ３－８ A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally halogenated, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R ｘ４ is H, halogen, C １－４ alkyl group, CN, OH or absent, or R ｘ４ and R ４ , R ｘ４ and R ５ or R ｘ４ and R ６ and the atoms connected thereto together form C ３－８ A cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group, and the heteroaryl group are optionally halogenated, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R ４ is H, C １－４ Alkyl group, C １－４ haloalkyl group or C ３－６ is a cycloalkyl group, R ５ is H, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, —NHC １－４ Alkyl group or C ３－６ is a cycloalkyl group, R ６ is H, halogen, ═O, CN, C １－４ Alkyl group or C １－４ is an alkoxy group, R ｘ５ is C １－４ alkyl group, CN, OH or absent, R ７ is C １－４ Alkyl group, C １－４ Haloalkyl group, C ３－６ a cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or R ７ and R ９ and the atoms to which they are connected together form a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and said alkyl, haloalkyl, cycloalkyl and heterocycloalkyl groups are optionally selected from halogen, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R ９’ and R ７ , or R ９’ and R ｘ５ and the atoms connected thereto are taken together as C ３－８ a cycloalkyl group, a phenyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, the phenyl group, the heterocycloalkyl group, and the heteroaryl group are optionally C １－４ Alkyl group, hydroxy C １－４ Alkyl group, mercapto C １－４ Alkyl group, halogen, haloC １－４ Alkyl group, ═O, OH, NH ２ , CN or R ８’ is substituted with 1 to 3 groups selected from R ８ is R ８’ , -OR ８’ or -(CH ２ ) ｒ R ８’ and R ８’ is C ３－６ a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; -N=S(=O)(C １－４ alkyl) ２ or -N(C ３－６ cycloalkyl)C(O)NH(C １－４ alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C １－４ Alkyl group, hydroxy C １－４ Alkyl group, mercapto C １－４ Alkyl group, halogen, haloC １－４ Alkyl group, ═O, OH, NH ２ , CN; R ９ is H, C １－４ Alkyl group or C １－４ is a haloalkyl group, Each R １０ are independently R ８’ , -OR ８’ , -NHR ８’ or -(CH ２ ) ｒ R ８’ and R １１ is C ３－６ a cycloalkyl group, said cycloalkyl group optionally containing 1 to 3 halogen atoms, CN, ═O, OH, C １－４ Alkyl group, hydroxy C １－４ Alkyl group and C １－４ substituted with haloalkyl groups; R １２ represents a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C １－６ Alkyl group, C １－４ Alkyl-CN, -CRaRb=N-O-C １－４ alkyl group, -C(NRaRb)=N-CN, -C(C １－４ -C(NRaRb)=CRa-NO ２、 -C(CH ３ ) ２ -CH ２ —O—C(O)NH ２ , -C(CH ３ ) ２ -CH ２ -NH-C(O)O(C １－４ alkyl), -C(CH ３ ) ２ -CH ２ -OC(O)NHCH ３ , -CH(CH ３ )-CH ２ —O—C(O)NH ２ , -CH(CH ３ )-CH ２ -NH-C(O)O(C １－４ alkyl), -CH(CH ３ )-CH ２ -OC(O)NHCH ３ , —C(O)—Ra, or —C(O)—(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, —SF ５ , C １－４ Alkyl group, C １－４ Alkyl-CN, Hydroxy-C １－４ Alkyl group, C １－４ Haloalkyl groups, -(CH ２ ) ｔ —O—C(O)NH ２ , -(CH ２ ) ｔ -NRa-C(O)NH ２ , -(CH ２ ) ｔ -NRa-C(=NH)NH ２ , -(CH ２ ) ｔ -NRa-C(O)-O-(C １－４ alkyl), -(CH ２ ) ｔ -NRa-C(C １－４ alkyl)=N—CN, —(CH ２ ) ｔ -NRa-C (NRaRb)=N-CN, -(CH ２ ) ｔ -NRa-C(NRaRb)=CRa-NO ２ , -(CH ２ ) ｔ -C(NRaRb)=N-CN, -(CH ２ ) ｔ -C(C １－４ alkyl)=N—CN, —(CH ２ ) ｔ -C(C １－４ alkyl)=N—O—(C １－４ alkyl), ═N—O—C １－４ an alkyl group, a 5- to 6-membered heteroaryl group, —(CH ２ ) ｔ -O-C １－４ Alkyl group, -(CH ２ ) ｔ -OC(O)NHCH ３ , -(CH ２ ) ｔ -O-C １－２ Haloalkyl groups, -(CH ２ ) ｔ -O-C ３－６ cycloalkyl groups, -(CH ２ ) ｔ -O-C １－４ Alkyl-O-C ３－６ cycloalkyl groups, -(CH ２ ) ｔ -COOH, -(CH ２ ) ｔ -NRaRb, -(CH ２ ) ｔ -C(O)NRaRb, -(CH ２ ) ｔ -NRa-C(O)CH ３ is substituted with a group Ra and Rb each independently represent H, halogen, or C. １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, halo C １－４ an alkoxy group or a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O; Optionally, Ra, Rb and the atoms connected thereto together form C ３－６ forming a cycloalkyl group, R １３ is a 7- to 11-membered spiro ring, a 4- to 10-membered parallel ring, a 5- to 8-membered heterocyclic bridged ring, S(O) ２ a 4- to 6-membered monocyclic heterocycloalkyl group containing one to three heteroatoms selected from N, S, and O; a 4-membered monocyclic heterocycloalkyl group containing one to three heteroatoms selected from N, S, and O; and a 7-membered monocyclic heterocycloalkyl group containing one to three heteroatoms selected from N, S, and O, wherein the spiro ring, parallel ring, heterocyclobridged ring, and monocyclic heterocycloalkyl group optionally contain one to three halogen atoms, CN, ═O, OH, C １－４ Alkyl group, hydroxy C １－４ Alkyl group and C １－４ substituted with haloalkyl groups; R １４ is -(CH ２ ) ｔ —O—C(O)NH ２ , -(CH ２ ) ｔ -OC(O)NHCH ３ , N, S, O, wherein the monocyclic heterocycloalkyl group optionally contains 1 to 3 halogen atoms, CN, ═O, OH, C １－４ Alkyl group and C １－４ substituted with haloalkyl groups; n and m are independently 0, 1, 2, or 3; r is selected from 1, 2, 3 or 4; t is selected from 0, 1, 2, 3, or 4; p is selected from 0 or 1; As a condition, Cy1 is 【Chemistry 7】 A compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, which is not:

