PDE4B inhibitors and uses thereof

Abstract

The invention relates to a compound as shown in a formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound and the stereoisomer or the pharmaceutically acceptable salt thereof, and application of the compound and the stereoisomer or the pharmaceutically acceptable salt thereof as a PDE4B inhibitor in preparation of drugs for treating related diseases, and all groups in the formula (I) are defined in the specification. # imgabs0 #

Description

PDE4B inhibitors and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with PDE4B selective inhibitory activity, its stereoisomers or pharmaceutically acceptable salts, and use thereof in preparing medicines for treating related diseases. Background Art

[0002] PDE4 inhibitors produce 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. Significant progress has also been made in the research and development of PDE4 inhibitors for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. The rationale behind the development of these drugs stems from the role of PDE4 in inhibiting the functions of a range of inflammatory cells and resident cells, which is believed to be involved in the pathogenesis of these diseases. Numerous clinical studies have demonstrated that cyclic adenosine monophosphate (cAMP) can block the proliferation and chemotaxis of inflammatory cells and inhibit the release of inflammatory and cytotoxic mediators in the lungs. Furthermore, PDE4 is particularly abundant in immune cells, inflammatory cells, and smooth muscle cells.

[0003] PDE4 inhibitors primarily exert their anti-inflammatory effects by inhibiting PDE4 hydrolysis, increasing cAMP levels in the body, suppressing the release of inflammatory factors, and promoting the production of anti-inflammatory mediators. Roflumilast is clinically used to treat COPD and has significant anti-inflammatory effects, inhibiting the release of inflammatory mediators such as TNF-α, interleukins, and chemokines by monocytes, macrophages, and T cells. However, these inhibitors are commonly associated with serious side effects such as nausea and vomiting, which limits their clinical application. Numerous studies have shown that in humans, isoform B of phosphodiesterase 4 (PDE4B) is associated with inflammatory responses and participates in the release of various inflammatory mediators, while isoform D is closely associated with side effects such as nausea and vomiting. This provides new insights into the discovery of PDE4 inhibitors with reduced side effects. Designing PDE4B inhibitors may reduce the impact of these side effects and promote further clinical application.

[0004] Phosphodiesterase 4 (PDE4A), a phosphodiesterase (PDE4B), is highly selective for cAMP and has four isoforms: PDE4A, 4B, 4C, and 4D, with at least 25 splice variants. The catalytic domains of the four PDE4 isoforms share high protein sequence homology, making inhibitors targeting the catalytic domain non-selective. However, most reported classical PDE4 inhibitors target the catalytic domain. In recent years, novel modes of action of PDE4 inhibitors have been reported, in which inhibitors interact simultaneously with both the catalytic domain and regulatory sequences, enabling the regulatory sequences to stabilize the protein's closed conformation, preventing cAMP entry and exerting inhibitory effects. Studies have discovered amino acid differences between PDE4B and 4D in these regulatory sequences, which can be exploited to design inhibitors that exhibit isoform selectivity. Therefore, targeting the two amino acid differences in PDE4B Leu674 / PDE4D Gln594 in the downstream regulatory region CR3 (Conserved Region 3) offers the potential to achieve selectivity for isoform B, while maintaining activity and minimizing inhibitor side effects.

[0005] A selective PDE4B inhibitor with good activity, high safety and few side effects has been discovered, which has good clinical development prospects and can be used to treat COPD or cancer or other proliferative diseases or conditions.

[0006] Summary of the Invention

[0007] The present invention provides a small molecule compound having PDE4B inhibitory activity, its stereoisomers or pharmaceutically acceptable salts, wherein the compound is represented by formula (I), and has high activity, low toxic side effects, excellent pharmacokinetic characteristics and bioavailability;

[0008] wherein, when Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L1)n-(L2)m-;

[0009] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-;

[0010] When Cy is selected from Cy7 and Cy9, L is -L4-;

[0011] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; in all embodiments of the present invention, unless otherwise specified, the connection site of L1 is arbitrary, for example, as L1 (-CR2=N-) connected to L2, its N atom and C atom can serve as the site of connection with L2;

[0012] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; in some embodiments, each L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; in some embodiments, each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0013] In some embodiments, each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C2-4 Alkynylidene, In some embodiments, each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0014] In all embodiments of the present invention, unless otherwise specified, the connection sites of L2 and the left and right groups are arbitrary, for example, as a terminal Both N atoms and C atoms can serve as sites for attachment to Cy;

[0015] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl; in some embodiments, R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl; in some embodiments, R L2 is H, methyl, ethyl, propyl or isopropyl;

[0016] L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 Substituted; In some embodiments, L3 is selected from In some embodiments, L3 is selected from

[0017] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O; in some embodiments, each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O;

[0018] L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0019] In some embodiments, L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; in some embodiments, L4 is 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, the 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; in some embodiments, L4 is selected from

[0020] In some embodiments, L4 is selected from

[0021] In some embodiments, L4 is

[0022] In some embodiments, L4 is In some embodiments, L4 is In some embodiments, L4 is 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)-;

[0023] X1 and X2 are independently CR X1 , O, S or N; In some embodiments, X1 and X2 are independently CR X1 , S or N; In some embodiments, X1, X2 are independently S or N; In some embodiments, X1, X2 are independently CR X1 or N; in some embodiments, X1, X2 are CR X1 ; In some embodiments, X1 and X2 are independently N;

[0024] X3, X4, X5 are independently C or N; in some embodiments, X3, X4 are independently N;

[0025] Ring B is heteroaryl or heterocycloalkyl and heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl is a 5-6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O; in some embodiments, Cy5 is selected from

[0026] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 3-6 Cycloalkyl, C 2-6 Alkynyl and NH2 groups; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 3-6 Cycloalkyl, C 2-6 Alkynyl and NH2 groups; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or RX1 , R is independently a 3-5 membered cycloalkyl group, or two R, R and R on adjacent ring atoms are X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0027] R1 is C 1-4 Alkyl, C 1-4Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; in some embodiments, R1 is C 1-4 Alkyl or C 1-4 haloalkyl, or R1 and R2 and the atoms to which they are attached together form a 5-7 membered monoheterocycloalkyl, a 6-8 membered cyclic heterocycloalkyl, a 7-9 membered spirocyclic heterocycloalkyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, and O, wherein the monoheterocycloalkyl, cyclic heterocycloalkyl, spirocyclic heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; in some embodiments, R1 is C 1-4 Alkyl or C 1-4 haloalkyl; or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0028] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0029] Or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0030] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0031] Or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0032] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 or R1 and R2 and the atoms to which they are attached together form a ring selected from the group consisting of:

[0033] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C1-4 In some embodiments, R1 and R2 and the atoms to which they are attached together form a ring selected from the group consisting of:

[0034] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0035] R2 is H, C 1-4 Alkyl or C 1-4 In some embodiments, R2 is H, C 1-4 Alkyl or C 1-4 haloalkyl; in some embodiments, R3 together with R2 and the atoms to which they are attached form a ring selected from: and optionally substituted by 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0036] R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 In some embodiments, R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent; or R3 and R2 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0037] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4Alkoxy, OH and NH2 group substitution;

[0038] Or R3 and R6 together with the atoms to which they are attached form C 5-7 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0039] In some embodiments, R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent;

[0040] Or R3 together with R2 and the atoms to which they are attached form a ring selected from the following: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0041] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0042] Or R3 and R6 together with the atoms to which they are attached form C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0043] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4Alkoxy, OH and NH2 groups are substituted; in some embodiments, R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the heteroaryl is optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; in some embodiments, R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present; or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms imidazolyl, pyrazolyl, pyrrolyl, thienyl or thiazolyl, and is optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0044] R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 In some embodiments, R4 is H, C 1-4 Alkyl or C 1-4 Haloalkyl; in some embodiments, R4 is H, methyl, ethyl, propyl, isopropyl, or halogenated methyl, ethyl, propyl, isopropyl, and halogen includes F, Cl, Br, I;

[0045] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 In some embodiments, R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -NHC 1-4 alkyl;

[0046] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 Alkoxy; in some embodiments, R6 is H, halogen, =O, CN, methyl, ethyl, propyl, isopropyl or methoxy, ethoxy, propoxy, isopropoxy;

[0047] R x5 C 1-4alkyl, CN, OH or absent; in some embodiments, R x5 is methyl, ethyl, propyl, isopropyl, CN, OH or absent;

[0048] R7 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 In some embodiments, R7 is C 1-4 Alkyl or C 1-4 Haloalkyl, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the heterocycloalkyl being optionally substituted by 1-3 heteroatoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 In some embodiments, R7 is C 1-4 Alkyl or C 1-4 haloalkyl, or R7 and R9 together with the atoms to which they are attached form a ring selected from:

[0049] The ring is optionally substituted by 1-3 atoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0050] In the present invention, R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ In some embodiments, R 9’ With R7, or R 9’ With R x5At least one group and the atoms connected thereto together form a 5-7 membered monoheterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the monoheterocycloalkyl, spirocyclic heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ In some embodiments, R 9’ Together with R7 and the atoms to which it is attached, it forms a ring selected from: and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0051] or R 9’ With R x5 and its connected atoms together to form and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The condition is that R 9’ With R7, or R 9’ With R x5 At least one of them is a ring;

[0052] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0053] R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O or -N=S(=O)(C 1-4 alkyl) 2 or -N (C3-6 cycloalkyl) C (O) NH (C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C1-4 alkyl, =O, OH, NH2, CN; in some embodiments, R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 alkyl, =O, OH, NH2, CN; in some embodiments, R 8’ C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0054] R9 is H, C 1-4 Alkyl or C 1-4 In some embodiments, R9 is H or C 1-4 Alkyl; in some embodiments, R9 is H, methyl, ethyl, propyl or isopropyl;

[0055] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0056] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 In some embodiments, the cycloalkyl is optionally substituted with 1-3 F, Cl, Br, I, CN, =O, OH, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, halogenated methyl, ethyl, propyl, isopropyl, etc., and halogen includes F, Cl, Br, I;

[0057] R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6Alkyl, C 1-4 Alkyl -CN, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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 alkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0058] In some embodiments, R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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 alkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0059] In some embodiments, R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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, cycloalkylene, arylene and heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; in some embodiments, R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxyl C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -C(NRaRb)=CRa-NO2 or -C(CH3) t-CH2-OC(O)NHCH3, wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene may be further substituted with 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl; in some embodiments, R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, or 5-10 membered heteroarylene, wherein the heterocycloalkylene, cycloalkylene, arylene, or heteroarylene is optionally further substituted with 1-3 halogens, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 In some embodiments, R 12 Selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, wherein the heterocycloalkylene and cycloalkylene are optionally further substituted by 1-3 halogens, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 In some embodiments, R 12is selected from 4-6 membered monoheterocycloalkylene, 6-10 membered heterocyclic ring, 7-8 membered heterocyclic bridged ring, 7-10 membered heterocyclic spiro ring, 3-6 membered monocycloalkylene, 6-10 membered carbocyclic ring, 7-8 membered carbocyclic bridged ring, 7-10 membered carbocyclic spiro ring, wherein the monoheterocycloalkylene, heterocyclic ring, heterocyclic bridged ring, heterocyclic spiro ring, monocycloalkylene, carbocyclic ring, carbocyclic bridged ring, carbocyclic spiro ring are optionally further substituted by 1-3 halogens, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 In some embodiments, R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, 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; the ring is optionally substituted by 1-3 atoms selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; in some embodiments, R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, -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; the ring is optionally substituted by 1-3 atoms selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; in some embodiments, R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 Alkyl) = N-CN, -C(NHC1-2 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; the ring is optionally substituted by 1-3 atoms selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3; in some embodiments, R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 Alkyl) = N-CN or -C(NHC 1-2 Alkyl) = CH-NO2; the ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl; in some embodiments, R 12 Selected from cycloalkyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C1-4 Alkyl, C 1-4 In some embodiments, R 12 Selected from -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;

[0060] Ra and Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O; or Ra, Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkoxy;

[0061] Alternatively, Ra, Rb and their atoms together form C 3-6 Cycloalkyl;

[0062] R 13 7-11 membered spirocyclic, 4-10 membered cyclic, 5-8 membered heterocyclic bridged ring, 4-6 membered monocyclic heterocycloalkyl containing S(O)2 group, 4 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the spirocyclic, cyclic, heterocyclic bridged ring, monocyclic heterocycloalkyl optionally substituted by 1-3 halogen, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 In some embodiments, R 13 Selected from The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 The radical of haloalkyl is substituted; R 14 Selected from -(CH2) t -OC(O)NH2, -(CH2) t-OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, CN, =O, OH, C 1-4 Alkyl and C 1-4 In some embodiments, R 14 Selected from -(CH2) t -OC(O)NH2, 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O; in some embodiments, R 14 Selected from -(CH2) t -OC(O)NH2, n and m are independently 0, 1, 2, or 3; in some embodiments, n is 0, 1, 2, or 3; in some embodiments, m is 0, 1, or 2;

[0063] r is 1, 2, 3, or 4; in some embodiments, r is 1 or 2;

[0064] t is selected from 0, 1, 2, 3, or 4; in some embodiments, t is selected from 0, 1, or 2;

[0065] p is selected from 0 or 1;

[0066] The condition is,

[0067] Cy1 is not

[0068] The present invention provides a more specific technical solution 1, a compound shown in Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0069] wherein, when Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L1)n-(L2)m-;

[0070] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-;

[0071] When Cy is selected from Cy7 and Cy9, L is -L4-;

[0072] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-;

[0073] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0074] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0075] L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 replace;

[0076] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O;

[0077] L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4Alkoxy, OH and NH2 group substitution;

[0078] In some embodiments, L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0079] X1 and X2 are independently CR X1 , O, S or N;

[0080] X3, X4, and X5 are independently C or N;

[0081] Ring B is a heteroaryl group or a heterocycloalkyl-heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0082] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0083] Or each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 3-6 Cycloalkyl, C 2-6 Alkynyl and NH2 group substitution;

[0084] Or each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1, or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0085] Or each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl or C 1-4 Haloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0086] R1 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0087] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0088] R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0089] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0090] R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0091] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0092] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0093] R x5 C 1-4 Alkyl, CN, OH or absent;

[0094] R7 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0095] R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0096] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0097] R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, -N=S(=O)(C 1-4 Alkyl)2 or -N(C 3-6 Cycloalkyl)C(O)NH(C 1-4 Alkyl), the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0098] R9 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0099] Each R 10 Independently R 8’ 、-OR8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0100] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0101] R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, C 1-4 Alkyl -CN, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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 alkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0102] Or, R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0103] Ra and Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O;

[0104] Alternatively, Ra, Rb and their atoms together form C 3-6 Cycloalkyl;

[0105] R 13 7-11 membered spirocyclic, 4-10 membered cyclic, 5-8 membered heterocyclic bridged ring, 4-6 membered monocyclic heterocycloalkyl containing S(O)2 group, 4 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the spirocyclic, cyclic, heterocyclic bridged ring, monocyclic heterocycloalkyl optionally substituted by 1-3 halogen, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0106] R 14 Selected from -(CH2) t -OC(O)NH2, -(CH2) t -OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, CN, =O, OH, C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0107] n and m are independently 0, 1, 2 or 3;

[0108] r is selected from 1, 2, 3 or 4;

[0109] t is selected from 0, 1, 2, 3 or 4;

[0110] p is selected from 0 or 1;

[0111] The condition is,

[0112] Cy1 is not

[0113] The present invention provides a more specific technical solution 2, a compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, when Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L1)n-(L2)m-;

[0114] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-;

[0115] When Cy is selected from Cy7 and Cy9, L is -L4-;

[0116] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-;

[0117] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0118] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0119] L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 replace;

[0120] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O;

[0121] L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0122] A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0123] X1 and X2 are independently CR X1 , O, S or N;

[0124] X3, X4, and X5 are independently C or N;

[0125] Ring B is a heteroaryl group or a heterocycloalkyl-heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0126] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, C 1-4 Halogenated alkyl or 3-5 membered cycloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0127] R1 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0128] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0129] R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0130] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0131] R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0132] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0133] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0134] R x5 C 1-4 Alkyl, CN, OH or absent;

[0135] R7 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0136] R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0137] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0138] R 8’ C 3-6Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O or -N=S(=O)(C 1-4 alkyl) 2 or -N (C3-6 cycloalkyl) C (O) NH (C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0139] R9 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0140] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0141] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0142] R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -C(NRaRb)=CRa-NO 2、 -C(CH3) t -CH2-OC(O)NH2, -C(O)-Ra or -C(CH3) t -CH2-OC(O)NHCH3, wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene may be further substituted with 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution; or R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxyl C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl) = N-CN or -C(NRaRb) = CRa-NO2, wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, = O, OH, -SF5, C 1-4 Alkyl, hydroxyl C1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl group substitution;

[0143] Ra and Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O;

[0144] Alternatively, Ra, Rb and their atoms together form C 3-6 Cycloalkyl;

[0145] R 13 7-11 membered spirocyclic, 4-10 membered cyclic, 5-8 membered heterocyclic bridged ring, 4-6 membered monocyclic heterocycloalkyl containing S(O)2 group, 4 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the spirocyclic, cyclic, heterocyclic bridged ring, monocyclic heterocycloalkyl optionally substituted by 1-3 halogen, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0146] R 14 Selected from -(CH2) t-OC(O)NH2, -(CH2) t -OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, CN, =O, OH, C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0147] n and m are independently 0, 1, 2 or 3;

[0148] r is selected from 1, 2, 3 or 4;

[0149] t is selected from 0, 1, 2, 3 or 4;

[0150] P is selected from 0 or 1;

[0151] The condition is,

[0152] Cy1 is not

[0153] The present invention provides a more specific technical solution 3, a compound shown in Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0154] When Cy is selected from Cy1, Cy2, Cy3 and Cy8, L is -(L1)n-(L2)m-;

[0155] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-;

[0156] When Cy is selected from Cy7 and Cy9, L is -L4-;

[0157] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-;

[0158] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0159] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0160] L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 replace;

[0161] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O;

[0162] L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0163] A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0164] X1 and X2 are independently CR X1 or N;

[0165] X3, X4, and X5 are independently C or N;

[0166] Ring B is a heteroaryl group or a heterocycloalkyl-heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0167] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0168] R1 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0169] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0170] R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0171] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0172] R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0173] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0174] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0175] R x5 C 1-4 Alkyl, CN, OH or absent;

[0176] R7 is C 1-4 Alkyl, C1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0177] R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0178] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0179] R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O or -N=S(=O)(C 1-4 alkyl) 2 or -N (C3-6 cycloalkyl) C (O) NH (C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0180] R9 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0181] Each R 10 Independently R 8’、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0182] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0183] R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxyl C 1-6 Alkyl, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl) = N-CN or -C(NRaRb) = CRa-NO2, wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, = O, OH, -SF5, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl group substitution;

[0184] Ra and Rb are each independently selected from H, halogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkoxy;

[0185] Alternatively, Ra, Rb and their atoms together form C 3-6 Cycloalkyl;

[0186] R 13 7-11 membered spirocyclic, 4-10 membered cyclic, 5-8 membered heterocyclic bridged ring, 4-6 membered monocyclic heterocycloalkyl containing S(O)2 group, 4 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the spirocyclic, cyclic, heterocyclic bridged ring, monocyclic heterocycloalkyl optionally substituted by 1-3 halogen, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0187] n and m are independently 0, 1, 2 or 3;

[0188] r is selected from 1, 2, 3 or 4;

[0189] t is selected from 0, 1, 2, 3 or 4;

[0190] The condition is,

[0191] Cy1 is not

[0192] The present invention provides a more specific technical solution 4, a compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

[0193] wherein, when Cy is selected from Cy1, Cy2, Cy3 and Cy8, L is -(L1)n-(L2)m-;

[0194] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-;

[0195] When Cy is selected from Cy7, L is -L4-;

[0196] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-;

[0197] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0198] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0199] L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 replace;

[0200] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O;

[0201] L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O and 5-6 membered cycloalkyl, 7-12 membered spirocycloheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocycloheterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0202] A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0203] X1 and X2 are independently CR X1 or N;

[0204] X3, X4, and X5 are independently C or N;

[0205] Ring B is a heteroaryl group or a heterocycloalkyl-heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0206] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or R X1 , R is independently a 3-5 membered cycloalkyl group, or two R, R and R on adjacent ring atoms are X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0207] R1 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0208] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0209] R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0210] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0211] R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0212] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0213] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0214] R x5 C 1-4Alkyl, CN, OH or absent;

[0215] R7 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0216] R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0217] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0218] R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or R 8’ is -N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0219] R9 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0220] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0221] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0222] R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, or 5-10 membered heteroarylene, wherein the heterocycloalkylene, cycloalkylene, arylene, or heteroarylene is optionally further substituted with 1-3 halogens, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0223] R 13 7-11 membered spirocyclic, 4-10 membered cyclic, 5-8 membered heterocyclic bridged ring, 4-6 membered monocyclic heterocycloalkyl containing S(O)2 group, 4 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the spirocyclic, cyclic, heterocyclic bridged ring, monocyclic heterocycloalkyl optionally substituted by 1-3 halogen, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0224] n and m are independently 0, 1, 2 or 3;

[0225] r is 1, 2, 3, or 4;

[0226] The condition is,

[0227] Cy1 is not

[0228] The present invention provides a more specific technical solution 5, a compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, when Cy is selected from Cy1, Cy2 and Cy3, L is -(L1)n-(L2)m-;

[0229] When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-;

[0230] L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-;

[0231] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups are substituted; or L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0232] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0233] L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 replace;

[0234] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O;

[0235] A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0236] X1 and X2 are independently CR X1 or N;

[0237] X3, X4, and X5 are independently C or N;

[0238] Ring B is a heteroaryl group or a heterocycloalkyl-heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0239] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or R X1 , R are independently 3-5 membered cycloalkyl, or two R, R and R on adjacent ring atoms are X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4Alkoxy, OH and NH2 group substitution;

[0240] R1 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0241] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0242] R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0243] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0244] R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0245] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0246] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0247] R x5 C 1-4 Alkyl, CN, OH or absent;

[0248] R7 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0249] R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0250] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0251] R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or R 8’is -N(C3-6 cycloalkyl)C(O)NH(C1-4 alkyl), wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0252] R9 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0253] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0254] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0255] n and m are independently 0, 1, 2 or 3;

[0256] r is 1, 2, 3, or 4;

[0257] The condition is,

[0258] Cy1 is not

[0259] Scheme 6 of the present invention, the compound as described in Schemes 1, 2, 3, 4, and 5 above, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl, imidazolyl, pyrrolyl, tetrahydropyrrolopyrrolyl, tetrahydropyrroloimidazolyl, or thienopyrrolyl;

[0260] R1 is C 1-4 Alkyl or C 1-4 haloalkyl, or R1 and R2 and the atoms to which they are attached together form a 5-7 membered monoheterocycloalkyl, a 6-8 membered cyclic heterocycloalkyl, a 7-9 membered spirocyclic heterocycloalkyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, and O, wherein the monoheterocycloalkyl, cyclic heterocycloalkyl, spirocyclic heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0261] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0262] R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent;

[0263] Or R3 and R2 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0264] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0265] Or R3 and R6 together with the atoms to which they are attached form C 5-7 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0266] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the heteroaryl is optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0267] R7 is C 1-4 Alkyl or C 1-4 Haloalkyl, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the heterocycloalkyl being optionally substituted by 1-3 heteroatoms selected from halogen, CN, C 1-4 Alkyl, C 1-4Alkoxy, OH and NH2 group substitution;

[0268] R 9’ With R7, or R 9’ With R x5 At least one group and the atoms connected thereto together form a 5-7 membered monoheterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the monoheterocycloalkyl, spirocyclic heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0269] r is 1 or 2.

[0270] Scheme 7 of the present invention, a compound as described in Schemes 1-6, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0271] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0272] L3 is selected from

[0273] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O;

[0274] L4 is selected from

[0275] In some embodiments, L4 is selected from

[0276] A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN;

[0277] Cy5 is selected from

[0278] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0279] Or each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C1-4 Alkyl, C 1-4 Alkoxy, OH, C 3-6 Cycloalkyl, C 2-6 Alkynyl and NH2 group substitution;

[0280] Or each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0281] Or, each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl or C 1-4 Haloalkyl, or two R, R and R on adjacent ring atoms X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0282] R1 is C1-4 Alkyl or C 1-4 alkyl halide;

[0283] Or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0284] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0285] R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent;

[0286] Or R3 together with R2 and the atoms to which they are attached form a ring selected from the following: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0287] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0288] Or R3 and R6 together with the atoms to which they are attached form C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0289] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present; or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms imidazolyl, pyrazolyl, pyrrolyl, thienyl or thiazolyl, and is optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0290] R4 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0291] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -NHC 1-4 alkyl;

[0292] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0293] R7 is C 1-4 Alkyl or C 1-4 haloalkyl, or R7 and R9 together with the atoms to which they are attached form a ring selected from:

[0294] The ring is optionally substituted by 1-3 atoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0295] or R 9’ Together with R7 and the atoms to which it is attached, it forms a ring selected from:

[0296] and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0297] or R 9’ With R x5 and its connected atoms together to form and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0298] The condition is R 9’ With R7, or R 9’ With R x5 At least one of them is a ring;

[0299] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0300] R8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, -N=S(=O)(C 1-4 Alkyl)2 or -N(C 3-6 Cycloalkyl)C(O)NH(C 1-4 Alkyl), the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0301] R9 is H or C 1-4 alkyl;

[0302] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0303] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0304] R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, -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; the ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0305] In some embodiments, R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, -C(NHC1-2 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; the ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0306] R 13 Selected from The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 haloalkyl radical substitution;

[0307] n is 0, 1, 2, or 3;

[0308] m is 0, 1, or 2;

[0309] r is 1 or 2;

[0310] t is selected from 0, 1 or 2.

[0311] Scheme 8 of the present invention, the compound as described in Scheme 1-6, its stereoisomer or pharmaceutically acceptable salt, wherein each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0312] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0313] L3 is selected from

[0314] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O;

[0315] L4 is selected from

[0316] A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN;

[0317] Cy5 is selected from

[0318] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or R X1 , R is independently a 3-5 membered cycloalkyl group or two R on adjacent ring atoms, R and R X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0319] R1 is C 1-4 Alkyl or C 1-4 alkyl halide;

[0320] Or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0321] Or R1 and R2 and the atoms to which they are attached together form a ring selected from: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0322] R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent;

[0323] Or R3 together with R2 and the atoms to which they are attached form a ring selected from the following: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0324] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0325] Or R3 and R6 together with the atoms to which they are attached form C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0326] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present; or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms imidazolyl, pyrazolyl, pyrrolyl, thienyl or thiazolyl, and is optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0327] R4 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0328] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -NHC 1-4 alkyl;

[0329] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0330] R7 is C 1-4 Alkyl or C 1-4 haloalkyl, or R7 and R9 together with the atoms to which they are attached form a ring selected from:

[0331] The ring is optionally substituted by 1-3 atoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0332] or R 9’Together with R7 and the atoms to which it is attached, it forms a ring selected from:

[0333] and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0334] or R 9’ With R x5 and its connected atoms together to form and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0335] The condition is R 9’ With R7, or R 9’ With R x5 At least one of them is a ring;

[0336] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0337] R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O or -N=S(=O)(C 1-4 Alkyl)2 or R 8’ -N(C 3-6 Cycloalkyl)C(O)NH(C 1-4 Alkyl), the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0338] R9 is H or C 1-4 alkyl;

[0339] Each R 10 Independently R 8’ 、-OR8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0340] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0341] R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, 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; the ring is optionally substituted by 1-3 atoms selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0342] or R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, -C(NHC 1-2 alkyl)=N-CN, -C(C 1-2 Alkyl) = N-CN or -C(NHC 1-2 alkyl)=CH-NO2 or selected from -C(CH3) t -CH2-OC(O)NH2, -C(O)-Ra or selected from -C(CH3) t -CH2-OC(O)NHCH3; the ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl or -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0343] R 13 Selected from The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 haloalkyl radical substitution;

[0344] n is 0, 1, 2, or 3;

[0345] m is 0, 1, or 2;

[0346] r is 1 or 2;

[0347] t is selected from 0, 1 or 2.

[0348] Scheme 9 of the present invention, a compound as described in Scheme 1-6, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, Alternatively, each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, or each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, or each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0349] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0350] L3 is selected from

[0351] Or L3 is selected from

[0352] Each R L3 are independently halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O;

[0353] A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN;

[0354] Cy5 is selected from

[0355] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or R X1 , R is independently a 3-5 membered cycloalkyl group, or two R, R and R on adjacent ring atoms are X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0356] R1 is C 1-4 Alkyl or C 1-4 alkyl halide;

[0357] Or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0358] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 or R1 and R2 and the atoms to which they are attached together form a ring selected from the group consisting of:

[0359] and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0360] R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent;

[0361] Or R3 together with R2 and the atoms to which they are attached form a ring selected from the following: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0362] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0363] Or R3 and R6 together with the atoms to which they are attached form C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0364] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present; or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms imidazolyl, pyrazolyl, pyrrolyl, thienyl or thiazolyl, and is optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0365] R4 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0366] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -NHC 1-4 alkyl;

[0367] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0368] R7 is C 1-4 Alkyl or C 1-4 haloalkyl, or R7 and R9 together with the atoms to which they are attached form a ring selected from:

[0369] The ring is optionally substituted by 1-3 atoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0370] or R 9’Together with R7 and the atoms to which it is attached, it forms a ring selected from:

[0371] and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0372] or R 9’ With R x5 and its connected atoms together to form and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0373] The condition is R 9’ With R7, or R 9’ With R x5 At least one of them is a ring;

[0374] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0375] R 8’ C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0376] R9 is H or C 1-4 alkyl

[0377] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0378] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0379] n is 0, 1, 2, or 3;

[0380] m is 0, 1, or 2;

[0381] r is 1 or 2.

[0382] Scheme 10 of the present invention is the compound described in Schemes 1-6 above, its stereoisomers or pharmaceutically acceptable salts, wherein:

[0383] Each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0384] or each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0385] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0386] L3 is selected from

[0387] Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O;

[0388] L4 is selected from

[0389] Or L4 is selected from

[0390] A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN;

[0391] Cy5 is selected from

[0392] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Haloalkyl, or R X1 , R is independently a 3-5 membered cycloalkyl group, or two R, R and R on adjacent ring atoms are X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0393] R1 is C 1-4 Alkyl or C 1-4 alkyl halide;

[0394] Or R1 and R2 and the atoms to which they are attached together form a ring selected from:

[0395] Or R1 and R2 together with the atoms to which they are attached form and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0396] R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent;

[0397] Or R3 together with R2 and the atoms to which they are attached form a ring selected from the following: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0398] Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0399] Or R3 and R6 together with the atoms to which they are attached form C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0400] R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present; or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms imidazolyl, pyrazolyl, pyrrolyl, thienyl or thiazolyl, and is optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0401] R4 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0402] R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -NHC 1-4 alkyl;

[0403] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0404] R7 is C 1-4 Alkyl or C 1-4 haloalkyl, or R7 and R9 together with the atoms to which they are attached form a ring selected from:

[0405] The ring is optionally substituted by 1-3 atoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0406] or R 9’Together with R7 and the atoms to which it is attached, it forms a ring selected from:

[0407] and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0408] or R 9’ With R x5 and its connected atoms together to form and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution;

[0409] The condition is R 9’ With R7, or R 9’ With R x5 At least one of them is a ring;

[0410] R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ;

[0411] R 8’ C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution;

[0412] R9 is H or C 1-4 alkyl;

[0413] Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ;

[0414] R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution;

[0415] R 12 Selected from cycloalkyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 haloalkyl radical substitution;

[0416] R 13 Selected from The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 haloalkyl radical substitution;

[0417] n is 0, 1, 2, or 3;

[0418] m is 0, 1, or 2;

[0419] r is 1 or 2.

[0420] Scheme 11 of the present invention is the compound described in Schemes 1-7 above, its stereoisomers or pharmaceutically acceptable salts, wherein:

[0421] Cy1 is selected from

[0422] Or choose Or choose

[0423] Cy2 is selected from

[0424] Cy4 is selected from Or choose Or choose Or choose Or choose Or choose

[0425] Cy5 is selected from

[0426] Cy7 is selected from

[0427] Or choose Or choose Or choose Or choose Or choose Or choose Or choose Or choose

[0428] Cy9 is selected from

[0429] Scheme 12 of the present invention, the compound as described in Schemes 1-7 above, its stereoisomers or pharmaceutically acceptable salts, wherein Cy1 is selected from Or Cy1 is selected from Or Cy1 is selected from Or Cy1 is selected from

[0430] Cy5 is selected from

[0431] Or Cy5 is selected from

[0432] Cy7 is selected from Or Cy7 is selected from Or Cy7 is selected from

[0433] Scheme 13 of the present invention is a compound as described in Schemes 1-7 above, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -(L1)n-(L2)m- is selected from: R6 is H;

[0434] -L3-Selected from:

[0435] -L4-Selected from: Or choose

[0436] Select any 1-3 R R One of the following structures: R R Each independently selected from F, Cl, Br, methyl, isopropyl, ethoxy, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, dimethylamino, In some embodiments, Select any 1-3 R R One of the following structures: R R Each independently selected from F, Cl, Br, methyl, ethynyl, propynyl, cyclopropyl, R X1 is H;

[0437] In some embodiments, Select any 1-3 R R One of the following structures: R R Each is independently selected from F, Cl, Br, methyl, ethynyl, propynyl or cyclopropyl; R X1 is H;

[0438] In some embodiments, Select any 1-3 R R One of the following structures: R R Each is independently selected from F, Cl, Br, methyl, ethynyl, propynyl or cyclopropyl; R X1 is H;

[0439] or R X1 Together with R6 and the atom to which it is attached, it forms a morpholinyl, furanyl, pyrrolyl, or thienyl group; in some embodiments, R X1 Together with R6 and the atom to which it is attached, it forms a morpholinyl, furyl or thienyl group.

[0440] Scheme 14 of the present invention is a compound as described in Schemes 1-7 above, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -(L1)n-(L2)m- is selected from: R6 is H;

[0441] -L3-Selected from:

[0442] -L4-Selected from:

[0443] Select any 1-3 R R One of the following structures: R REach is independently selected from F, Cl, Br, methyl, ethynyl or cyclopropyl; R X1 is H;

[0444] or R X1 Together with R6 and the atom to which it is attached, it forms a morpholinyl, furyl or thienyl group.

[0445] Scheme 15 of the present invention is the compound as described in Schemes 1-5 above, its stereoisomers or pharmaceutically acceptable salts,

[0446] Among them, L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0447] A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0448] X1 and X2 are independently CR X1 , S or N;

[0449] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0450] R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0451] Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0452] R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0453] R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, C 1-4 Alkyl -CN, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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 alkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution;

[0454] Ra and Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O;

[0455] p is selected from 0 or 1.

[0456] Scheme 16 of the present invention is the compound as described in Scheme 15 above, its stereoisomer or pharmaceutically acceptable salt,

[0457] Among them, L4 is

[0458] R 12 Selected from -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.

[0459] Scheme 17 of the present invention, as described in the above formula (I) or (II), its stereoisomer or pharmaceutically acceptable salt,

[0460] L4 is Or L4 is R6 and R X1 and the atoms to which they are attached together form a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si;

[0461] A is -S(O)-;

[0462] R1 and R2 together with the atoms to which they are attached form

[0463] R 12 Selected from -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;

[0464] Select any 1-3 R R One of the following structures: R R Each is independently selected from F, Cl, methyl, ethyl, isopropyl, ethoxy, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, and dimethylamino.

[0465] Scheme 18 of the present invention, as described in the above formula (I), its stereoisomers or pharmaceutically acceptable salts,

[0466] Cy is selected from Cy1, Cy2, Cy4, Cy5, Cy7 and Cy9;

[0467] 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-;

[0468] Cy1 is selected from

[0469] Cy2 is selected from

[0470] Cy4 is selected from

[0471] Cy5 is selected from

[0472] Cy7 is selected from

[0473] Cy9 is selected from

[0474] -(L1)n-(L2)m- is selected from: R6 is H;

[0475] -L3-Selected from:

[0476] -L4-Selected from:

[0477] Select any 1-3 R R One of the following structures: R R Each independently selected from F, Cl, Br, methyl, isopropyl, ethoxy, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, dimethylamino, R X1 is H;

[0478] or R X1 Together with R6 and the atom to which it is attached, it forms a morpholinyl, furyl, pyrrolyl or thienyl group.

[0479] Scheme 19 of the present invention, as described in the above formula (I), its stereoisomers or pharmaceutically acceptable salts,

[0480] Cy is selected from Cy1 and Cy7;

[0481] When Cy is selected from Cy1, L is -(L1)n-(L2)m-; when Cy is selected from Cy7, L is -L4-;

[0482] Cy1 is selected from

[0483] Cy1 is selected from

[0484] Cy7 is selected from

[0485] -(L1)n-(L2)m- is selected from: R6 is H;

[0486] -L4-Selected from:

[0487] Select any 1-3 R R One of the following structures: R R Each independently selected from F, Cl, Br, methyl, isopropyl, ethoxy, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, dimethylamino, R X1 is H;

[0488] or R X1 Together with R6 and the atom to which it is attached, it forms a morpholinyl, furyl, pyrrolyl or thienyl group.

[0489] Scheme 20 of the present invention is a compound selected from one of the structures in Table 1, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0490] Table 1:

[0491] Scheme 21 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:

[0492] Table 2:

[0493] "abs" refers to absolute configuration.

[0494] The present invention also provides a composition or pharmaceutical preparation comprising a compound according to any of the foregoing embodiments, a stereoisomer or pharmaceutically acceptable salt thereof, 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 "dose strength").

[0495] Furthermore, the composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any one of the aforementioned schemes, its stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0496] The present invention also provides the use of a compound according to any of the aforementioned embodiments, or a stereoisomer or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating / preventing a PDE4B-mediated disease. Furthermore, the PDE4B-mediated disease is cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.

[0497] The present invention also provides a method for treating a disease in a mammal or human, comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any of the foregoing schemes. The disease is preferably cancer or COPD, idiopathic pulmonary fibrosis, or interstitial lung disease. Preferably, the therapeutically effective amount is 1-1500 mg. In some embodiments, the mammal described in the present invention does not include humans.

[0498] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein that will alleviate 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 the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 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, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-60 0mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 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, 10-50 0mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10- 50mg, 10-40mg, 10-30mg, 10-20mg; 20-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg , 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0499] In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the compound of the present invention or its stereoisomer, solvate, or pharmaceutically acceptable salt;

[0500] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of a compound of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as a "preparation specification"). In some embodiments, the pharmaceutical composition includes but is not limited to 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 , 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg of a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0501] A method for treating a disease in a mammal, 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 1-1500 mg. The disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0502] A method for treating a disease in a mammal or a human comprises administering a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100 -1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 1 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, 1500 mg / day.

[0503] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, and 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 above-mentioned pharmaceutical composition.