2. Ring B is a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a tetrahydropyrrolopyrrolyl group, a tetrahydropyrroloiimidazolyl group, or a thienopyrrolyl group; R １ is C １－４ Alkyl group or C １－４ haloalkyl group, or R １ and R ２ and the atoms connected thereto together form a 5-7 membered monocyclic heterocycloalkyl group, a 6-8 membered parallel cyclic heterocycloalkyl group, a 7-9 membered spirocyclic heterocycloalkyl group, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, B, O, and said monocyclic heterocycloalkyl group, parallel cyclic heterocycloalkyl group, spirocyclic heterocycloalkyl group, and heteroaryl group optionally containing halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R ２ is H, C １－４ Alkyl group or C １－４ is a haloalkyl group, R ３ is H, halogen, C １－４ alkyl group, CN, OH or absent, or R ３ and R ２ and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl groups are optionally selected from halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from or R ３ and R ４ , or R ３ and R ５ and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, or a phenyl group containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycloalkyl group, phenyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from or R ３ and R ６ and the atoms connected thereto together form C ５－７ A cycloalkyl group, a 5- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally selected from halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R ｘ４ is H, halogen, C １－４ alkyl group, CN, OH or absent, or R ｘ４ and R ４ , or R ｘ４ and R ５ and the atoms to which they are connected together form a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, said heteroaryl group optionally containing halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R ７ is C １－４ Alkyl group or C １－４ haloalkyl group, or R ７ and R ９ and the atoms to which they are connected together form a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, said heterocycloalkyl group optionally containing halogen, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R ９’ and R ７ , or R ９’ and R ｘ５ and the atoms connected thereto together form a 5- to 7-membered monocyclic heterocycloalkyl group, a 7- to 10-membered spirocyclic heterocycloalkyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycloalkyl group, spirocyclic heterocycloalkyl group, and heteroaryl group are optionally C １－４ Alkyl group, hydroxy C １－４ Alkyl group, mercapto C １－４ Alkyl group, halogen, haloC １－４ Alkyl group, ═O, OH, NH ２ , CN or R ８’ is substituted with 1 to 3 groups selected from 2. The compound of claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2.