[0504] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0505] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0506] Synthesis route

[0507] Patent documents such as WO2013026797A1 describe methods for preparing PDE4B inhibitors. Those skilled in the art can combine this document with known organic synthesis techniques to prepare the compounds of the present invention, using commercially available chemicals and / or compounds described in chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0508] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (e.g., those listed above) offer custom synthesis services.

[0509] the term

[0510] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0511] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0512] "Halo" or "halogen substitution" means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens.

[0513] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one isotope, deuterium. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, more preferably 1-10 deuterium atoms, more preferably 1-6 deuterium atoms, and even more preferably 1-3 deuterium atoms.

[0514] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, further preferably an alkyl group having 1 to 4 carbon atoms, and further preferably an alkyl group having 1-2 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 chain isomers thereof.

[0515] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0516] "Cycloalkyl" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which, unless otherwise specified, usually has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and further preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Or cycloheptyl, etc.

[0517] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", non-limiting examples of which include cyclopropylene, cyclobutylene, and the like.

[0518] "Heterocycle" or "heterocyclyl" 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 nitrogen, oxygen, or sulfur, and includes monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. This definition includes heterocycloalkyl and heteroaryl groups. The nitrogen and sulfur atoms in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, wait.

[0519] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0520] "Carbocycle" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridged rings, bicyclic cyclic rings and bicyclic spirocycles, etc., unless otherwise specified, and has 3 to 12 carbon atoms, preferably 3-10 carbon atoms, and more preferably 3-6 carbon atoms. Its definition includes cycloalkyl and aryl. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc., the bicyclic bridge ring includes etc., double ring and ring include etc., bicyclic spiro ring includes wait.

[0521] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0522] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0523] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0524] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, -OC 1-8 Alkyl, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl, more preferably -OC 1-2 Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0525] "Haloalkoxy" refers to -O-haloalkyl, unless otherwise specified, -O-haloC 1-8 Alkyl, preferably -O-halogenated C 1-6 Alkyl, more preferably -O-halogenated C 1-4Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0526] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0527] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

[0528] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furyl, and the like.

[0529] "Heterocycloalkyl" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle, generally having 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, heterocycloalkyl also contains 1-3 heteroatoms selected from N, S, O, Si, and P as ring members. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, and the like.

[0530] "Alkylamino" or "alkylamino" refers to an amino group substituted with a single or double alkyl group, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0531] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0532] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0533] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0534] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0535] "Excipient" refers to a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (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, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, 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) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0536] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0537] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0538] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. BRIEF DESCRIPTION OF THE DRAWINGS

[0539] FIG1 shows that compound 51 inhibits the expression of TNF-α in mouse lung tissue induced by LPS in a dose-dependent manner.

[0540] FIG2 shows that compound 84 inhibited the expression of TNF-α in mouse lung tissue induced by LPS in a dose-dependent manner. DETAILED DESCRIPTION

[0541] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0542] Dess-Martin reagent; 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxyl-3-(1H)-one

[0543] DIPEA: N,N-diisopropylethylamine

[0544] NMP; N-methylpyrrolidone

[0545] TBDMSCl: tert-butyldimethylsilyl chloride

[0546] DMAP: 4-dimethylaminopyridine

[0547] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0548] T3P: Propylphosphonic acid tricyclic anhydride

[0549] Example 1

[0550] Step 1: Under 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-necked flask and heated to 45°C for 48 h. The system was acidified by adding 1N hydrochloric acid, and extracted three times with 200 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 36 g of crude compound 1C, which was used directly in the next reaction.

[0551] LCMS m / z=249.1[M+H] + .

[0552] Step 2: Under a nitrogen atmosphere, add 80 mL of dichloromethane to a three-necked flask and cool the system to -10°C. Add titanium tetrachloride (4.9 mL, 44.4 mmol), followed by the slow addition of isopropanol (3.4 mL, 44.4 mmol) and allow to react for 30 min. Dissolve crude compound 1C (10 g) in 10 mL of DCM and slowly add to the system. Then, add triethylamine (17 mL, 121 mmol) and allow to react at -10°C for 2 h. After the starting material disappears, quench the reaction by adding 42 mL of 3N hydrochloric acid. After warming to room temperature, extract three times with 200 mL of ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to yield 8 g of crude compound 1D, which is used directly in the next step.

[0553] 1 H NMR (400MHz, CDCl3) δ4.36(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).

[0554] Step 3: Dissolve 8 g of the crude product of compound 1D in a mixed solvent of methanol: concentrated hydrochloric acid = 150 mL:15 mL, add urea (24 g, 400 mmol), heat the system to 90°C and react for 24 h, collect the solid generated in the system and wash it twice with water, and then dry it to obtain 6.4 g of the crude product of compound 1E, which is directly used in the next reaction.

[0555] LCMS m / z=245.1[M+H] + .

[0556] Step 4: Add 6.4 g of crude compound 1E to a round-bottom flask, add 100 mL of water and 8 g of sodium hydroxide (200 mmol), and heat to 85°C for 24 hours. Adjust the system to acidic by adding hydrochloric acid. Collect the resulting solid and dry it to obtain 3 g of crude compound 1F. Use it directly in the next reaction.

[0557] LCMS m / z=196.9[MH] - .

[0558] Step 5: Under nitrogen, dissolve 3 g of crude compound 1F in 60 mL of acetonitrile, add phosphorus oxychloride (5.7 mL, 61 mmol), and heat to 90°C for 48 h. After cooling, pour the mixture into 300 mL of water, collect the resulting solid, and dry it to obtain 1 g of crude compound 1G.

[0559] LCMS m / z=235.0and 237.0[M+H] + .

[0560] Step 6: Under a nitrogen atmosphere, 1 g of crude compound 1G was dissolved in 30 mL of acetonitrile. 1.5 g of crude compound 1H salt (for methods, see patent WO2013 / 026797A1) and triethylamine (5 mL, 36 mmol) were added. The mixture was heated to 80°C and reacted for 18 h. After cooling to room temperature, the reaction system was concentrated and extracted three times with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford 740 mg of crude compound 1I, which was used directly in the next step.

[0561] LCMS m / z=300.1[M+H] + .

[0562] Step 7: Dissolve 740 mg of crude compound 1I in 30 mL of acetic acid, add 2 mL of 30% hydrogen peroxide, and react at room temperature for 2 h. After the starting material disappears, extract three times with 50 mL of ethyl acetate. Dry the organic phase over anhydrous sodium sulfate and concentrate to yield 540 mg of crude compound 1J, which is used directly in the next step.

[0563] LCMS m / z=316.1[M+H] + .

[0564] Step 8: Under a nitrogen atmosphere, 270 mg of crude compound 1J, 220 mg of 4-(4-chlorophenyl)piperidine (1.12 mmol), and DIPEA (5.2 mmol, 0.86 mL) were dissolved in 30 mL of 1,4-dioxane and heated to 100°C for 18 h. The reaction mixture was concentrated and separated by thin-layer chromatography to afford 246 mg of crude racemic compound 1. Chiral separation afforded compound 1-1 (77 mg, 19%) and compound 1-2 (70 mg, 17%).

[0565] LCMS m / z=475.2[M+H] + .

[0566] 1H NMR (400MHz, DMSO-d6) δ7.35–7.25(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).

[0567] Chiral separation method: Instrument: Waters 150SFC; Column: Chiralpak Column (250×30 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.

[0568] Example 2

[0569] Step 1: Under nitrogen, 270 mg of crude compound 1J, 320 mg of crude compound 2A (refer to US20140228286A1), and DIPEA (0.86 mL, 5.2 mmol) were dissolved in 30 mL of 1,4-dioxane and heated to 100°C for 18 hours. The reaction mixture was concentrated and separated by thin-layer chromatography to afford 226 mg of crude racemic compound 2. Chiral separation afforded compounds 2-1 (54 mg, 13%) and 2-2 (40 mg, 10%).

[0570] LCMS m / z=477.2[M+H] + .

[0571] 1 H NMR(400MHz,DMSO-d6)δ8.86(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).

[0572] Chiral separation method: Instrument: Waters 150SFC; Column: Chiralpak Column (250×30 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.

[0573] Example 3

[0574] Using compound 3A and methyl 4-chlorobutyrate as raw materials and referring to the operation of Example 1, compound 3 (35 mg, 22%) was obtained.

[0575] 1 H NMR(400MHZ,DMSO-d6)δ8.86(s,2H),6.48(s,1H),4.88(t,1H),4.67(d,2H),3.70(m,2H),3.17(s,1H),3.0 0-3.06(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).

[0576] LCMS (ESI): =463.2[M+H] + .

[0577] Example 4

[0578] Step 1: Compound 3 was prepared by chiral separation to give compounds 3-1 (26.1 mg) and 3-2 (21.1 mg, 22%).

[0579] Chiral separation method: Instrument: Waters 150SFC; 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); Gradient: 70% phase B isocratic elution; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm.

[0580] Compound 3-1, retention time: 1.328 min. 1 H NMR(400MHZ,DMSO-d6)δ8.86(s,2H),6.48(s,1H),4.88(t,1H),4.67(d,2H),3.70(m,2H),3.17(s,1H),3.0 0-3.06(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).

[0581] LCMS (ESI): =463.2[M+H] + .

[0582] Compound 3-2, retention time: 2.125 min. 1 H NMR(400MHZ,DMSO-d6)δ8.86(s,2H),6.48(s,1H),4.88(t,1H),4.67(d,2H),3.7 0(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).

[0583] LCMS (ESI): =463.2[M+H] + .

[0584] Example 5

[0585] Step 1: Add 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) to 400 mL of N,N-dimethylformamide solvent, stir at room temperature overnight, and then filter. The filtrate is concentrated under reduced pressure to obtain the target compound, which is directly used in the next reaction.

[0586] LCMS m / z=217.1[M+1] +

[0587] Step 2: Add raw material 4B (2.9 g, 13.41 mmol) to thionyl chloride (30 mL), heat to 90°C and stir for 4 hours, then concentrate to remove excess thionyl chloride, dissolve with ethyl acetate, wash with saturated sodium bicarbonate solution, dry, filter, concentrate, and separate by silica gel column chromatography (PE:EA (v / v) = 1:0 to 6:1) to obtain the target compound 4C (3.1 g, yield 91%).

[0588] LCMS m / z=253.0[M+1] +

[0589] 1 H NMR (400MHz, CDCl3) δ8.58(s,1H),3.72(s,3H),3.59(s,2H).

[0590] Step 3: Add raw material 4C (3.9 g, 15.41 mmol), raw material 4D (3.32 g, 15.41 mmol) and triethylamine (3.12 g, 30.82 mmol) to acetonitrile solvent (70 mL), then heat to 50°C and stir for 16 hours. After cooling and concentration, dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Separate by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1) to obtain the target compound 4E (2.6 g, yield 39%).

[0591] LCMS m / z=432.1[M+1] +

[0592] 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 under ice bath. The mixture was then slowly warmed to room temperature and stirred for 16 hours. The reaction was quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated 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).

[0593] LCMS m / z=404.2[M+1] +

[0594] Step 5: Add raw material 4F (0.6 g, 1.49 mmol) to dry dichloromethane (10 mL), add triethylamine (0.45 g, 4.44 mmol) and methanesulfonyl chloride (0.34 g, 2.97 mmol) reagents under ice bath, then slowly warm to room temperature and stir for 1 hour. Quench the reaction with water, extract with dichloromethane, wash with saturated sodium bicarbonate solution and brine, respectively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the target compound 4F (0.85 g, 100% yield).

[0595] LCMS m / z=482.1[M+1] +

[0596] Step 6: Add raw material 4G (0.85 g, 1.76 mmol) to dry N,N-dimethylformamide (10 mL) solvent, add sodium hydride reagent (0.28 g, 7.04 mmol, 60% in oil) under ice bath, then slowly warm to room temperature, stir for 1 hour, quench the reaction with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, and separate it by silica gel column chromatography (PE:EA (v / v) = 1:0 to 8:1) to obtain the target compound 4H (0.45 g, yield 66%).

[0597] LCMS m / z=386.1[M+1] +

[0598] 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).

[0599] Step 7: The raw material 4H (400 mg, 1.04 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (29 mg, 0.1 mmol), water (19 mg, 1.04 mmol) and tetraisopropyl titanate (14 mg, 0.051 mmol) were added to dichloromethane (10 mL) solvent, stirred at room temperature for half an hour, and then tert-butyl peroxide (120 mg, 1.35 mmol) was added. Stirring was continued for 3 hours, and then diluted with water, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried and filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EA (v / v) = 1:0 to 2:3) to obtain the target compound 4I (0.40 g, yield 96%).

[0600] LCMS m / z=402.1[M+1] +

[0601] Step 8: Raw material 4I (0.4 g, 0.99 mmol), raw 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), then heated to 95°C with stirring 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 and separated by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1) to obtain the target compound 4J (0.5 g, yield 90%).

[0602] LCMS m / z=563.2[M+1] +

[0603] Step 9: The raw material 4J (0.6 g, 1.07 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, and then 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 and purified by silica gel column chromatography (DCM: anhydrous methanol (v / v) = 1:0 to 10:1) to obtain the title compound 4K (0.3 g, yield 62%).

[0604] LCMS m / z=449.2[M+1] +

[0605] 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).

[0606] Step 10: The raw material 4K (300 mg, 0.67 mmol) was separated and purified by chiral HPLC to obtain the target compound 4-1 (100 mg) and the target compound 4-2 (100 mg).

[0607] Instrument name: Waters 150SFC; chromatographic 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 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: dissolved in acetonitrile).

[0608] Compound 4-1 peak time: 0.578 min

[0609] LCMS m / z=449.2[M+1] +

[0610] 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).

[0611] Compound 4-2 peak time: 0.812 min

[0612] LCMS m / z=449.2[M+1] +

[0613] 1 H NMR (400 MHz, DMSO-d 6) 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).

[0614] Example 6

[0615] Step 1: To a 150-ml sealed tube containing (1-ethoxycyclopropyloxy)trimethylsilane (7 g, 40.23 mmol) and acetic acid (1.21 g, 20.12 mol) dissolved in tetraethylene glycol dimethyl ether (30 ml), was added ethoxycarbonylmethylenetriphenylphosphine (14 g, 40.23 mol) dissolved in dichloromethane (6 ml). The mixture was reacted in an oil bath at 100°C for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated to remove dichloromethane. The residue was then purified by rapid column chromatography (eluent ratio: EA / PE = 0% to 10%) to obtain the title compound 5B (4 g, 79%).

[0616] Compound 5B and ethyl mercaptoacetate were used as starting materials and the procedure was carried out according to Example 1 to obtain compound 5 (50 mg, 33%).

[0617] Chiral separation of compound 5:

[0618] Compound 5 (50 mg) was used for separation to obtain 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%).

[0619] Split conditions:

[0620] Instrument: Waters 150MGM; Column: DAICEL CHIRALPAK AD;

[0621] Mobile phase: A for CO2 and B for EtOH (0.1% NH3·H2O); Gradient: B 40%; Flow rate: 120 mL / min; Back pressure: 100 bar;

[0622] Column temperature: 35°C; wavelength: 220 nm; cycle: 13 min;

[0623] Compound 5-1:

[0624] 1 H 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).

[0625] Compound 5-2:

[0626] 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).

[0627] Example 7

[0628] Compound 3A and methyl acrylate were used as raw materials and the reaction was carried out in the same manner as in Example 1 (first and second steps) to obtain compound 6C (35 g, 97%).

[0629] LC-MS (ESI): m / z = 161.1 [M+H] +

[0630] 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 imidazole (38.25 g, 562.5 mmol) were added at room temperature and stirred for 3 h. After the reaction, most of the methanol was removed by evaporation, water (50 mL) was added, and the mixture was extracted twice with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent ratio: EA:PE = 0% to 50%) to obtain the title compound 6D (26.7 g, 69%).

[0631] LC-MS (ESI): m / z = 209.1 [M+H] +

[0632] Step 4: Compound 6D (12 g, 61.86 mmol) was dissolved in a 4 M hydrogen chloride-dioxane solution (100 mL) at room temperature under a nitrogen atmosphere. The mixture was then heated to 100°C and allowed to react overnight. A large amount of solid precipitated. After completion of the reaction, the solid was filtered and spin-dried to afford crude compound 6E (9 g, 80%). This was used directly in the next reaction without further purification.

[0633] LC-MS (ESI): m / z = 195.1 [M+H] +

[0634] 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. Benzyltrimethylammonium chloride (3.83 g, 20.62 mmol) was then added at room temperature. The mixture was then heated to 150°C and allowed to react for 7 h. After completion of the reaction, the reaction solution was slowly added to a saturated sodium bicarbonate solution (100 mL) in an ice bath. The mixture was extracted twice with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent ratio: EA:PE = 0% to 50%) to yield the title compound 6F (1.1 g, 46%).

[0635] Step 6: Compound 6F (1.1 g, 4.78 mmol) was dissolved in 1,4-dioxane (12 mL) at room temperature. 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 allowed to react overnight. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent ratio: MeOH:DCM = 0% to 10%) to yield the title compound 6G (600 mg, 43%).

[0636] LC-MS (ESI): m / z = 296.3 [M+H] +

[0637] 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, 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, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (eluent ratio: MeOH:DCM = 0% to 10%) to give the title compound 6H (300 mg, 47%).

[0638] LC-MS (ESI): m / z = 312.3 [M+H] +

[0639] 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. The mixture was then heated to 100°C and allowed to react overnight. After completion of the reaction, the crude product was concentrated under reduced pressure and separated by preparative HPLC to obtain racemate 6 (70 mg, 31%). Separation method: 1. Apparatus: Waters 2767 Preparative HPLC; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate: 12 mL / min.

[0640] Preparative separation of the racemate using the following preparative chromatography conditions: 1. Instrument: Waters 150SFC; 2. Column: Chiralpak IC-Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase: A for CO₂ and B for MeOH (0.1% NH₃·H₂O); 4. Gradient: B 35%; 5. Flow rate: 100 mL / min. The chiral separation yielded the title compound 6-1 (30 mg, 13.3%, retention time: 1.092 min, absolute configuration undetermined) and the title compound 6-2 (31 mg, 13.7%, retention time: 1.761 min, absolute configuration undetermined).

[0641] Compound 6-1 1 H NMR(400MHz, Methanol-d4)δ7.22–7.16(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).

[0642] LC-MS (ESI): m / z = 471.1 [M+H] +

[0643] Compound 6-2 1H NMR(400MHz, Methanol-d4)δ7.33–7.27(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).

[0644] LC-MS (ESI): m / z = 471.1 [M+H] +

[0645] Example 8

[0646] Using compounds 6H and 2A as starting materials, following the procedure described in Example 2, racemate 7 (80 mg, 35%) was obtained. Isolation method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative Chromatography Conditions: a. Mobile Phase A, B Composition: Mobile Phase A: Acetonitrile; Mobile Phase B: Water (containing 0.1% ammonium acetate). b. Gradient elution, mobile phase A content ranging from 10% to 55%. c. Flow rate: 12 mL / min.

[0647] The chiral preparative separation of the racemate was performed using the following preparative chromatographic conditions: 1. Instrument: Waters 150SFC; 2. Column: Chiralpak IC-Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase: A for CO₂ and B for MeOH (0.1% NH₃·H₂O); 4. Gradient: B 35%; 5. Flow rate: 100 mL / min. The chiral separation yielded the title compound 7-1 (31 mg, 13.6%, retention time: 1.400 min, absolute configuration undetermined) and the title compound 7-2 (33 mg, 14.5%, retention time: 1.681 min, absolute configuration undetermined).

[0648] Compound 7-1 1H NMR(400MHz,Methanol-d4)δ8.75(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).

[0649] LC-MS (ESI): m / z = 473.2 [M+H] +

[0650] Compound 7-2 1 H NMR(400MHz,Methanol-d4)δ8.75(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).

[0651] LC-MS (ESI): m / z = 473.2 [M+H] +

[0652] Example 9

[0653] Step 1: Compound 3H (3.7 g, 12.3 mmol) was separated by chiral column to give compounds 8A-P1 (1.1 g, 30%) and 8A-P2 (0.9 g, 24%). Chiral separation method: Instrument: Waters 150SFC; 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.

[0654] Compound 8A-P1, retention time: 0.614 min. 1H NMR(400MHZ,DMSO-d6)δ7.58(s,1H),4.91(t,1H),3.68(d,2H),3.25-3.18(m,1H),3.11-3.03(m,1H),2.8 6–2.76(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).

[0655] LCMS (ESI): =302.1 [M+H] + .

[0656] Compound 8A-P2, retention time: 1.148 min. 1 H NMR(400MHZ,DMSO-d6)δ7.58(s,1H),4.91(t,1H),3.68(d,2H),3.25-3.18(m,1H),3.11-3.03(m,1H),2.8 6–2.76(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).

[0657] LCMS (ESI): =302.1 [M+H] + .

[0658] Step 2: Dissolve compound 8A-P1 (0.10 g, 0.33 mmol), 8B (77 mg, 0.40 mmol, synthesis method reference CN103145607), and DIPEA (0.13 mg, 0.99 mmol) in dioxane (10 mL) and stir at 85°C for 16 h. After completion of the reaction, concentrate under reduced pressure. HPLC yields compound 8-1 (60 mg, 40%).

[0659] Preparation Method: Instrument: Abilene 1290 Infinity II Preparative LC; Chromatographic Column: XSelect@Prep C18 (19 mm × 250 mm); Samples were dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Preparative Chromatographic Conditions: Mobile Phase A, B Composition: Mobile Phase A: 5 mmol ammonium acetate, Mobile Phase B: methanol; Gradient elution, Mobile Phase B content from 50% to 85%; Flow Rate: 15 ml / min; Elution Time: 18 min; Retention Time: 16.8.

[0660] Compound 8-1, 1H NMR(400MHZ,DMSO-d6)δ7.48(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).

[0661] The synthesis and preparation of compound 8-2 (45 mg, 36%) were the same as those of compound 8-1.

[0662] Compound 8-2, 1 H NMR(400MHZ,DMSO-d6)δ7.48(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).

[0663] LCMS (ESI): =459.50 [M+H] + .

[0664] Example 10

[0665] Step 1: In a 250 mL single-necked flask, substrate 9A (5.0 g, 20.77 mmol) was added, followed by dissolution with dioxane (100 mL) and water (20 mL). Sodium carbonate (6.6 g, 62.31 mmol), 9B (7.1 g, 22.85 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.5 g, 2.08 mmol) were then added. The mixture was stirred overnight at 100°C under nitrogen. The reaction mixture was diluted with water (50 mL), filtered through celite, and 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 afford the title compound 9C (5.0 g, 81%).

[0666] LC-MS(ESI): m / z=240.1[M-56+H]+.

[0667] Step 2: Substrate 9C (1.0 g, 3.38 mmol) was added to a 50 mL single-necked bottle, dissolved in methanol (5 mL) and dioxane hydrochloride (4 M, 5 mL), and stirred at room temperature for 3 h. The reaction solution was concentrated to obtain the title compound 9D (0.79 g, 100%).

[0668] LC-MS (ESI): m / z = 196.2 [M+H] + .

[0669] Step 3: Dissolve compound 8A-P1 (0.10 g, 0.33 mmol), 9D (77 mg, 0.40 mmol), and DIPEA (0.13 mg, 0.99 mmol) in dioxane (10 mL) and stir at 85°C for 16 h. After the reaction, the solvent was removed by vortexing. HPLC yielded compound 9-1 (70 mg, 46%).

[0670] Preparation Method: Instrument: Abilene 1290 Infinity II Preparative LC; Chromatographic Column: XSelect@Prep C18 (19 mm × 250 mm); Samples were dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Preparative Chromatographic Conditions: Mobile Phase A, B Composition: Mobile Phase A: 5 mmol ammonium acetate, Mobile Phase B: methanol; Gradient elution, Mobile Phase B content: 50%-85%; Flow Rate: 15 ml / min; Elution Time: 18 min; Retention Time: 16.5 min.

[0671] The synthesis of compound 9-2 (60 mg, 48%) was carried out under the same preparation and separation conditions as compound 9-1.

[0672] Compound 9-1, 1 H NMR(400MHZ,DMSO-d6)δ8.89(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).

[0673] Compound 9-2, 1H NMR(400MHZ,DMSO-d6)δ8.89(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).

[0674] LCMS (ESI): =461.50 [M+H] + .

[0675] Example 11

[0676] Step 1: Dissolve compound 3H (150 mg, 0.50 mmol), 4-(4-chlorophenyl)piperidine hydrochloride (131 mg, 0.55 mmol), and DIPEA (260 mg, 2.00 mmol) in dioxane and react at 90°C for 16 h. After the reaction, the solvent was removed by vortexing, and compounds 10-1 (44.3 mg, 19%) and 10-2 (26.5 mg, 11%) were prepared by SFC.

[0677] Chiral separation method: Instrument: Waters 150SFC; Column: Chiralcel OX Column (250×30 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.

[0678] Compound 10-1, retention time: 1.128 min. 1H NMR(400MHZ,DMSO-d6)δ7.38–7.29(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),2.1 8–2.08(m,2H),2.03–1.89(m,1H),1.83-1.71(m,4H),1.55–1.41(m,2H).

[0679] LCMS (ESI): =461.2 [M+H] + .

[0680] Compound 10-2, retention time: 1.609 min. 1 H NMR(400MHZ,DMSO-d6)δ7.38–7.29(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),2.54-2.5 1(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).

[0681] LCMS (ESI): =461.2 [M+H] + .

[0682] Example 12

[0683] 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 completion of the reaction, the product was concentrated under reduced pressure. Compounds 11-1 (29.2 mg, 13%) and 11-2 (39.9 mg, 17%) were prepared by SFC.

[0684] Chiral separation method: Instrument: Waters 150 SFC; Column: 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); Gradient: 45% phase B isocratic elution; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm.

[0685] Compound 11-1, retention time: 1.192 min. 1 H NMR(400MHZ,DMSO-d6)δ7.42–7.17(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),3.10-3.0 4(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).

[0686] LCMS (ESI): =462.2[M+H] + .

[0687] Compound 11-2, retention time: 1.766 min. 1 H NMR(400MHZ,DMSO-d6)δ7.42–7.17(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),3.10-3.0 4(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).

[0688] LCMS (ESI): =462.2[M+H] + .

[0689] Example 13

[0690] Step 1: Compound 12A (3.00 g, 20.10 mmol) and compound 12B (3.74 g, 20.10 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (30 mL) was added to dissolve the mixture. N,N-diisopropylethylamine (7.79 g, 60.30 mmol) was added to the reaction solution and stirred at 80°C for 16 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated that the reaction was complete. Water (20 mL) was added to the reaction solution, stirred for 5 min, and extracted with ethyl acetate (20 mL). 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%).

[0691] LCMS m / z=299.1[M+1] +

[0692] Step 2: Compound 12C (1.0 g, 3.35 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). A 4 N solution of dioxane hydrochloride (10 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid remained, yielding the target compound 12D (0.80 g, crude product).

[0693] LCMS m / z=199.1[M+1] +

[0694] Step 3: Add 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) to a 100 mL single-necked flask. After the addition is complete, the system is protected by nitrogen and stirred at 90°C for 16 h. The reaction solution is concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yields the title compound 12-1 (60 mg, 48%).

[0695] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 35% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 13.50 min.

[0696] The synthesis and isolation of compound 12-2 (58 mg, 47%) were the same as those of compound 12-1.

[0697] LCMS m / z=464.2[M+1] +

[0698] Compound 12-1, 1 H NMR(400MHZ,DMSO-d6)δ8.44(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).

[0699] Compound 12-2, 1 H NMR(400MHZ,DMSO-d6)δ8.44(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).

[0700] Example 14

[0701] Step 1: Compound 13A (1.00 g, 5.45 mmol) and compound 13B (1.16 g, 5.45 mmol) were weighed into a 100 mL single-necked bottle, and then 1,4-dioxane (30 mL) was added to dissolve them. Sodium tert-butoxide (1.57 g, 16.34 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.27 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0 After the addition of 1,000 mmol (0.34 g, 0.55 mmol), the mixture was stirred at 90 degrees for 16 h. The reaction was complete as shown by TLC (petroleum ether:ethyl acetate = 5:1). Water (20 mL) was added to the reaction solution, and the mixture was stirred for 5 min. Ethyl acetate (20 mL) was added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 13C (1.0 g, yield: 58%).

[0702] LCMS m / z=315.1[M+1] +

[0703] Step 2: Compound 13C (0.30 g, 0.95 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). A 4 N solution of dioxane hydrochloride (10 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid remained, yielding the target compound 13D (0.20 g, crude product).

[0704] LCMS m / z=215.1[M+1] +

[0705] Step 3: Add 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) to a 100 mL single-necked flask. After the addition is complete, the system is protected by nitrogen and stirred at 90°C for 16 h. The reaction solution is concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yields the title compound 13-1 (12 mg, 9%).

[0706] Preparation method: Apparatus: Waters 2767 preparative liquid chromatography; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Samples were dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content ranging from 45% to 85%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 12.80 min.

[0707] The synthesis and isolation of compound 13-2 (40 mg, 30%) were the same as those of compound 13-1.

[0708] LCMS m / z=480.2[M+1] +

[0709] Compound 13-1, 1 H NMR(400MHz,DMSO-d6)δ6.84(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).

[0710] Compound 13-2,1 H NMR(400MHz,DMSO-d6)δ6.84(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).

[0711] Example 15

[0712] Using compound (3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester and 9A as raw materials, the process was carried out with reference to Example 13 to obtain compound 14-1 (76 mg, 59.6%).

[0713] The synthesis and purification of compound 14-2 (83 mg, 65.1%) were the same as compound 14-1.

[0714] Compound 14-1: 1 H NMR(400MHz,DMSO-d6)δ8.39(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).

[0715] Compound 14-2: 1 H NMR(400MHz,DMSO-d6)δ8.39(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).

[0716] LC-MS (ESI): m / z = 490.6 [M+H]+ .

[0717] Example 16

[0718] Step 1: 8A-P1 (80 mg, 0.26 mmol) and 6B (120 mg, synthesis method refers to WO2020099886) were dissolved in 1,4-dioxane (10 mL), DIPEA (0.5 mL) was added, and the reaction was continued at 90 ° C overnight. LCMS detected that the reaction of the raw materials was complete. The system was concentrated, water (100 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 20:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through a column (DCM:MeOH = 1:0~0:1) to obtain compound 15-1 (84 mg, 66.2%).

[0719] The synthesis and purification of compound 15-2 (88 mg, 69.8%) were the same as those of compound 15-1.

[0720] Compound 15-1: 1 H NMR(400MHz,DMSO-d6)δ7.21–7.10(m,2H),6.58–6.50(m,2H),6.46(s,1H),4.92–4.8 5(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),2.58–2.5 1(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).

[0721] Compound 15-2: 1H NMR(400MHz,DMSO-d6)δ7.20–7.11(m,2H),6.58–6.50(m,2H),6.46(s,1H),4.93–4.8 4(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),2.58–2.5 2(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).

[0722] LC-MS (ESI): m / z = 488.6 [M+H] + .

[0723] Example 17

[0724] Using compounds 16A and 16B as starting materials and following the procedure described in Example 10, compound 16-1 (50 mg, 20%) was obtained.

[0725] The synthesis of compound 16-2 (50 mg, 20%) was carried out using 8A-P2 as the starting material. The preparation and isolation were the same as those of compound 16-1.

[0726] Preparation Method: Instrument: SHIMADZU LC-20AP; Chromatographic Column: Phenomenex C18; Dissolve the sample in acetonitrile and water and filter through a 0.45 μm filter to prepare a sample solution. Preparative Chromatography Conditions: Mobile Phase A, B Composition: Mobile Phase A: 10 mmol ammonium bicarbonate, Mobile Phase B: acetonitrile; Gradient elution, Mobile Phase B content from 30% to 60%; Flow Rate: 25 ml / min; Elution Time: 15 min; Retention Time: 3.3 min.

[0727] Compound 16-1, 1H NMR(400MHz,DMSO-d6)δ7.34(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).

[0728] Compound 16-2, 1 H NMR(400MHz,DMSO-d6)δ7.34(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).

[0729] LCMS (ESI): =473.2[M+H] + .

[0730] Example 18

[0731] Using compounds 17A and 16B as starting materials and following the procedure described in Example 10, compound 17-1 (30 mg, 12%) was obtained.

[0732] The synthesis of compound 17-2 (48 mg, 19%) was carried out using 8A-P2 as the starting material. The preparation and isolation were the same as those of compound 17-1.

[0733] Preparation method: Instrument: Waters 150 SFC; Chromatographic column: Chiralpak IG Column (250×30 mm, ID 30 mm, 10 μm particle size); Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO2, Mobile phase B: EtOH + ACN (0.1% NH3·H2O); b. Isocratic elution, mobile phase B content 65%; c. Flow rate 100 mL / min; d. Elution time 15 min; e. Back pressure 100 bar; f. Column temperature: 25°C.

[0734] Compound 17-1, 1 H NMR(400MHz,DMSO-d6)δ8.84(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).

[0735] Compound 17-2, 1 H NMR(400MHz,DMSO-d6)δ8.84(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).

[0736] LCMS (ESI): =475.1[M+H] + .

[0737] Example 19

[0738] Step 1: Compound 18A (1.50 g, 13.62 mmol) and di-tert-butyl dicarbonate (5.95 g, 27.24 mmol) were weighed into a 100 mL single-necked flask and dissolved in water (30 mL). Sodium bicarbonate (3.43 g, 40.86 mmol) was added to the reaction solution and stirred for 16 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated complete reaction with the precipitation of a solid, which was directly filtered to obtain the target compound 18B (1.5 g, 35% yield).

[0739] 1 H NMR(400MHZ,DMSO-d6)δ3.96-4.06(m,8H),1.42(s,18H).

[0740] Step 2: Compound 18B (1.50 g, 4.83 mmol) and p-toluenesulfonic acid (0.83 g, 4.83 mmol) were weighed into a 100-mL single-necked flask, and isopropyl acetate (30 mL) was added to dissolve the mixture. The mixture was stirred at 60°C for 4 h. TLC analysis (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete and a solid precipitated from the reaction solution. The target compound 18C (1.5 g, 100% yield) was obtained by direct filtration.

[0741] 1 H NMR(400MHZ,DMSO-d6)δ3.96-4.03(m,8H),1.42(s,9H).

[0742] Step 3: Compound 18C (0.30 g, 1.43 mmol) and 2-chloro-5-chloropyrimidine (0.21 g, 1.43 mmol) were weighed into a 100-mL single-necked flask, and 1,4-dioxane (20 mL) was added for dissolution. N,N-diisopropylethylamine (0.55 g, 4.26 mmol) was added to the reaction solution and stirred at 80°C for 16 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated complete reaction. Water (20 mL) was added to the reaction solution, 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: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 18D (0.2 g, yield: 43%).

[0743] LCMS m / z=323.1[M+1] +

[0744] Step 4: Compound 18D (0.2 g, 0.62 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). A 4 N solution of dioxane hydrochloride (10 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid remained, yielding the target compound 18E (0.15 g, crude product).

[0745] LCMS m / z=223.1[M+1] +

[0746] Step 5: To a 100 mL single-necked vial, add compound 8A-P2 (single configuration, uncertain configuration) (150 mg, 0.50 mmol), compound 18E (110 mg, 0.50 mmol), and N,N-diisopropylethylamine (0.20 g, 1.51 mmol). After the addition is complete, the system is protected by nitrogen and stirred at 90°C for 16 h. The reaction solution is concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yields the title compound 18 (single configuration, uncertain configuration) (30 mg, 12%).

[0747] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 30% to 70%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 10.80 min.

[0748] LCMS m / z=488.1[M+1] +

[0749] 1 H NMR(400MHZ,DMSO-d6)δ8.45(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).

[0750] Example 20

[0751] Step 1: Compound 19A (1 g, 4.44 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the nitrogen atmosphere was replaced three times. The reaction system was cooled to -78 ° C., and lithium bis(trimethylsilyl)amide (8.88 mmol) was added dropwise. After maintaining at -78 ° C. for 30 min, N-phenylbis(trifluoromethylsulfonyl)imide (2.59 g, 6.66 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) was added dropwise. The temperature was kept at -78 ° C. for 30 min and then transferred to room temperature for 2 h. After the reaction was completed, a saturated ammonium chloride solution (30 ml) was added to quench the reaction. The organic phase was extracted with ethyl acetate (3×40 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid column chromatography (eluent ratio: EA / PE = 0% to 10%) to obtain compound 19B (1.3 g, 82%).

[0752] LCMS (ESI): m / z = 302.2 [M+H-56] +

[0753] Step 2: To compound 19B (1.3 g, 3.64 mmol) dissolved in 1,4-dioxane (20 ml) was added bistriphenylphosphine palladium dichloride (260 mg, 0.37 mmol), pinacol diboron (1.11 g, 4.37 mmol), and potassium acetate (1.07 g, 10.92 mmol) under nitrogen. The mixture was reacted in an oil bath at 90°C for 18 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated and directly purified by rapid column chromatography (eluent ratio: EA / PE = 0% to 10%) to yield the desired compound 19C (0.89 g, 73%).

[0754] LCMS (ESI): m / z = 280.2 [M+H-56] +

[0755] Step 3: To compound 19C (0.89 g, 2.65 mmol) dissolved in 1,4-dioxane / water (10 ml / 2 ml) under nitrogen was added 5-chloro-2-iodobenzene (574 mg, 2.41 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (176 mg, 0.24 mmol), and sodium carbonate (766 mg, 7.32 mmol). The mixture was reacted in an oil bath at 90°C for 18 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated and directly purified by rapid column chromatography (eluent ratio: EA / PE = 0% to 10%) to afford the desired compound 19D (0.44 g, 52%).

[0756] LCMS (ESI): m / z = 264.2 [M+H-56] +

[0757] Step 4: Compound 19D (220 mg, 0.69 mmol) was dissolved in 1,4-dioxane (2 ml) with hydrochloric acid, stirred at room temperature for 1 h, and directly dried to obtain the hydrochloride compound 19E (170 mg).

[0758] LCMS (ESI): m / z = 220.1 [M+H] +

[0759] Step 5: Dissolve intermediate 8A-P2 (single configuration, uncertain configuration) (100 mg, 0.33 mmol) in 1,4-dioxane (5 ml). Add the hydrochloride salt of 19E (85 mg, 0.33 mmol) and diisopropylethylamine (128 mg, 0.99 mmol). The reaction system is placed in an oil bath at 100°C for 15 h. After completion of the reaction, cool to room temperature and monitor the reaction by LCMS. The product is then spin-dried and sent for preparative HPLC separation. Method: 1. Instrument: Waters 2767 Preparative HPLC; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate 12 mL / min. Retention time 7.0 min to yield compound 19 (130 mg, 81%).

[0760] LCMS (ESI): m / z = 485.3 [M+H] +

[0761] Compound 19 splitting:

[0762] Compound 19 (130 mg) was used for separation, and 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 after separation.