3. Each L ２ is independently 【Chemistry 8】 CO, O, NR Ｌ２ , C １－４ Alkylene group, C ２－４ Alkenylene group, C ２－４ alkynylene groups, 【Chemistry 9】 is selected from R Ｌ２ is H, C １－４ Alkyl group or C ３－６ is a cycloalkyl group, L ３ teeth, 【Chemistry 10】 is selected from Each R Ｌ３ are independently halogen, ═O, CN, C １－４ Alkyl group or C １－４ alkoxy groups, or R Ｌ３ and R Ｘ１ and the atoms connected thereto together form C ３－６ forming a cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; L ４ teeth, 【Chemistry 11】 is selected from A is —S(O)—, —C(O)—, —B(OH)—, —S—, or —S(═N)—CN; Cy5 is 【Chemistry 12】 is selected from Each R Ｘ１ , R independently represents H, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, —N(CH ３ ) ２ , -NH(CH ３ ), C ２－４ Alkynyl group, NHSO ２ NH ２ , NHCONH ２ , NHCOC １－４ Alkyl group, CONHC １－４ Alkyl group, NHSO ２ C １－４ Alkyl group, SO ２ NHC １－４ Alkyl group, SO ２ C １－４ Alkyl group, SCF ３ , SF ５ , 3- to 5-membered cycloalkyl group, C １－４ a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; Ｘ１ , or R Ｘ１ and R ６ and the atoms connected thereto together form C ３－６ A cycloalkyl group, a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and the cycloalkyl group, the heterocycloalkyl group optionally contains halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R １ is C １－４ Alkyl group or C １－４ is a haloalkyl group, or R １ and R ２ and the atoms connected thereto together form the following ring: 【Chemistry 13】 and optionally halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R ３ is H, halogen, C １－４ alkyl group, CN, OH or absent, or R ３ and R ２ and the atoms connected thereto together form the following ring: 【Chemistry 14】 and optionally halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from or R ３ and R ４ , or R ３ and R ５ and the atoms connected thereto together form a 5-6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, or a phenyl group containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycloalkyl group, phenyl group, and heteroaryl group are optionally selected from halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from or R ３ and R ６ and the atoms connected thereto together form C ５－６ Form a cycloalkyl group or a 5-6 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and optionally halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from R ｘ４ is H, halogen, C １－４ alkyl group, CN, OH or absent, or R ｘ４ and R ４ , or R ｘ４ and R ５ and the atoms connected thereto together form an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, and optionally a halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R ４ is H, C １－４ Alkyl group or C １－４ is a haloalkyl group, R ５ is H, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group or -NHC １－４ is an alkyl group, R ６ is H, halogen, ═O, CN, C １－４ Alkyl group or C １－４ is an alkoxy group, R ７ is C １－４ Alkyl group or C １－４ haloalkyl group, or R ７ and R ９ and the atoms connected thereto together form the following ring: 【Chemistry 15】 and forming a ring selected from the group consisting of: １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ is substituted with 1 to 3 groups selected from or R ９’ and R ７ and the atoms connected thereto together form the following ring: 【Chemistry 16】 and optionally forming a ring selected from C １－４ Alkyl group, hydroxy C １－４ Alkyl group, mercapto C １－４ Alkyl group, halogen, haloC １－４ Alkyl group, ═O, OH, NH ２ , CN or R ８’ is substituted with 1 to 3 groups selected from or R ９’ and R ｘ５ and the atoms connected to them together 【Chemistry 17】 and optionally forming C １－４ Alkyl group, hydroxy C １－４ Alkyl group, mercapto C １－４ Alkyl group, halogen, haloC １－４ Alkyl group, ═O, OH, NH ２ , CN or R ８’ is substituted with 1 to 3 groups selected from As a condition, R ９’ and R ７ , or R ９’ and R ｘ５ At least one pair of R ８ is R ８’ , -OR ８’ or -(CH ２ ) ｒ R ８’ and R ８’ is C ３－６ a cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, and P; a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; -N=S(=O)(C １－４ alkyl) ２ or -N(C ３－６ cycloalkyl)C(O)NH(C １－４ alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally C １－４ Alkyl group, hydroxy C １－４ Alkyl group, mercapto C １－４ Alkyl group, halogen, haloC １－４ Alkyl group, ═O, OH, NH ２ , CN; R ９ is H or C １－４ is an alkyl group, Each R １０ are independently R ８’ , -OR ８’ , -NHR ８’ or -(CH ２ ) ｒ R ８’ and R １１ is C ３－６ a cycloalkyl group, said cycloalkyl group optionally containing 1 to 3 halogen atoms, CN, ═O, OH, C １－４ Alkyl group, hydroxy C １－４ Alkyl group and C １－４ substituted with haloalkyl groups; R １２ represents a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopropyl group, an adamantyl group, a tetrahydropyranyl group, a piperidinyl group, an oxacyclopentyl group, an oxacyclohexyl group, 【Chemistry 18】 C １－４ Alkyl-CN, -C(NHC １－２ alkyl)=N—CN, —C(C １－２ alkyl)=N—CN, —C(NHC １－２ alkyl)=CH-NO ２、 -CH(CH ３ )-CH ２ -NH-C(O)O(CH ３ ), -C(CH ３ ) ２ -CH ２ -NH-C(O)O(CH ３ ), -CH(CH ３ )-CH ２ —O—C(O)NH ２ , -C(CH ３ ) ２ -CH ２ —O—C(O)NH ２ , -C(O)-Ra, -CH(CH ３ )-CH ２ -OC(O)NHCH ３ or -C(CH ３ ) ２ -CH ２ -OC(O)NHCH ３ wherein the ring is optionally selected from halogen, CN, OH, —SF ５ , C １－４ Alkyl group, C １－４ Alkyl-CN, Hydroxy-C １－４ Alkyl group, C １－４ Haloalkyl groups, -(CH ２ ) ｔ —O—C(O)NH ２ , -(CH ２ ) ｔ -NH-C(O)NH ２ , -(CH ２ ) ｔ -NH-C(=NH)NH ２ , -(CH ２ ) ｔ -NH-C(O)-O-(C １－２ alkyl), -(CH ２ ) ｔ -NH-C(C １－２ alkyl)=N—CN, —(CH ２ ) ｔ -NH-C(NHC １－２ alkyl)=N—CN, —(CH ２ ) ｔ -NH-C(NHC １－２ alkyl)=CH-NO ２ , -(CH ２ ) ｔ -C(NHC １－２ alkyl)=N—CN, —(CH ２ ) ｔ -C(C １－２ alkyl)=N—CN, —(CH ２ ) ｔ -C(C １－２ alkyl)=N—O—(C １－２ alkyl), ═N—O—C １－２ an alkyl group, a 5- to 6-membered heteroaryl group, —(CH ２ ) ｔ -O-C １－４ Alkyl group, -(CH ２ ) ｔ -OC(O)NHCH ３、 - (CH ２ ) ｔ -O-C １－２ Haloalkyl groups 、 - (CH ２ ) ｔ -O-C ３－６ cycloalkyl groups, -(CH ２ ) ｔ -O-C １－４ Alkyl-O-C ３－６ cycloalkyl groups, -(CH ２ ) ｔ -COOH, -(CH ２ ) ｔ -NRaRb, -(CH ２ ) ｔ -C(O)NRaRb, -(CH ２ ) ｔ -NRa-C(O)CH ３ is substituted with 1 to 3 groups selected from R １３ teeth, 【Chemistry 19】 wherein the ring is optionally selected from halogen, CN, OH, C １－４ Alkyl group, hydroxy C １－４ Alkyl group, C １－４ substituted with 1 to 3 groups selected from haloalkyl groups; n is 0, 1, 2 or 3; m is 0, 1 or 2; r is 1 or 2; 3. The compound of claim 2, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein t is selected from 0, 1 or 2.