[0763] Split conditions:

[0764] Instrument: Waters 150MGM; Column: DAICEL CHIRALPAK AD;

[0765] Mobile phase: A for CO2 and B for EtOH (0.1% NH3·H2O); Gradient: B 40%; Flow rate: 120 mL / min; Back pressure: 100 bar;

[0766] Column temperature: 35°C; wavelength: 220 nm; cycle: 13 min;

[0767] Compound 19-1:

[0768] 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).

[0769] Compound 19-2:

[0770] 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,2 H),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).

[0771] Example 21

[0772] Step 1: Compound 20A (1.4 g, 5.0 mmol) was dissolved in 1,4-dioxane (30 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (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 nitrogen atmosphere was evacuated three times, and the mixture was heated to 45 ° C for 14 h. After that, the mixture was passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 20B (1.7 g, 99%).

[0773] LC-MS (ESI): m / z = 284.1 [M-56] +

[0774] Step 2: Compound 20B (340.0 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL), and bis(triphenylphosphine)palladium dichloride (70.0 mg, 0.1 mmol), triethylamine (202.0 mg, 2.0 mmol), trimethylsilyl acetylene (130.0 mg, 1.3 mmol) and cuprous iodide (8.0 mg, 0.05 mmol) were added. The atmosphere was purged with nitrogen three times, heated to 50°C for 14 h, and then passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 20C (240.0 mg, 72%).

[0775] LC-MS (ESI): m / z = 302.1 [M-56] +

[0776] Step 3: Compound 20C (240.0 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.0 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 20D (150.0 mg, 87%), which was used directly in the next step.

[0777] LC-MS (ESI): m / z = 258.1 [M+H] +

[0778] 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 reacted at room temperature for 2 h, concentrated, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound 20E (70.0 mg, 65%).

[0779] LC-MS (ESI): m / z = 186.1 [M+H] +

[0780] 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, uncertain configuration) (230.0 mg, 0.8 mmol) was added. The mixture was heated to 90°C for 12 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 20 (120.0 mg, 62%).

[0781] LC-MS (ESI): m / z = 451.1 [M+H] +

[0782] 1H NMR(400MHz,DMSO-d6)δ8.90(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,2 H),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).

[0783] Example 22

[0784] Step 1: Compound 18C (0.50 g, 2.38 mmol) and 1-chloro-4-iodobenzene (0.68 g, 2.68 mmol) were weighed into a 100 mL single-necked bottle, and then 1,4-dioxane (30 mL) was added to dissolve. 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.15 g, 0.24 mmol), sodium tert-butoxide (0.69 g, 7.14 mmol), tris(dibenzylideneacetone)dipalladium (0.0001), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.0001) were added to the reaction solution. .14 ​​g, 0.24 mmol). After the addition was completed, the mixture was stirred at 85 degrees for 16 h. TLC (petroleum ether:ethyl acetate = 5:1) showed that the reaction was complete. Water (20 mL) was added to the reaction solution, stirred for 5 min, and ethyl acetate (20 mL) was added for extraction. 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 21A (0.28 g, yield: 37%).

[0785] LCMS m / z=321.1[M+1] +

[0786] Step 2: Compound 21A (0.2 g, 0.62 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). A 4N solution of dioxane hydrochloride (10 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure to yield the target compound 21B (0.15 g, crude product).

[0787] LCMS m / z=221.1[M+1] +

[0788] Step 3: Add 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) to a 100 mL single-necked flask. After the addition is complete, the system is protected by nitrogen and stirred at 90°C for 16 h. The reaction solution is concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yields the title compound 21 (50 mg, 20%).

[0789] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 12.20 min.

[0790] LCMS (ESI): m / z = 486.1 [M+1] +

[0791] 1 H NMR(400MHZ,DMSO-d6)δ7.21(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).

[0792] Example 23

[0793] Step 1: Dissolve 22A (5.0 g, 33.6 mmol), 1,4-dioxo-8-azaspiro[4.5]decane (5.3 g, 36.9 mmol), and DIPEA (13.0 g, 100.8 mmol) in 100 mL of dioxane. Heat the mixture to 80°C and react for 2 h. Pour the reaction mixture into ice water and extract twice with ethyl acetate. The combined organic phases are dried and the solvent removed by rotary evaporation. Purification by silica gel column chromatography (PE:EA = 20:1) affords the target compound 22B (8.5 g, 99% yield).

[0794] LCMS (ESI): m / z = 256.2 [M+H] +

[0795] Step 2: Dissolve raw material 22B (8.5 g, 33.2 mmol) in 30 mL of tetrahydrofuran, add 120 mL of 10% sulfuric acid, and heat to 90°C for 12 h under reflux. After TLC confirms the reaction is complete, cool to room temperature and adjust the pH to neutral with saturated sodium bicarbonate. Wash with ethyl acetate (100 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain the target compound 22C (6.2 g, 88% yield), which is used directly in the next step.

[0796] LCMS (ESI): m / z = 212.3 [M+H] +

[0797] Step 3: The raw material 22C (6.2 g, 29.2 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (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. After stirring at room temperature for 4 h, the reaction was completed after TLC monitoring, and the mixture was concentrated and purified by silica gel column chromatography (PE:EA=50:1) to obtain the target compound 22D (10.6 g, 73% yield).

[0798] LCMS (ESI): m / z = 494.0 [M+H] +

[0799] Step 4: Combine starting material 22D (6.50 g, 13.2 mmol), pinacol diboron (4.02 g, 15.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (190 mg, 0.26 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (144 mg, 0.26 mmol) in dioxane (65 mL). Stir the mixture at room temperature for 15 min. Potassium acetate (2.58 g, 26.4 mmol) was added and the mixture was reacted at 90°C for 16 h. After completion of the reaction, the mixture was monitored by TLC and LCMS. Purification by silica gel column chromatography (PE:EA = 20:1) afforded the title compound 22E (3.37 g, 79% yield).

[0800] LCMS (ESI): m / z = 322.4 [M+H] +

[0801] Step 5: Compound 22E (500 mg, 1.55 mmol) and 8A-P2 (422 mg, 1.40 mmol) were suspended in 10 mL of a 4:1 dioxane:water mixture and reacted at 90°C for 4 h. After completion of the reaction, the reaction solution was added dropwise to ice water and filtered. The filtrate was extracted three times with dichloromethane. The organic phase and the filter residue were combined, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to afford the target compound 22 (142 mg, 23%).

[0802] 1 H NMR(400MHz,DMSO-d6)δ8.45(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).

[0803] LCMS (ESI): m / z = 461.19 [M+H] +

[0804] Example 24

[0805] Step 1: Under nitrogen, sodium hydride (3.56 g, 88.98 mmol) was slowly added to a solution of diethyl cyanomethylphosphonate (12.61 g, 71.18 mmol) in tetrahydrofuran (100 mL). After complete addition, the reaction mixture was stirred at room temperature for 1 hour. 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 hours, quenched with water (200 mL), and extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 23B (6.50 g, yield: 57.18%).

[0806] 1H NMR (400MHz, CDCl3) δ7.66–7.65(m,1H),7.53–7.52(m,1H),7.51–7.48(m,1H),7.31–7.28(m,1H),3.74(s,2H).

[0807] Step 2: Compound 23B (6.00 g, 31.31 mmol) was dissolved in methanol (120 mL), followed by the addition of Raney nickel (1 g). The reaction mixture was replaced with hydrogen atmosphere and stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: DCM:MEOH = 10:1) to obtain the target compound 23C (1.60 g, yield: 26.12%).

[0808] 1 H NMR (400MHz, CDCl3) δ7.47–7.46(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).

[0809] 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 heated to 70°C and stirred for 3 h. The reaction mixture was cooled to room temperature, concentrated, washed with aqueous sodium hydroxide, and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was purified by column chromatography (eluent: DCM:MEOH = 20:1 to 10:1) to afford the target compound 23D (250 mg, yield: 14.72%).

[0810] LCMS m / z=208.1[M+H] +

[0811] Step 4: Dissolve compound 8A-P2 (200 mg, 0.66 mmol) and compound 23D (250 mg, 1.20 mmol) in 1,4-dioxane (6 mL), then add DIPEA (235 mg, 1.82 mmol). After the addition is complete, heat to 85°C and stir under nitrogen for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1) and further purified by prep.HPLC (preparative method: instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); the sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonia); b. gradient elution, mobile phase A content from 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%).

[0812] LCMS m / z=473.2[M+H] +

[0813] 1 H NMR (400MHz, CDCl3) δ7.45–7.44(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).

[0814] Example 25

[0815] Step 1: 24A (5 g, 24.18 mmol), 1-tert-butoxycarbonyl-3-aminocyclobutanamine (5 g, 29.02 mmol), and N,N-diisopropylethylamine (9.38 g, 72.54 mmol) were added to acetonitrile (50 mL) and the reaction mixture was heated to 60°C for 16 h. After the reaction was complete, 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 layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 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 and purified by silica gel column chromatography (eluent EA / PE = 0-60%) to afford the title compound 24B (7 g, 84.44%).

[0816] LC-MS (ESI): m / z = 343.1 [M+H] + .

[0817] Step 2: 24B (7 g, 20.42 mmol), tetraisopropyl titanate (0.58 g, 2.04 mmol), and water (0.37 g, 20.42 mmol) were added sequentially to dichloromethane (100 mL) and stirred for 10 min. Tert-butyl hydroperoxide (7.89 g, 61.26 mmol, 70% purity) was then added and 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 solution, and the layers were separated. The organic phase was washed with aqueous sodium thiosulfate (50 mL) and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA / PE = 0-100%) to yield compound 24C (6 g, 82.6%).

[0818] 24C (5 g) was subjected to chiral separation. The title compounds 24C-1 (2.2 g, 44%, retention time: 0.853 min) and 24C-2 (1.6 g, 32%, retention time: 1.070 min) were obtained by chiral separation. Chiral preparation method: Instrument: Waters 150 SFC; Column: Chiralpak AS Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% 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.

[0819] LC-MS (ESI): m / z = 359.1 [M+H] + .

[0820] 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 temperature was raised to 100°C for 4 h. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH / DCM = 0-10%) to afford the title compound 24D-1 (1.2 g, 79.34%).

[0821] By referring to the above operation, 24C-2 (1 g, 2.79 mmol) was used as the starting material to obtain 24D-2 (1.2 g, 79.34%).

[0822] LC-MS (ESI): m / z = 542.2 [M+H] + .

[0823] Step 4: Add 24D-1 (1.2 g, 2.21 mmol) to dichloromethane (15 mL), then add trifluoroacetic acid (4 mL), and react at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to obtain crude product 24E-1 (1.7 g).

[0824] By referring to the above operation, 24D-2 (1.2 g, 2.21 mmol) was used as the starting material to obtain 24E-2 (1.7 g).

[0825] LC-MS (ESI): m / z = 442.2 [M+H] + .

[0826] Step 5: Crude 24E-1 (1.7 g) and 3-fluoro-1-iodopropane (0.61 g, 3.25 mmol) were added to tetrahydrofuran (20 mL), followed by a 5 mol / L aqueous solution of sodium hydroxide (0.52 g, 13 mmol). 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, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM = 0-15%) to yield the product (0.6 g, 55%).

[0827] 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) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Column: ChiralPak AD, 250×30 mm ID, 10 μm; Mobile phases: A: carbon dioxide and B: isopropanol (0.1% ammonia in water); 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.

[0828] Referring to the above operation, 24E-2 (1.7 g) was used as the starting material to obtain the compound (0.7 g, 64%), and chiral separation gave 24-3 and 24-4.

[0829] Chiral preparations yielded 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 preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Column: ChiralPak AD, 250×30 mm ID, 10 μm; Mobile phases: A: carbon dioxide and B: ethanol (0.1% ammonia in water); 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.

[0830] (Compound 24-1)

[0831] 1 H NMR(400MHz,DMSO-d6)δ8.01(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,1 H),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).

[0832] LC-MS (ESI): m / z = 502.2 [M+H]+ .

[0833] (Compound 24-2)

[0834] 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.51-7.47(m,2H),7.41-7.37(m,2H),6. 26(s,1H),4.56-4.49(m,2H),4.42-4.37(m,1H),3.88(dd,1H),3.80-3.71(m,1 H),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).

[0835] LC-MS (ESI): m / z = 502.2 [M+H] + .

[0836] (Compound 24-3)

[0837] 1 H NMR (400MHz, CDCl3) δ7.38-7.26(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),2.93-2.8 7(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).

[0838] LC-MS (ESI): m / z = 502.2 [M+H] + .

[0839] (Compound 24-4)

[0840] 1H NMR(400MHz, CDCl3)δ7.38-7.26(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).

[0841] LC-MS (ESI): m / z = 502.2 [M+H] + .

[0842] Example 26

[0843] 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. Under nitrogen protection, the mixture was heated to 70°C and stirred overnight. The mixture was cooled to room temperature, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was dried to obtain compound 25B (24 g, crude product), which was used directly in the next step without isolation and purification.

[0844] LCMS(ESI):=235.1,237.1[M+H] + .

[0845] Step 2: The 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. The mixture was separated by silica gel chromatography (DCM:MeOH, v / v = 10:1) to obtain compound 25C (8 g, two-step yield 48.7%).

[0846] LCMS (ESI): =172.1[M+H] + .

[0847] Step 3: Compound 25C (8 g, 46.73 mmol) was dissolved in a mixed solvent of methanol / ethanol (120 mL, v / v = 1:1), and potassium carbonate (12.92 g, 93.45 mmol) was added thereto. The mixture was stirred and heated to 90°C for 3 hours. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. 150 ml of ethyl acetate was added, the solid was dissolved and filtered out, and the solvent was dried to obtain compound 25D (3.25 g, 36%).

[0848] LCMS (ESI): =140.0 [M+H] + .

[0849] Step 4: 25D (3.25 g, 23.35 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (7.09 g, 70.06 mmol) and a catalytic amount of 4-dimethylaminopyridine (285 mg, 2.34 mmol) were added thereto. The mixture was cooled in an ice bath, and di-tert-butyl dicarbonate (10.2 g, 46.71 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h, and the mixture was directly dried by spin drying. The mixture was separated by silica gel column chromatography (EA:PE = 1:3) to give compound 25E (4.45 g, 79.6%).

[0850] LCMS (ESI): =184.1 [M+H] + .

[0851] Step 5: Dissolve 25E (4.45 g, 18.60 mmol) in tetrahydrofuran (50 mL) under nitrogen atmosphere and ice-cool. Add borane tetrahydrofuran complex (55.8 mL, 1.0 mol / L) dropwise. After completion of the addition, allow to react at room temperature for 3 hours. Cool with ice-cool, quench the reaction with a small amount of methanol, and evaporate the solvent under reduced pressure to obtain the crude product. Separate the crude product by silica gel column chromatography (EA:PE = 1:3) to afford compound 25F (2.26 g, 53.9%).

[0852] LCMS (ESI): =170.1[M+H] + .

[0853] Step 6: 25F (2.26 g, 10.03 mmol) was dissolved in chloroform (25 mL), and a catalytic amount of glacial acetic acid was added. Liquid bromine (1.6 g, 10.03 mmol) was added dropwise under ice-cooling. The mixture was stirred at room temperature overnight. 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 the mixture was directly spin-dried and separated by silica gel column chromatography (EA:PE = 1:3) to give compound 25G (2.26 g, 74.1%).

[0854] LCMS(ESI):=248.1,250.1[M+H] + .

[0855] 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 mixed solution of 1,4-dioxane and water (27.5 mL, v / v = 10:1). After nitrogen replacement, the mixture was reacted at 80 ° C for 3 hours, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain compound 25H (640 mg, 58.0%).

[0856] LCMS(ESI):=280.1,282.1[M+H] + .

[0857] Step 8: 25H (300 mg) was added to dioxane hydrochloride (5 mL, 4N), and the mixture was reacted at room temperature for 2 hours. The mixture was then dried to obtain compound 25I (300 mg, crude product), which was used directly in the next step.

[0858] LCMS(ESI):=236.1,238.1[M+H] + .

[0859] Step 9: 8A-P2 (150 mg, 0.50 mmol), 25I (200 mg, crude product), and DIPEA (321 mg, 2.49 mmol) were added to 1,4-dioxane (5 mL), and the reaction was carried out at 80°C for 3 hours. The solvent was dried and the product was prepared by HPLC. Sodium bicarbonate was added to the prepared solution to adjust the pH to 7-8. The product was extracted with dichloromethane and concentrated to obtain compound 25 (65 mg, 26.1%).

[0860] Preparative HPLC separation method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative HPLC conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA). b. Gradient elution, mobile phase A content from 5% to 50%. c. Flow rate: 12 mL / min. d. Elution time: 20 min.

[0861] LCMS (ESI): =502.1[M+H] + .

[0862] 1 H NMR(400MHz,Chloroform-d)δ7.52–7.45(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).

[0863] Example 27

[0864] Step 1: Compound 26A (3.00 g, 16.92 mmol) and compound 12B (3.78 g, 20.30 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (30 mL) was added to dissolve the mixture. N,N-diisopropylethylamine (6.56 g, 50.76 mmol) was added to the reaction solution and stirred at 80°C for 16 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated that the reaction was complete. Water (20 mL) was added to the reaction solution, stirred for 5 min, and extracted with ethyl acetate (20 mL). 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%).

[0865] LCMS m / z=343.1[M+1] +

[0866] Compound 26 (80 mg, 27%) was obtained by using compound 26B and trimethylethynylsilane as starting materials and following the procedure described in Example 21.

[0867] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 35% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 12.50 min.

[0868] LCMS m / z=454.2[M+1] +

[0869] 1 H NMR(400MHZ,DMSO-d6)δ8.50(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).

[0870] Example 28

[0871] Step 1: Add raw material 27A (3 g, 14.49 mmol) to 60 mL of dry tetrahydrofuran solvent, add lithium aluminum tetrahydride (270 mg, 7.25 mmol) reagent under ice bath, stir on ice bath for half an hour, warm to room temperature and stir for 3 hours, quench with water, add a small amount of dilute hydrochloric acid, and then extract with ethyl acetate three times, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate and use it directly in the next reaction.

[0872] Step 2: The raw material 27B (2 g, 12.12 mmol) was dissolved in dichloromethane (50 mL) solvent, and then triethylamine (2.45 g, 24.24 mmol), imidazole (1.65 g, 24.24 mmol) and tert-butyldimethylsilyl chloride (2.74 g, 18.18 mmol) were added. The mixture was stirred at room temperature overnight, diluted with water, extracted with dichloromethane, 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 20:1) to obtain 27C (1.8 g, yield 53%).

[0873] 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).

[0874] Step 3: The raw materials 3-thiophenone (8 g, 78.28 mmol) and diethyl oxalate (11.44 g, 78.28 mmol) were added to anhydrous ethanol solvent (70 mL), and sodium tert-butoxide (7.9 g, 82.21 mmol) was added under ice bath, and stirring was continued for 2 hours. Then, glacial acetic acid (5.17 g, 86.11 mmol) was added, and then tert-butyl 4-hydrazinopiperidine-1-carboxylate hydrochloride (16.85 g, 78.28 mmol) was added. Stirring was continued for 20 hours, 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 obtain 27E (8 g, yield 27%).

[0875] LCMS m / z=382.2[M+1] +

[0876] Step 4: Add raw material 27E (6 g, 15.73 mmol) to a mixed solvent of tetrahydrofuran (30 mL) and methanol (30 mL), and then add lithium hydroxide (0.76 g, 31.65 mmol) dissolved in 15 mL of water. Stir at room temperature for 2 hours. TLC monitors the reaction completion of the raw material. After concentration, dilute with water, adjust the pH to 2-3 with 2 M hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate for direct use in the next reaction.

[0877] LCMS m / z=354.1[M+1] +

[0878] Step 5: Add raw material 27F (4 g, 11.32 mmol) and diphenylphosphoryl azide (5.67 g, 14.72 mmol) to tert-butanol (100 mL), followed by triethylamine (1.72 g, 16.98 mmol). Under nitrogen protection, heat to 85°C and stir for 4 hours. Cool, concentrate, dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify and separate by silica gel column chromatography (PE:EA (v / v) = 1:0 to 4:1) to obtain the target compound 27G (4 g, yield 83%).

[0879] LCMS m / z=425.2[M+1] +

[0880] 1H 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).

[0881] Step 6: Add raw material 27G (4 g, 9.42 mmol) to anhydrous methanol (5 mL), followed by 20 mL of 1,4-dioxane hydrochloride solution (4 M). Stir at room temperature for 4 hours. LCMS monitoring shows that the reaction is complete. Concentrate directly to dryness for the next reaction.

[0882] LCMS m / z=225.1[M+1] +

[0883] Step 7: The raw 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-bis(diphenylphosphino-9,9-dimethylxanthene) (0.57 g, 0.98 mmol), and sodium tert-butoxide (1.89 g, 19.62 mmol) were added to 1,4-dioxane (100 mL) respectively. The mixture was heated to 85°C under nitrogen and stirred for 16 hours. The mixture was cooled and filtered. The filtrate was diluted with water, extracted with ethyl acetate, 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 4:1) to obtain the target compound 27I (0.8 g, yield 24%).

[0884] LCMS m / z=335.1[M+1] +

[0885] Step 8: The raw 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 under ice bath and stirred on ice bath for 1 hour. Then, the reagent 27C (1.17 g, 4.18 mmol) was added. After stirring on ice bath for half an hour, the mixture was warmed to room temperature and stirred for 3 hours. LCMS monitored the complete reaction of the raw material. The reaction was quenched by adding water, and the solvent was removed by concentration under reduced pressure using an oil pump. The target compound 27J (0.8 g, yield 91%) was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 1:0 to 5:1).

[0886] LCMS m / z=419.2[M+1]+

[0887] Step 9: Raw material 27J (200 mg, 0.48 mmol), 1,1'-bi-2-naphthol (69 mg, 0.24 mmol), water (9 mg, 0.48 mmol) and tetraisopropyl titanate (68 mg, 0.24 mmol) were added to dichloromethane (10 mL) solvent, stirred at room temperature for half an hour, and then tert-butyl peroxide (65 mg, 0.72 mmol) was added. Stirring was continued for 3 hours, and then diluted with water, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried and filtered, and the filtrate was concentrated and purified by TLC (DCM:MeOH=5:1) to obtain the target compound 27 (0.01 g, yield 5%).

[0888] LCMS m / z=435.2[M+1] +

[0889] 1 H NMR(400MHz,CD3OD-d4)δ7.14-7.17(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).

[0890] Example 29

[0891] 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 for 14 h. The mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 28B (5.2 g, 98%).

[0892] LC-MS (ESI): m / z = 260.0 [M+H] +

[0893] Step 2: Compound 28B (2.0 g, 7.7 mmol) was dissolved in dichloromethane (40 mL), and m-chloroperbenzoic acid (1.5 g, 8.5 mmol) was added under ice-cooling. The mixture was slowly warmed to room temperature and reacted overnight. The reaction was concentrated to obtain compound 28C (1.7 g, 80%), which was used directly in the next step.

[0894] LC-MS (ESI): m / z = 276.0 [M+H] +

[0895] Step 3: Compound 28C (0.7 g, 2.4 mmol) was dissolved in 1,4-dioxane (40.0 mL), and compound 9D (461.0 mg, 2.4 mmol) and diisopropylethylamine (1.3 g, 9.4 mmol) were added. The mixture was heated to 90°C for 12 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound 28D (380.0 mg, 37%).

[0896] LC-MS (ESI): m / z = 435.1 [M+H] +

[0897] Step 4: Compound 28D (380 mg) was subjected to chiral separation to obtain compound 28-1 (100 mg) and compound 28-2 (101 mg).

[0898] Preparation method: Instrument: MGⅡpreparative SFC (SFC-14), column: ChiralPak AD, 250×30mmI.D., 5μm mobile phase: (A for CO2 and B for MeOH (0.1% NH3·H2O); gradient: 50% phase B elution; flow rate: 100mL / min, back pressure: 100bar, column temperature: 25℃, wavelength: 220nm, cycle time: 3.3min. Sample preparation: sample concentration 10mg / mL, acetonitrile solution injection: 3.5mL each time. After separation, the fraction was dried by rotary evaporation at a bath temperature of 35℃ to obtain P1 (retention time: 1.334 minutes, designated as compound 28-1) and P2 (retention time: 1.840 minutes, designated as compound 28-2).

[0899] LC-MS (ESI): m / z = 435.6 [M+H] +

[0900] 1 H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.96(s,1H),7.37(s,1H),7.29(s,1H),4.92–4.89(m,1H),4.43(s,2H),3.9 5(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).

[0901] LC-MS (ESI): m / z = 435.6 [M+H] +

[0902] 1 H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.96(s,1H),7.37(s,1H),7.29(s,1H),4.92–4.89(m,1H),4.43(s,2H),3.9 5(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).

[0903] Example 30

[0904] Step 1: Under nitrogen in an ice bath, methanol (1 mL, 23.00 mmol) was slowly added dropwise to a mixture containing 29A (1.50 g, 7.70 mmol, referenced in patent WO2010078348A1) and a 4 M dioxane hydrochloride solution (6 mL, 23.00 mmol). After complete addition, the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 5°C, followed by the addition of sodium methoxide (830 mg, 15.4 mmol) and 7N methanolic ammonia solution (1.6 mL), followed by stirring at room temperature for 16 hours. A methanolic solution of sodium methoxide (1.10 g dissolved in 4.5 mL of methanol) was added to the reaction mixture at room temperature and stirred for 30 minutes. (2-Chloro-3-dimethylamino-2-propenyl)-dimethyl-ammonium hexafluorophosphate (2.00 g) was then added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to a small volume, followed by the addition of 2-methyltetrahydrofuran (100 mL) and washing twice with water (80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product, which was purified three times by column chromatography (eluent: DCM:MeOH = 100:1 to 10:1) to obtain the target compound 29B (120 mg, yield: 8.52%).

[0905] LC-MS (ESI): m / z = 196.2 [M+H] +

[0906] 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 then DIPEA (130 mg, 1.00 mmol) was added. The mixture was heated to 85° C. and stirred for 16 h under nitrogen protection. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (eluent: dichloromethane:methanol = 100:1 to 10:1) and further prepped for HPLC (preparative method: instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); the sample was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter to prepare a sample solution; preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonia); b. gradient elution, mobile phase A content from 20% to 80%; c. flow rate: 15 mL / min; d. elution time: 15 min; retention time: 7.0 min) to obtain the target compound 29 (3.5 mg, 2.29%).

[0907] LCMS m / z=462.1[M+H] +

[0908] 1 H NMR (400MHz, CDCl3) δ8.61(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).

[0909] Example 31

[0910] 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 for 14 h, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 30B (500 mg, 36%).

[0911] LC-MS (ESI): m / z = 286.1 [M+1] +

[0912] Step 2: Compound 30B (600.0 mg, 1.75 mmol), (S)-(-)-1,1'-bi-2-naphthol (50.0 mg, 0.18 mmol), tetraisopropyloxytitanium (25.0 mg, 0.088 mmol), and water (32.0 mg, 1.75 mmol) were dissolved in dichloromethane (10 mL). The atmosphere was purged with nitrogen three times and stirred at room temperature for one hour. Tert-butyl peroxide (170.0 mg, 1.93 mmol) was then added and stirred for 1.5 hours. The mixture was quenched with saturated aqueous sodium thiosulfate solution. The aqueous phase was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford compound 30C (430.0 mg, 81%).

[0913] LC-MS (ESI): m / z = 302.1 [M+H] +

[0914] 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 for 12 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 30 (290.0 mg, 44%).

[0915] LC-MS (ESI): m / z = 461.1 [M+H] +

[0916] 1 H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.35–7.21(m,1H),6.58(s,1H),4.9 1(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).

[0917] Example 32

[0918] 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 for 14 h, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 31B (600 mg, 24%).

[0919] LC-MS (ESI): m / z = 260.1 [M+1] + Step 2: Compound 31B (600.0 mg, 2.31 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (600.0 mg, 3.49 mmol) was added and 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%).

[0920] LC-MS (ESI): m / z = 276.1 [M+H] +

[0921] Step 3: Dissolve compound 31C (632.0 mg, 2.29 mmol) in 1,4-dioxane (10.0 mL), add compound 9D (540.0 mg, 2.75 mmol) and N,N-diisopropylethylamine (890 mg, 6.87 mmol), heat to 90°C for 12 h, cool to room temperature, concentrate, and perform column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 31 (440.0 mg, 44%).

[0922] LC-MS (ESI): m / z = 435.1 [M+H] +

[0923] 1 H NMR(400MHz,DMSO-d6)δ8.90(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).

[0924] Example 33

[0925] Step 1: Compound 31 (380 mg) was subjected to chiral separation to obtain compound 32-1 (165 mg) and compound 32-2 (180 mg).

[0926] 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 injection: 1.0 mL each time. After separation, the fraction was dried by rotary evaporation at a bath temperature of 35°C to obtain P1 (retention time: 1.730 minutes, set as compound 32-1) and P2 (retention time: 1.948 minutes, set as compound 32-2).

[0927] LC-MS (ESI): m / z = 435.1 [M+H] +

[0928] 1 H NMR(400MHz,DMSO-d6)δ8.89(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).

[0929] LC-MS (ESI): m / z = 435.1 [M+H] +

[0930] 1 H NMR(400MHz,DMSO-d6)δ8.89(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).

[0931] Example 34

[0932] Compound 33A and 4,4-dimethyl-[1,4]silapiperidine hydrochloride were used as starting materials and the reaction mixture was subjected to the procedure described in Example 31 to obtain compound 33 (0.6 g, 45%).

[0933] LC-MS (ESI): m / z = 474.1 [M+H] +

[0934] Compound 33 (600 mg) was subjected to chiral resolution to give compound 33-1 (200 mg) and compound 33-2 (202 mg).

[0935] Preparation: Instrument: Waters 150 SFC, Chiralcel column (250×30mm×10µm), mobile phase: (A for CO2; B for 0.1% NH3·H2O in MEOH); gradient: 35% phase B; flow rate: 100mL / min, backpressure: 100bar, column temperature: 25°C, wavelength: 220nm, cycle time: 3.0min. Sample preparation: Sample concentration: 10mg / mL, acetonitrile solution injection: 3.0mL per injection. After separation, the fraction was dried on a rotary evaporator at 35°C to yield P1 (retention time: 1.592 minutes, designated as compound 33-1) and P2 (retention time: 2.079 minutes, designated as compound 33-2).

[0936] LC-MS (ESI): m / z = 474.1 [M+H] +

[0937] 1 H NMR(400MHz,DMSO-d6)δ8.78(s,2H),7.18(s,1H),4.37(s,2H),4.05(d,2H),3.90–3.87(m,4H),3.4 1–3.36(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).

[0938] LC-MS (ESI): m / z = 474.1 [M+H] +

[0939] 1 H NMR(400MHz,DMSO-d6)δ8.78(s,2H),7.19(s,1H),4.37(s,2H),4.05(d,2H),3.90–3.87(m,4H),3.4 6–3.31(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).

[0940] Example 35

[0941] Using compounds 13A and 12B as starting materials and following the procedure described in Example 14, compound 34 (160 mg, 53%) was obtained.

[0942] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 12.60 min.

[0943] LCMS m / z=454.2[M+1] +

[0944] 1 H NMR(400MHZ,DMSO-d6)δ6.92(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).

[0945] Example 36

[0946] 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, synthesis reference: WO2014124860A1) was added. The mixture was heated to 90°C for 12 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 35F (360.0 mg, 72%).

[0947] LC-MS (ESI): m / z = 437.1 [M+H] +

[0948] 1H NMR(400MHz,DMSO-d6)δ8.90(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).

[0949] Step 2: Compound 35F (0.8 g, 2.0 mmol) was dissolved in dichloromethane (15 mL). Trichloroacetyl isocyanate (452.0 mg, 2.4 mmol) was added under ice-cooling. The reaction was continued for 1 h and concentrated to obtain 35G (1.2 g, 99%), which was used directly in the next step.

[0950] LC-MS (ESI): m / z = 624.0 [M+1] +

[0951] 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. After reacting at room temperature for 2.5 hours, the mixture was concentrated, extracted with dichloromethane, dried, and concentrated to obtain compound 35 (0.6 g, 62%).

[0952] LC-MS (ESI): m / z = 480.2 [M+1] +

[0953] 1 H NMR (400MHz, DMSO-d6) δ8.90(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).

[0954] Example 37

[0955] Step 1: Dissolve 36A (360 mg, 1.21 mmol, referenced in patent synthesis: WO2011124524A1) in 1,4-dioxane (8 mL). Add 20D (515 mg, 1.45 mmol) and N,N-diisopropylethylamine (780 mg, 6.05 mmol) sequentially. Heat to 85°C and stir under nitrogen for 16 hours. Allow the reaction mixture to return to room temperature, dilute with water (50 mL), and extract three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product. Purification by column chromatography (eluent: DCM:MeOH = 100:1 to 15:1) afforded the target compound 36B (590 mg, yield: 94.07%).

[0956] LC-MS (ESI): m / z = 519.2 [M+H] +

[0957] 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. TLC (developing solvent: DCM:MeOH = 15:1) was performed until the starting material disappeared. 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 obtain the crude product. The crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 10:1) to obtain the target compound 36C (350 mg, yield: 73.92%).

[0958] LC-MS (ESI): m / z = 447.2 [M+H] +

[0959] Step 3: Compound 36C (350 mg, 0.78 mmol) was subjected to chiral separation to obtain compound 36-1 (13.0 mg) and compound 36-2 (3.2 mg).

[0960] Analytical methods: 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.

[0961] Preparation method: Instrument: SHIMADZU LC-20AP, Column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm). Mobile phase: A: n-hexane, B: ethanol (0.1% NH₃·H₂O); Gradient: 8% B; Flow rate: 110 mL / min; Column temperature: 25°C; Wavelength: 254 nm; Cycle time: 16 min. Sample preparation: Sample concentration: 1.5 mg / mL; 2 mL of ethanol solution injected per sample. After separation, the fraction was dried on a rotary evaporator at 40°C to yield compound 36-1 (retention time: 5.716 minutes) and compound 36-2 (retention time: 6.890 minutes).

[0962] Compound 36-1: LCMS m / z=447.2 [M+H] +

[0963] 1 H NMR(400MHz, CDCl3)δ8.77(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).

[0964] Compound 36-2: LCMS m / z=447.2 [M+H] +

[0965] 1 H NMR(400MHz, CDCl3)δ8.77(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).

[0966] Example 38

[0967] Step 1: Dissolve compound 35F (2.0 g, 4.58 mmol) in dichloromethane (100 mL) and add Dess-Martin periodinane (2.92 g, 6.88 mmol). Stir at room temperature overnight. The reaction mixture is quenched with saturated aqueous sodium thiosulfate, and the aqueous phase is extracted with dichloromethane. The organic phase is dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford compound 37B (1.2 g, 60%).

[0968] LC-MS (ESI): m / z = 435.2 [M+H] +

[0969] Step 2: Compound 37B (220 mg, 0.51 mmol) was dissolved in 7.0 M ammonia-methanol solution (5 mL). After stirring at room temperature for half an hour, glyoxal (1 mL, 40 wt.% in water) was added and stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford 130 mg of a pale yellow solid. This was then prepared by reverse phase chromatography (acetonitrile:water = 1 / 99 to 99 / 1) to afford compound 37 (100 mg, 40%).

[0970] LC-MS (ESI): m / z = 473.2 [M+H] +

[0971] 1 H NMR (400MHz, DMSO-d6) δ11.38(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).

[0972] Example 39

[0973] Step 1: Compound 37B (1.2 g, 2.76 mmol) was dissolved in 1,2-dichloroethane (100 mL), and ammonium acetate (21.3 g, 275.94 mmol) was added. The mixture was stirred at room temperature overnight, and then sodium triacetoxyborohydride (5.85 g, 27.60 mmol) was added. After reacting at room temperature for 2 h, the reaction was quenched by adding saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, 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%).

[0974] LC-MS (ESI): m / z = 436.2 [M+H] + .

[0975] Step 2: Compound 38B (100 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (35 mg, 0.35 mmol) was added under ice-cooling. After stirring for five minutes, methyl chloroformate (24 mg, 0.25 mmol) was added and the mixture was allowed to react at 0°C for 1 h. The reaction was quenched with water, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, filtered, concentrated, and then reverse-phase treated (acetonitrile:water = 1 / 99 to 99 / 1) to afford compound 38 (50 mg, 44%).

[0976] LC-MS (ESI): m / z = 494.2 [M+H] +

[0977] 1 H NMR(400MHz,DMSO-d6)δ8.90(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).

[0978] Example 40

[0979] Step 1: Dissolve compound 38B (100 mg, 0.23 mmol) in methanol (5 mL), add methyl N-cyanoethylimidate (25 mg, 0.26 mmol), and stir at room temperature overnight. The reaction mixture was concentrated and subjected to reverse phase preparation (acetonitrile:water = 1 / 99 to 99 / 1) to afford compound 39 (50 mg, 43%).

[0980] LC-MS (ESI): m / z = 502.2 [M+H] +

[0981] 1H NMR(400MHz,DMSO-d6)δ8.90(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).

[0982] Example 41

[0983] Step 1: Compound 24A (3.00 g, 14.46 mmol) and imidazole (1.18 g, 17.35 mmol) were weighed into a 100 mL single-necked flask and dissolved in acetonitrile (30 mL). N,N-diisopropylethylamine (5.61 g, 43.38 mmol) was added and stirred at 70°C for 16 h. Completion of the reaction was monitored by TLC (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 then purified by column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to obtain the target compound 40E (1.0 g, 29% yield).

[0984] LCMS m / z=239.1[M+1] +

[0985] Step 2: Compound 40E (1.0 g, 4.19 mmol) was weighed into a 100 mL single-necked 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. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). Water (50 mL) was added and stirred for 5 min. Extraction with dichloromethane (30 mL) was performed. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain the target compound 40F (0.63 g, 59% yield).

[0986] LCMS m / z=255.1[M+1] +

[0987] Step 3: Compound 40F (300 mg, 1.18 mmol) was added to a 100 mL single-necked flask and dissolved in dioxane (10 mL). Compound 40C (300 mg, 1.42 mmol) and N,N-diisopropylethylamine (0.46 g, 3.54 mmol) were then added. After the addition was complete, the system was stirred at 85°C for 16 h under nitrogen atmosphere. TLC (dichloromethane:methanol = 10:1) confirmed the reaction was complete. 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 then purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the target compound 40G. After chiral separation, the target compound 40-1 (200 mg) and compound 40-2 (120 mg) were obtained.

[0988] Chiral separation method: Instrument: Waters 150 SFC; Column: Chiralpak IC Column (250×30 mm, ID 30 mm, 10 μm particle size); Mobile phase: AA 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.

[0989] LCMS m / z=433.2[M+1] +

[0990] Compound 40-1, 1 H NMR(400MHZ,DMSO-d6)δ8.59(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).

[0991] Compound 40-2, 1 H NMR(400MHZ,DMSO-d6)δ8.59(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).