4. Cy1 is 【Chemistry 20】 is selected from Cy2 is 【Chemical 21】 is selected from Cy4 is 【Chemical 22】 is selected from Cy5 is 【Chemical 23】 is selected from Cy7 is 【Chemistry 24】 【Chemistry 25】 is selected from Cy9 is 【Chemical 26】 3. The compound of claim 1 or 2, a stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

5. - (L １ ) n-(L ２ ) m- is 【Chemical 27】 and R ６ is H, -L ３ -teeth, 【Chemical Formula 28】 is selected from -L ４ -teeth, 【Chemical 29】 is selected from 【Chemistry 30】 optionally, 1 to 3 R Ｒ The following structure substituted with: 【Chemical 31】 and R Ｒ each independently represents F, Cl, Br, a methyl group, an isopropyl group, an ethoxy group, a methoxy group, an ethynyl group, a propynyl group, a cyclopropyl group, a cyclobutyl group, a dimethylamino group, 【Chemical 32】 and R Ｘ１ is H, or R Ｘ１ and R ６ and the atoms to which they are linked together form a morpholino group, a furyl group, a pyrrolyl group, or a thienyl group, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4. 【Request 6】 【Chemical 33】 Here, L ４ teeth, 【Chemical 34】 a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 7- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; a 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O; and a 7- to 12-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered heterocycloalkyl group, the 5- to 6-membered heterocycloalkyl-fused 5- to 6-membered cycloalkyl group, and the spirocyclic heterocycloalkyl group are optionally halogenated, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from A is —S(O)—, —C(O)—, —B(OH)—, —S—, —S(═N)—CN, or —C(═N)—CN, X １ , X ２ is an independent CR Ｘ１ , S or N; R Ｌ２ is H, C １－４ Alkyl group or C ３－６ is a cycloalkyl group, R ６ is H, halogen, ═O, CN, C １－４ Alkyl group or C １－４ is an alkoxy group, Each R Ｘ１ , R independently represents H, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, —N(CH ３ ) ２ , -NH(CH ３ ), C ２－６ Alkynyl group, NHSO ２ NH ２ , NHCONH ２ , NHCOC １－４ Alkyl group, CONHC １－４ Alkyl group, NHSO ２ C １－４ Alkyl group, SO ２ NHC １－４ Alkyl group, SO ２ C １－４ Alkyl group, SCF ３ , SF ５ , 3- to 5-membered cycloalkyl group, C １－４ a haloalkyl group or a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; Ｘ１ , or R Ｘ１ and R ６ and the atoms connected thereto together form C ３－８ A cycloalkyl group, a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally substituted with halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R １ and R ２ and the atoms to which they are connected together form a 5-10 membered heterocycloalkyl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, B, O, and said cycloalkyl, heterocycloalkyl and heteroaryl groups optionally contain halogen, ═O, CN, C １－４ Alkyl group, C １－４ Alkoxy groups, OH and NH ２ and is substituted with 1 to 3 groups selected from R １２ represents a 4- to 10-membered heterocycloalkylene group, a 3- to 10-membered cycloalkylene group, a 6- to 10-membered arylene group, a 5- to 10-membered heteroarylene group, a