[0992] Example 42

[0993] Step 1: Compound 41A (1.0 g, 3.95 mmol) and piperazine (0.41 g, 4.7 mmol) were weighed into a 100 mL vial and dissolved in dioxane (20 mL). Sodium tert-butoxide (0.76 g, 7.9 mmol), tris(dibenzylideneacetone)dipalladium (0.11 g, 0.20 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (250 mg, 0.40 mmol) were then added sequentially. After completion, the mixture was stirred at 80°C for 12 h. TLC monitoring (petroleum ether:ethyl acetate = 5:1) confirmed the reaction was complete. 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 then purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 41B (0.50 g, 47%).

[0994] LCMS m / z=259.1[M+1] +

[0995] Step 2: To a 100 mL single-necked flask, compound 8A-P2 (350 mg, 1.16 mmol) and compound 41B (300 mg, 1.16 mmol) were added 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. TLC monitoring (dichloromethane:methanol = 10:1) indicated the reaction was complete. Water (20 mL) was added and stirred for 5 min. Extraction was then performed with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the target compound 41C (0.40 g, 66%).

[0996] LCMS m / z=524.2[M+1] +

[0997] Step 3: Compound 41C (0.35 g, 0.67 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). Potassium carbonate (0.27 g, 1.94 mmol) was added and stirred for 2 h. TLC monitoring (dichloromethane:methanol = 10:1) confirmed the reaction was complete. The reaction mixture was filtered under reduced pressure and concentrated to yield the title compound. The crude product was purified by preparative HPLC to afford the title compound 41 (200 mg, 66%).

[0998] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 12.50 min.

[0999] LCMS m / z=452.2[M+1] +

[1000] 1 H NMR(400MHZ,DMSO-d6)δ7.31(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).

[1001] Example 43

[1002] Using compound 24A and 1,2,4-triazole as raw materials and referring to Example 41, compounds 42-1 and 42-2 were obtained.

[1003] 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: 120 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm.

[1004] Compound 42-1: retention time: 1.217 min. 1H NMR(400MHz,DMSO-d6)δ9.60(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).

[1005] LCMS (ESI): m / z = 434.2 [M+H] +

[1006] Compound 42-2: retention time: 1.570 min. 1 H NMR(400MHz,DMSO-d6)δ9.60(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).

[1007] LCMS (ESI): m / z = 434.2 [M+H] +

[1008] Example 44

[1009] Step 1: To a 250 mL single-necked flask were added 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). The mixture was reacted at room temperature for 6 hours. The temperature was then raised to 60°C and the reaction was continued for 24 hours. The filtrate was filtered, added with ethyl acetate (500 mL), and washed with water (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was then performed by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to afford 43B (10.0 g, 64.5% yield).

[1010] LC-MS (ESI): m / z = 336.2 [M+H] + .

[1011] Step 2: To a 250 mL single-necked flask were added 43B (10.0 g, 29.9 mmol), ethyl acetate (100 mL), and palladium on carbon (2 g) in sequence. The mixture was hydrogenated and reacted at room temperature for 12 h. After filtration, the filtrate was concentrated under reduced pressure to give 43C (7.0 g, 76.9% yield).

[1012] LC-MS (ESI): m / z = 306.2 [M+H] + .

[1013] Step 3: To a 100 mL single-necked flask were added acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), and cuprous iodide (2.24 g, 11.8 mmol) in sequence. The mixture was heated to 65°C, and 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 h. After turning off the heating, the reaction was continued for 12 h. 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).

[1014] LC-MS(ESI):m / z=361.2[M-56+H] + .

[1015] Step 4: Methanol (10 mL), 43D (0.5 g, 1.20 mmol), and palladium on carbon (100 mg) were added sequentially to a 50 mL single-necked flask. After hydrogenation at room temperature for 16 h, the filtrate was filtered and concentrated under reduced pressure to give 43E (0.3 g, 86.1% yield).

[1016] LC-MS(ESI):m / z=235.2[M-56+H] + .

[1017] Step 5: To a 50 mL single-necked flask were added 43E (0.3 g, 1.03 mmol) and hydrogen chloride-dioxane solution (4N, 15 mL) in sequence. The mixture was reacted at room temperature for 1 h and concentrated under reduced pressure to afford 43F (0.27 g, 99.6% yield).

[1018] LC-MS (ESI): m / z = 191.2 [M+H] + .

[1019] Step 6: To a 50 mL single-necked flask were added 35H (287 mg, 1.0 mmol), 43F (270 mg, 1.03 mmol), dioxane (10 mL), and DIPEA (774 mg, 6.0 mmol) in sequence. The mixture was reacted at 100°C for 12 hours. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to yield 400 mg of the mixture.

[1020] 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) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% 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.

[1021] (Compound 43G-1)

[1022] 1 H NMR(400MHz,DMSO-d6)δ7.43(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).

[1023] LC-MS (ESI): m / z = 442.2 [M+H] + .

[1024] (Compound 43G-2)

[1025] 1 H NMR(400MHz,DMSO-d6)δ7.44(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),4.02–3.8 1(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).

[1026] LC-MS (ESI): m / z = 442.2 [M+H] + .

[1027] Step 7: To a 50 mL single-necked flask, dichloromethane (5 mL) and 43G-1 (60 mg, 0.14 mmol) were added sequentially. Trichloroacetyl isocyanate (52 mg, 0.28 mmol) was added dropwise at 0°C. The mixture was reacted at room temperature for 1 h. The mixture was concentrated under reduced pressure to give the crude product of 43H, which was directly used in the next step.

[1028] LC-MS (ESI): m / z = 629.1 [M+H] + .

[1029] Step 8: Into a 50 mL single-necked flask were added the crude product of 43H, methanol (2 mL), water (2 mL), and potassium carbonate (38 mg, 0.28 mmol) in sequence. The mixture was reacted at room temperature overnight. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to give the title compound 43 (40 mg, two-step yield 60.6%).

[1030] 1 H NMR(400MHz,DMSO-d6)δ7.69(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).

[1031] LC-MS (ESI): m / z = 485.2 [M+H] + .

[1032] Example 45

[1033] Step 1: 4-Chloroiodobenzene (5.82 g, 24.41 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a 250 mL three-necked flask. The atmosphere was replaced with nitrogen. 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. The mixture was maintained at -78°C for 1 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA / PE = 0-35%) to yield the target compound 44B (4 g, 53.36%).

[1034] LC-MS (ESI): m / z = 338.1 [M+H] + .

[1035] Step 2: Add 44B (4 g, 11.84 mmol) to a mixture of dichloromethane (45 mL) and trifluoroacetic acid (15 mL) and react at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and then used for the next reaction.

[1036] LC-MS (ESI): m / z = 220.1 [M+H] + .

[1037] Step 3: To a 100 mL single-necked flask were added 35H (0.5 g, 1.74 mmol), 44C (0.7 g, 2.09 mmol), dioxane (20 mL), and DIPEA (1.12 g, 8.67 mmol) in sequence. The mixture was reacted at 100°C for 5 h. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH / DCM = 0-10%) to yield 700 mg of the mixture.

[1038] The title compound 44D-1 (300 mg, 36.6%, retention time: 0.786 min) and the title compound 44D-2 (240 mg, 29.3%, retention time: 0.993 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% 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: 5.5 min.

[1039] Step 4: Add 44D-2 (0.1 g, 0.21 mmol) to dichloromethane (5 mL), cool to 0°C, and add trichloroacetyl isocyanate (0.06 g, 0.32 mmol) dropwise. React at 0°C for 1 h. Concentrate the reaction mixture under reduced pressure to dryness to obtain a crude product (0.14 g), which is directly used in the next reaction.

[1040] LC-MS (ESI): m / z = 660.0 [M+H] + .

[1041] Step 5: Methanol (3 mL) and water (3 mL) were added to the crude product 44E (0.14 g), followed by potassium carbonate (0.09 g, 0.64 mmol). The reaction was allowed to react at room temperature for 16 h. Water (10 mL) was added to the reaction solution, which was extracted with dichloromethane (10 mL x 2). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH / DCM = 0-10%) to afford compound 44 (80 mg, 74%).

[1042] (Compound 44)

[1043] 1 H NMR (400MHz, DMSO-d6) δ7.53–7.35(m,5H),6.47(s,2H),6.26(s,1H),4.47–4.30(m,2H),3.95–3.91(m,1H),3.77–3.53(m ,3H),3.46-3.34(m,1H),3.23–3.01(m,3H),2.97–2.78(m,3H),2.67–2.57(m,1H),2.45–2.09(m,4H),1.91–1.72(m,2H).

[1044] LC-MS (ESI): m / z = 514.1 [M+H] + .

[1045] Example 46

[1046] Using compound 19C and 4-bromophenylcyclobutane as starting materials and referring to Examples 20 and 36, compound 45-1 (42 mg, 96%) and compound 45-2 (25 mg, 93%) were obtained.

[1047] Compound 45-1

[1048] LCMS (ESI): m / z = 505.2 [M+H] +

[1049] 1H NMR(400MHz, CDCl3)δ=7.26–7.23(m,1H),7.13(s,1H),6.99(d,1H),5.97 (s,1H),5.64(s,1H),4.79(s,1H),4.53(s,1H),4.07–3.91(m,1H),3.89–3 .66(m,3H),3.59(s,2H),3.42–3.37(m,1H),3.15(s,4H),3.12-3.08(d,1 H),3.06–2.91(m,3H),2.63(d,1H),2.50–2.13(m,4H),2.04–1.83(m,2H).

[1050] Compound 45-2

[1051] LCMS (ESI): m / z = 505.2 [M+H] +

[1052] 1 H NMR(400MHz, CDCl3)δ=7.26–7.25(m,1H),7.13(s,1H),6.99(d,1H),5.97 (s,1H),5.59(s,1H),4.75(s,2H),4.50(t,1H),3.96(s,1H),3.89–3.69(m ,2H),3.60(s,2H),3.42-3.35(m,1H),3.16(s,4H),3.12–3.07(m,1H),3.0 6–2.92(m,3H),2.63(d,1H),2.38(s,2H),2.23(s,2H),1.95–1.88(m,2H).

[1053] Example 47

[1054] Using compound 19C and 5-chloro-2-iodopyrimidine as starting materials and referring to Examples 20 and 36, compound 46-1 (42 mg, 91%) and compound 46-2 (41 mg, 94%) were obtained.

[1055] LCMS (ESI): m / z = 515.2 [M+H] +

[1056] 1H NMR (400MHz, CDCl3)δ=8.62(s,2H),6.86(s,1H),5.56(s,1H),4.76(s,2H),4.52–4.45(m,2H),4.12–3.73(m,3H),3.68(s,1H),3.62-3.54(m,1H) ),3.45–3.23(m,2H),3.22–3.11(m,1H),3.10–2.89(m,3H),2.84(d,1H) ,2.46–2.30(m,2H),2.31–2.16(m,2H),2.06–1.80(m,2H),1.67(s,2H).

[1057] LCMS (ESI): m / z = 515.2 [M+H] +

[1058] 1 H NMR(400MHz, CDCl3)δ=8.62(s,2H),6.86(s,1H),5.58(s,1H),4.72(s,2H),4.56-4.47(m,2H),4.13–3.53(m,5H),3.45-3.36(m ,1H),3.32–3.13(m,2H),3.10-2.97(m,3H),2.86-2.82(m,1H),2.42-2.35(m,2H),2.24(s,2H),1.98-1.86(m,2H),1.62(s,2H).

[1059] Example 48

[1060] Step 1: Compound 20B (1.0 g, 3.0 mmol), cyclopropylboronic acid (356.0 mg, 4.0 mmol), palladium acetate (25.0 mg, 0.15 mmol), tricyclohexylphosphine (84.2 mg, 0.3 mmol), potassium phosphate (2.3 g, 10.5 mmol), and finally toluene (14 mL) and water (0.7 mL) were added. The mixture was purged with nitrogen three times and heated to 100°C for 3 h. The mixture was passed through a short silica gel column, washed with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 47A (820.0 mg, 91%).

[1061] LC-MS (ESI): m / z = 302.1 [M+H] +

[1062] Step 2: Compound 47A (820.0 mg, 2.7 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5.0 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 47B (1.0 g, 99%), which was used directly in the next step.

[1063] LC-MS (ESI): m / z = 202.1 [M+H] +

[1064] Step 3: Compound 47B (400.0 mg, 2.0 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 35H (540.0 mg, 2.0 mmol) and diisopropylethylamine (1.0 g, 8.0 mmol) were added. The mixture was heated to 90°C for 12 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 47C (180.0 mg, 20%).

[1065] LC-MS (ESI): m / z = 453.1 [M+H] +

[1066] Step 4: Compound 47C (0.13 g, 0.28 mmol) was dissolved in dichloromethane (5 mL). Trichloroacetyl isocyanate (64.0 mg, 0.34 mmol) was added under ice-cooling. The reaction was continued for 1 h and concentrated to obtain 47D (0.18 g, 99%), which was used directly in the next step.

[1067] Step 5: Compound 47D (0.18 g, 0.28 mmol) was dissolved in methanol (2 mL), and water (2 mL) and potassium carbonate (0.1 g, 0.8 mmol) were added. The mixture was reacted at room temperature for 2.5 hours, concentrated, extracted with dichloromethane, dried, and concentrated to obtain compound 47 (0.07 g, 51%).

[1068] LC-MS (ESI): m / z = 496.2 [M+1] +

[1069] 1 H NMR(400MHz,DMSO-d6)δ8.54(s,2H),7.62(s,1H),7.18(s,1H),6.49(s,2H),4.43–4.40(m,3H),3.97(s,2H),3.54–3.39(m,1H), 3.25–3.17(m,1H),2.99–2.85(m,2H),2.65(s,2H),2.46–2.11(m,4H),2.00–1.70(m,4H),1.08–0.97(m,2H),0.89–0.78(m,2H).

[1070] Example 49

[1071] Step 1: 35H (0.20 g, 0.69 mmol) was added to a 50 mL single-necked bottle and dissolved in dioxane (10 mL). 9D (0.21 g, 0.92 mmol) and diisopropylethylamine (0.26 g, 2.05 mmol) were added and reacted at 90°C overnight. The reaction solution was concentrated, purified by HPLC, and freeze-dried to obtain the title compound 48D (130 mg, 42%).

[1072] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content from 30% to 70%; c. Flow rate: 15 mL / min; d. Elution time: 15 min; Retention time: 8.0 min.

[1073] 1 H NMR (400MHz, DMSO-d6) δ8.89(s,2H),7.34(s,1H),7.31–7.26(m,1H),4.83(t,1H),4.46(s,2H),3.97(t,2H),3.75(d,2H),3. 45-3.41(m,1H),3.24-3.21(m,1H),2.98-2.83(m,2H),2.65(s,2H),2.43–2.28(m,2H),2.25–2.14(m,2H),1.90–1.73(m,2H).

[1074] LC-MS (ESI): m / z = 447.1 [M+H] + .

[1075] Step 2: 48D (60 mg, 0.13 mmol) was added to a 50 mL single-necked flask and dissolved in anhydrous dichloromethane (15 mL). Trichloroacetyl isocyanate (30 mg, 0.16 mmol) was added dropwise under ice bath conditions. The mixture was stirred in an ice bath for 4 h. The reaction was monitored by TLC (DCM:MeOH = 10:1) to ensure completion of the reaction. The reaction solution was concentrated to obtain the title compound 48E (85 mg, crude product), which was used directly in the next step.

[1076] Step 3: In a 50 mL single-necked flask, 48E (85 mg, 0.13 mmol) was added and dissolved in methanol (6 mL). Potassium carbonate (54 mg, 0.39 mmol) was added and stirred at room temperature for 6 h. The reaction mixture was concentrated and separated by SFC to obtain the target compound 48 (30 mg, 47%).

[1077] Preparation method: Instrument: SFC Prep 150; Chromatographic column: Torus AP (19 mm × 250 mm); Sample was dissolved in MeOH and filtered through a 0.45 μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO2, Mobile phase B: MeOH; b. Isocratic elution, Mobile phase B content: 20%; c. Flow rate: 40 mL / min; d. Elution time: 20 min; Retention time: 8.5 min.

[1078] LCMS m / z=490.2[M+1] +

[1079] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,2H),7.64(s,1H),7.29(s,1H),6.50(s,2H),4.57–4.32(m,4H),3.98(t,2H), 3.51–3.38(m,1H),3.26–3.15(m,1H),3.03–2.81(m,2H),2.65(s,2H),2.41-2.23(m,4H),1.90–1.74(m,2H).

[1080] Example 50

[1081] Step 1: Under nitrogen, 49A (1.00 g, 8.39 mmol) was dissolved in tetrahydrofuran (30 mL). After the solution cooled to -78°C, n-butyllithium (810 mg, 12.59 mmol) was slowly added. After the addition was complete, the reaction mixture was warmed to -40°C and stirred for 1 hour. The temperature was then lowered to -78°C, and a solution of iodine (2.56 g, 10.07 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was then allowed to return to room temperature and stirred for 1 hour. The reaction was quenched with water (100 mL) and extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 49B (700 mg, yield: 34.03%).

[1082] 1H NMR (400MHz, DMSO-d6) δ7.76–7.73(m,2H),7.38–7.36(m,2H).

[1083] Using compounds 49B and 9B as starting materials and referring to Examples 10 and 36, compound 49 (15 mg, 46.21%) was obtained.

[1084] LCMS m / z=495.10[M+H] +

[1085] 1 H NMR(400MHz,DMSO-d6)δ7.73–7.69(m,2H),7.67(s,1H),7.41–7.34(m,2H),7.10(s,1H),6.49(s,2H),4.51(s,2H),4.44–4.38(m,2H),4.03– 4.00(m,2H),3.49–3.41(m,1H),3.26–3.19(m,1H),3.01–2.94(m,1H), 2.91–2.86(m,1H),2.69(s,2H),2.44–2.25(m,4H),1.88–1.82(m,2H).

[1086] Example 51

[1087] Using compounds 50A and 9B as starting materials and following the procedure described in Example 50, compound 50 (20 mg, 26%) was obtained.

[1088] LC-MS (ESI): m / z = 459.2 [M+H] +

[1089] 1 H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.63(s,1H),6.76–6.63(m,1H),6.48(s,2H),4.42–4.34(m,4H),3.94(t,2H),3.4 9–3.38(m,1H),3.26–3.16(m,1H),3.03–2.82(m,2H),2.54(s,2H),2.45–2.18(m,4H),2.09(d,3H),1.91–1.77(m,2H).

[1090] Example 52

[1091] Step 1: Dissolve compound 32-1 (100 mg, 0.23 mmol) in dichloromethane (5 mL), add trichloroacetyl isocyanate (52 mg, 0.28 mmol) under ice-cooling, and stir under ice-cooling for one hour. The reaction solution is concentrated to obtain compound 51A (110 mg, 70%).

[1092] Step 2: Compound 51A (110 mg, 0.18 mmol) was dissolved in methanol (5 mL). Potassium carbonate (73 mg, 0.53 mmol) and water (5 mL) were added under ice-cooling and stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford compound 51 (40 mg, 46%).

[1093] LC-MS (ESI): m / z = 478.1 [M+H] +

[1094] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,2H),7.29(s,1H),6.70–6.40(m,3H),4.50(s,2H),4.30(s,2H),4 .01(t,2H),3.49–3.37(m,1H),3.30–3.23(m,1H),3.02–2.92(m,1H),2.91–2.82(m,1H),2.67(s, 2H),1.46(d,6H).

[1095] Example 53

[1096] Step 1: Dissolve compound 30 (100 mg, 0.22 mmol) in dichloromethane (5 mL), add trichloroacetyl isocyanate (52 mg, 0.28 mmol) under ice-cooling, and stir under ice-cooling for one hour. The reaction mixture is concentrated to obtain compound 52A (110 mg, 77%).