hydroxy-C １－６ Alkyl group, C １－４ Alkyl-CN, -CRaRb=N-O-C １－４ alkyl group, -C(NRaRb)=N-CN, -C(C １－４ -C(NRaRb)=CRa-NO ２、 -C(CH ３ ) ２ -CH ２ —O—C(O)NH ２ , -C(CH ３ ) ２ -CH ２ -NH-C(O)O(C １－４ alkyl), -C(CH ３ ) ２ -CH ２ -OC(O)NHCH ３ , -CH(CH ３ )-CH ２ —O—C(O)NH ２ , -CH(CH ３ )-CH ２ -NH-C(O)O(C １－４ alkyl), -CH(CH ３ )-CH ２ -OC(O)NHCH ３ , —C(O)—Ra, or —C(O)—(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkylene group, cycloalkylene group, arylene group, or heteroarylene group optionally further comprises 1 to 3 halogen atoms, such as CN, ═O, OH, —SF ５ , C １－４ Alkyl group, C １－４ Alkyl-CN, Hydroxy-C １－４ Alkyl group, C １－４ Haloalkyl groups, -(CH ２ ) ｔ —O—C(O)NH ２ , -(CH ２ ) ｔ -NRa-C(O)NH ２ , -(CH ２ ) ｔ -NRa-C(=NH)NH ２ , -(CH ２ ) ｔ -NRa-C(O)-O-(C １－４ alkyl), -(CH ２ ) ｔ -NRa-C(C １－４ alkyl)=N—CN, —(CH ２ ) ｔ -NRa-C (NRaRb)=N-CN, -(CH ２ ) ｔ -NRa-C(NRaRb)=CRa-NO ２ , -(CH ２ ) ｔ -C(NRaRb)=N-CN, -(CH ２ ) ｔ -C(C １－４ alkyl)=N—CN, —(CH ２ ) ｔ -C(C １－４ alkyl)=N—O—(C １－４ alkyl), ═N—O—C １－４ an alkyl group, a 5- to 6-membered heteroaryl group, —(CH ２ ) ｔ -O-C １－４ Alkyl group, -(CH ２ ) ｔ -OC(O)NHCH ３ , -(CH ２ ) ｔ -O-C １－２ Haloalkyl groups, -(CH ２ ) ｔ -O-C ３－６ cycloalkyl groups, -(CH ２ ) ｔ -O-C １－４ Alkyl-O-C ３－６ cycloalkyl groups, -(CH ２ ) ｔ -COOH, -(CH ２ ) ｔ -NRaRb, -(CH ２ ) ｔ -C(O)NRaRb, -(CH ２ ) ｔ -NRa-C(O)CH ３ is substituted with a group Ra and Rb each independently represent H, halogen, or C. １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, halo C １－４ an alkoxy group or a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O; 2. The compound of claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein p is selected from 0 or 1.

7. L ４ teeth, 【Chemistry 35】 and R １２ is -C(CH ３ ) ２ -CH ２ —O—C(O)NH ２ , -C(CH ３ ) ２ -CH ２ -NH-C(O)O(C １－４ alkyl), -C(CH ３ ) ２ -CH ２ -OC(O)NHCH ３ , -CH(CH ３ )-CH ２ —O—C(O)NH ２ , -CH(CH ３ )-CH ２ -NH-C(O)O(C １－４ alkyl), -CH(CH ３ )-CH ２ -OC(O)NHCH ３ 7. The compound of claim 6, a stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

8. 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures in Table 1.

9. 2. The compound of claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures in Table 2.

10. A pharmaceutical composition or pharmaceutical formulation comprising the compound according to any one of claims 1 to 9, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

11. 11. The pharmaceutical composition or formulation according to claim 10, comprising 1 to 1500 mg of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

12. Use of a compound according to any one of claims 1 to 9, a stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating / preventing a PDE4B-mediated disease.

13. 10. A method for treating a disease in a mammal or human, said method comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, said therapeutically effective amount being preferably 1 to 1500 mg, and said disease being preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

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