[1097] Step 2: Compound 52A (110 mg, 0.18 mmol) was dissolved in methanol (5 mL). Potassium carbonate (73 mg, 0.53 mmol) and water (5 mL) were added under ice-cooling and stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford compound 52 (40 mg, 44%).

[1098] LC-MS (ESI): m / z = 504.1 [M+H] +

[1099] 1 H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.34–7.20(m,1H),6.84(s,1H),6.47(s,2H),4.49(d,2H),4.46–4.31(m,2H),4.00(t,2H), 3.48–3.38(m,1H),3.29–3.20(m,1H),3.02–2.84(m,2H),2.66(s,2H),2.25–2.10(m,2H),1.95–1.79(m,2H),1.70–1.56(m,4H).

[1100] Example 54

[1101] Step 1: Compound 3H (500 mg, 1.66 mmol), dichloromethane (10 mL), m-chloroperbenzoic acid (342 mg, 1.99 mmol), and N,N-dimethylformamide (100 mL) were added sequentially to a 50 mL single-necked flask. After reacting at room temperature for 2 hours, dichloromethane (20 mL) was added and the mixture was washed with water (30 mL x 2) and saturated sodium bicarbonate solution (30 mL x 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 54B (480 mg, 91.2% yield).

[1102] LC-MS (ESI): m / z = 318.1 [M+H] + .

[1103] Step 2: To a 50 mL single-necked flask were added 54A (240 mg, 0.75 mmol), 9D (173 mg, 0.75 mmol), dioxane (10 mL), and DIPEA (484 mg, 3.75 mmol) in sequence. The mixture was reacted at 100°C for 12 hours. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to afford the title compound 54 (42 mg, 11.7% yield).

[1104] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,2H),7.28(s,1H),6.73(s,1H),5.01–4.90(m,1H),4.44(s,2H),4.02–3.86(m,2H),3.77– 3.66(m,2H),3.47–3.38(m,2H),2.77–2.69(m,2H),2.64(s,2H),2.41–2.29(m,2H),2.26–2.11(m,4H),1.94–1.72(m,2H).

[1105] LC-MS (ESI): m / z = 477.1 [M+H] + .

[1106] Example 55

[1107] Step 1: Under nitrogen, compound 55A (100 mg, 0.22 mmol, synthesis reference: WO2014124860A1) was dissolved in dichloromethane (10 mL). Trichloroacetyl isocyanate (50 mg, 0.27 mmol) was slowly added dropwise with stirring in an ice bath. After addition, the reaction mixture was stirred at 0°C for 1 h. A spot microplate reader (developing solvent: DCM / MeOH = 10:1) revealed the disappearance of the starting material. The reaction mixture was then concentrated under reduced pressure to afford crude product 55B (160 mg), which was used directly in the next step.

[1108] Step 2: Crude compound 55B (140 mg, 0.22 mmol) was dissolved in methanol (6 mL), followed by the addition of potassium carbonate (90 mg, 0.66 mmol) at room temperature. The mixture was stirred under nitrogen for 1.5 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1) and further purified by reverse-phase column chromatography (eluent: water:acetonitrile = 100:1 to 1:9) to afford the target compound 55 (95 mg, 87.91%).

[1109] LCMS m / z=492.10[M+H] +

[1110] 1 H NMR(400MHz, DMSO-d6)δ8.86(s,2H),7.59(s,1H),6.48(s,2H),4.72–4.69(m,2H),4.38–4.32(m,2H),3.46–3.40(m,1H),3.25–3.16(m,2 H),3.10–3.04(m,2H),2.97–2.85(m,2H),2.40–2.27(m,2H),2.22–2.19(m,2H),1.98–1.95(m,2H),1.89–1.80(m,2H),1.68–1.60(m,2H).

[1111] Example 56

[1112] Using compounds 56A and 9B as starting materials and following the procedure described in Example 50, compound 56 (5.2 mg, 6%) was obtained.

[1113] LCMS (ESI): m / z = 511.0 [M+H] +

[1114] 1 H NMR(400MHz,DMSO-d6)δ8.10–8.03(m,1H),7.99–7.92(m,1H),7.65(s,1H),7.53–7.38(m,2H),6.90(s,1H),6.49(s,2H),4.48–4.40(m,4H),4.1 0–3.98(m,2H),3.45-3.40(m,1H),3.28–3.18(m,1H),3.03–2.93(m,1H) ,2.91–2.85(m,1H),2.76(s,2H),2.39–2.29(m,4H),1.88-1.82(m,2H).

[1115] Example 57

[1116] Compounds 26E and 35H were used as starting materials and the reaction mixture was subjected to the procedure described in Example 49 to obtain compound 57 (20 mg, 43%).

[1117] LCMS m / z=483.20[M+H] +

[1118] H NMR(400MHZ,DMSO-d6)δ8.50(s,2H),7.66(s,1H),6.49(s,2H),4.32–4.40(m,2H),4.28(s,1H),3.83( s,8H),3.40–3.48(m,1H),3.18–3.26(m,1H),2.84–2.99(m,2H),2.21–2.41(m,4H),1.76–1.88(m,2H).

[1119] Example 58

[1120] Compounds 13D and 35H were used as starting materials and the reaction mixture was subjected to the procedure described in Example 49 to obtain compound 58 (20 mg, 17%).

[1121] LCMS m / z=509.20[M+H] +

[1122] H NMR(400MHZ,DMSO-d6)δ7.50(s,1H),6.85(d,1H),6.47(s,2H),6.34–6.36(m,2H),4.38(s,2H),3.74–3.82(m,2H), 3.40–3.42(m,4H),3.01–3.21(m,9H),2.83–2.95(m,2H),2.27–2.47(m,2H),2.16–2.23(m,2H),1.76–1.84(m,3H).

[1123] Example 59

[1124] Using compound 24A and pyrazole as starting materials and referring to Example 41, compound 59-1 (30 mg) and compound 59-2 (50 mg) were obtained.

[1125] Chiral separation 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); Gradient: 45% phase B isocratic elution; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 9.3 min.

[1126] LCMS m / z=433.2[M+1] +

[1127] Compound 59-1, retention time 2.01 min, 1 H NMR(400MHZ,DMSO-d6)δ8.75(s,1H),8.02(s,1H),6.85(d,1H),6.68(d,1H),6.36–6.38(m,2H), 3.86–4.01(m,2H),3.55–3.71(m,3H),3.40–3.50(m,2H),3.11–3.26(m,6H),2.97–3.05(m,5H).

[1128] Compound 59-2, retention time 2.48 min, 1H NMR(400MHZ,DMSO-d6)δ8.76(s,1H),8.02(s,1H),6.85(d,1H),6.67(d,1H),6.36–6.38(m,2H), 3.86–4.01(m,2H),3.55–3.71(m,3H),3.41–3.49(m,2H),3.11–3.24(m,6H),2.97–3.05(m,5H).

[1129] Example 60

[1130] Step 1: Dissolve 60A (5.00 g, 20.07 mmol) in ethanol (100 mL) at room temperature. Add iron powder (6.72 g, 120.41 mmol) in portions, followed by the slow dropwise addition of concentrated hydrochloric acid (2.12 g, 20.37 mmol). After the addition is complete, stir the reaction mixture under nitrogen for 4 hours at room temperature. After TLC monitoring, quench the reaction with aqueous ammonia. Filter the filtrate, dilute with water (100 mL), and extract three times with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 4:1) to obtain the target compound 60B (3.00 g, yield: 68.21%).

[1131] LC-MS (ESI): m / z = 220.20 [M+H] +

[1132] 1 H NMR (400MHz, CDCl3) δ7.22–7.18(m,1H),7.12–7.09(m,1H),7.04–7.03(m,1H),6.78–6.75(m,1H),3.86(br s,2H).

[1133] Using compounds 60B and 24A as starting materials and referring to Example 37, compound 60-1 (100 mg) and compound 60-2 (160 mg) were obtained.

[1134] Analytical methods: 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.

[1135] Preparation: Instrument: SHIMADZU LC-20AP, Column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm). Mobile Phase: A: n-hexane, B: ethanol (0.1% NH₃·H₂O); Gradient: 8% B; Flow Rate: 110 mL / min; Column Temperature: 25°C; Wavelength: 254 nm; Cycle Time: 16 min. Sample Preparation: Sample Concentration: 1.5 mg / mL; 2 mL of ethanol solution injected per sample. After separation, the fractions were dried on a rotary evaporator at 40°C to yield Compound 60-1 (retention time: 5.716 minutes) and Compound 60-2 (retention time: 6.890 minutes).

[1136] Compound 60-1:

[1137] LCMS m / z=565.5[M+H] +

[1138] 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.90(s,2H),8.60(s,1H),7.98–7.90(m,1H),7.63–7.60(m,2H),7.31–7.24(m,1H),4.54– 4.42(m,2H),4.08–3.96(m,2H),3.62–3.54(m,1H),3.36–3.28(m,1H),3.15–3.09(m,1H),3.04–2.99(m,1H),2.74–2.65(m,2H).

[1139] Compound 60-2:

[1140] LCMS m / z=565.5[M+H] +

[1141] 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.90(s,2H),8.60(s,1H),7.98–7.90(m,1H),7.63–7.59(m,2H),7.31–7.24(m,1H),4.55– 4.41(m,2H),4.08–3.96(m,2H),3.62–3.54(m,1H),3.36–3.28(m,1H),3.15–3.09(m,1H),3.04–2.99(m,1H),2.75–2.66(m,2H).

[1142] Example 61

[1143] Step 1: In a 100 mL single-necked flask, 35H (1.0 g, 3.47 mmol) was added and dissolved in dichloromethane (20 mL). m-Chloroperbenzoic acid (1.2 g, 6.94 mmol) was added and stirred at room temperature overnight. The reaction mixture was washed with aqueous sodium hydroxide (5%, 20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 61A (1.0 g, 95%).

[1144] LC-MS (ESI): m / z = 304.1 [M+H] + .

[1145] Step 2: In a 50 mL single-necked flask, 61A (0.2 g, 0.66 mmol) was added and dissolved in dioxane (10 mL). 9D (0.18 g, 0.79 mmol) and N,N-diisopropylethylamine (0.26 g, 1.98 mmol) were then added sequentially and stirred at 95°C overnight. The reaction mixture was concentrated, slurried with methanol (10 mL) for 0.5 h, filtered, and dried to obtain the title compound 61 (0.25 g, 82%).

[1146] LC-MS (ESI): m / z = 463.1 [M+H] + .

[1147] 1 H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.30–7.28(m,1H),6.12(s,1H),5.02(t,1H),4.49(s,2H),4.00(t,2H),3.71( d,2H),3.49–3.46(m,2H),3.10–3.06(m,2H),2.67(s,2H),2.53–2.51(m,2H),2.20–2.06(m,2H),1.89–1.74(m,2H).

[1148] Example 62

[1149] Step 1: Compound 35F (860.0 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (346.0 mg, 2.0 mmol) was added. After reacting at room temperature for 4 h, a small amount of sodium bicarbonate was added to quench the reaction. The mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 62 (120.0 mg, 12%).

[1150] LC-MS (ESI): m / z = 453.1 [M+H] +

[1151] 1H NMR(400MHz,DMSO-d6)δ8.91(s,2H),7.34(s,1H),6.12(s,1H),5.02(s,1H),4.70(s,1H),4.51(s,2H),4.0 0(d,2H),3.71(d,2H),3.48(t,2H),3.08(t,2H),2.68(s,2H),2.53(s,2H),2.14(t,2H),1.97–1.68(m,2H).

[1152] Example 63

[1153] Step 1: Compound 63A (2.0 g, 10.0 mmol) was dissolved in dichloromethane (5 mL) and water (5 mL), followed by the addition of potassium bifluoride (1.6 g, 20.0 mmol) and finally difluorobromomethyltrimethylsilane (2.0 g, 10.0 mmol). The mixture was reacted at room temperature overnight, extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 63B (2.0 g, 81%).

[1154] LC-MS (ESI): m / z = 252.1 [M+H] +

[1155] Step 2: Compound 63B (0.8 g, 3.1 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5.0 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 63C (1.0 g, 99%), which was used directly in the next step.

[1156] LC-MS (ESI): m / z = 152.1 [M+H] +

[1157] Using compounds 63C and 24A as starting materials and following the procedure described in Example 34, compound 63 (35.0 mg, 28%) was obtained.

[1158] LC-MS (ESI): m / z = 487.2 [M+1] +

[1159] 1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.82(s,1H),7.34(s,1H),6.70(t,1H),4.69(s,1H),4.46(s,2H),4.27(q,2H),3. 96(s,2H),3.54–3.36(m,1H),3.24–3.17(m,1H),3.00-2.85(m,2H),2.66(s,2H),2.45–2.18(m,4H),1.90–1.84(m,2H).

[1160] 19 F NMR(377MHz,DMSO-d6)δ-80.12(s).

[1161] Example 64

[1162] Step 1: Dissolve compound 64A (5.0 g, 24.8 mmol) in tetrahydrofuran (50 ml) and add sodium hydride (1.1 g, 27.5 mmol). Stir at room temperature for 1 hour, then add iodomethane (3.9 g, 27.5 mmol) and react for 12 hours. Pass the mixtu...

Claims

1. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, When Cy is selected from Cy1, Cy2, Cy3, Cy8 and Cy10, L is -(L1)n-(L2)m-; When Cy is selected from Cy4, Cy5 and Cy6, L is -L3-; When Cy is selected from Cy7 and Cy9, L is -L4-; L1 is -NR4-, -CR5=N-, -CR5=CR5-, or -CR5R5-; L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 , 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spiro heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkylene, alkenylene, alkynylene, monoheterocycloalkyl, heterocyclic heterocycloalkyl, bridged heterocycloalkyl and spiro heterocycloalkyl optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl; L3 is heterocycloalkylene or heterocycloalkylene-(CH2) r -, wherein the heterocycloalkylene group is a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 R L3 replace; Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O; L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independently CR X1 , O, S or N; X3, X4, and X5 are independently C or N; Ring B is a heteroaryl group or a heterocycloalkyl-heteroaryl group, wherein the heteroaryl group is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl group is a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O; Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R1 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide; R3 is H, halogen, C 1-4 Alkyl, CN, OH or not present, or R3 and R2, R3 and R6, R3 and R4, or R3 and R5 and the atoms to which they are connected together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, R x4 With R5 or R x4 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl; R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl; R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy; R x5 C 1-4 Alkyl, CN, OH or absent; R7 is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl or 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R 9’ With R7, or R 9’ With R x5 At least one group and its connected atoms together form C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution; R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ; R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, -N=S(=O)(C 1-4 Alkyl)2 or -N(C 3-6 Cycloalkyl)C(O)NH(C 1-4 Alkyl), the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution; R9 is H, C 1-4 Alkyl or C 1-4 alkyl halide; Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ; R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution; R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, C 1-4 Alkyl -CN, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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 alkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution; Ra and Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O; Alternatively, Ra, Rb and their atoms together form C 3-6 Cycloalkyl; R 13 Selected from 7-11 membered spiro ring, 4-10 membered cyclic ring, 5-8 membered heterocyclic bridge ring, 4-6 membered monocyclic heterocycloalkyl containing S(O)2 group, 4 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7 membered monocyclic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O Alkyl, the spiro ring, the cyclic ring, the heterocyclic bridge ring, the monocyclic heterocyclic alkyl group is optionally substituted by 1-3 halogen, CN, =O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution; R 14 Selected from -(CH2) t -OC(O)NH2, -(CH2) t -OC(O)NHCH3, 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, CN, =O, OH, C 1-4 Alkyl and C 1-4 haloalkyl radical substitution; 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; The condition is, Cy1 is not 2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, in, Ring B is pyrazolyl, imidazolyl, pyrrolyl, tetrahydropyrrolopyrrolyl, tetrahydropyrroloimidazolyl or thienopyrrolyl; R1 is C 1-4 Alkyl or C 1-4 haloalkyl, or R1 and R2 and the atoms to which they are attached together form a 5-7 membered monoheterocycloalkyl, a 6-8 membered cyclic heterocycloalkyl, a 7-9 membered spirocyclic heterocycloalkyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, and O, wherein the monoheterocycloalkyl, cyclic heterocycloalkyl, spirocyclic heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide; R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent; Or R3 and R2 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Or R3 and R6 together with the atoms to which they are attached form C 5-7 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present, or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the heteroaryl is optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R7 is C 1-4 Alkyl or C 1-4 Haloalkyl, or R7 and R9 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the heterocycloalkyl being optionally substituted by 1-3 heteroatoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R 9’ With R7, or R 9’ With R x5 At least one group and the atoms connected thereto together form a 5-7 membered monoheterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the monoheterocycloalkyl, spirocyclic heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution; r is 1 or 2.

3. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt, in, Each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl; L3 is selected from Each R L3 are independently selected from halogen, ═O, CN, C 1-4 Alkyl or C 1-4 Alkoxy, or R L3 With R X1 and its connected atoms together C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O; L4 is selected from A is -S(O)-, -C(O)-, -B(OH)-, -S-, or -S(=N)-CN; Cy5 is selected from Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-4 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R1 is C 1-4 Alkyl or C 1-4 alkyl halide; Or R1 and R2 and the atoms to which they are attached together form a ring selected from: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R3 is H, halogen, C 1-4 Alkyl, CN, OH or absent; Or R3 together with R2 and the atoms to which they are attached form a ring selected from the following: and optionally 1-3 selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Or R3 and R4, or R3 and R5 and the atoms to which they are attached together form a 5-6 membered heterocycloalkyl, a 5-6 membered heteroaryl or a phenyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Or R3 and R6 together with the atoms to which they are attached form C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R x4 H, halogen, C 1-4 Alkyl, CN, OH or not present; or R x4 With R4, or R x4 Together with R5 and the atoms to which it is attached, it forms imidazolyl, pyrazolyl, pyrrolyl, thienyl or thiazolyl, and is optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R4 is H, C 1-4 Alkyl or C 1-4 alkyl halide; R5 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -NHC 1-4 alkyl; R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy; R7 is C 1-4 Alkyl or C 1-4 haloalkyl, or R7 and R9 together with the atoms to which they are attached form a ring selected from: The ring is optionally substituted by 1-3 atoms selected from halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; or R 9’ Together with R7 and the atoms to which it is attached, it forms a ring selected from: and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution; or R 9’ With R x5 and its connected atoms together to form and optionally 1-3 selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN or R 8’ The group substitution; The condition is R 9’ With R7, or R 9’ With R x5 At least one of them is a ring; R8 is R 8’ 、-OR 8’ or -(CH2) r R 8’ ; R 8’ C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, -N=S(=O)(C 1-4 Alkyl)2 or -N(C 3-6 Cycloalkyl)C(O)NH(C 1-4 Alkyl), the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, mercapto C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, =O, OH, NH2, CN group substitution; R9 is H or C 1-4 alkyl; Each R 10 Independently R 8’ 、-OR 8’ 、-NHR 8’ or -(CH2) r R 8’ ; R 11 C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogen, CN, ═O, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 haloalkyl radical substitution; R 12 Selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropyl, adamantane, tetrahydropyranyl, piperidinyl, oxalyl, oxalyl, 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; the ring is optionally substituted by 1-3 atoms selected from halogen, CN, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH 3、 -(CH2) t -OC 1-2 Haloalkyl 、 -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution; R 13 Selected from The ring is optionally substituted by 1-3 groups selected from halogen, CN, OH, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 haloalkyl radical substitution; 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.

4. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt, Cy1 is selected from Cy2 is selected from Cy4 is selected from Cy5 is selected from Cy7 is selected from Cy9 is selected from 5. The compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt, -(L1)n-(L2)m- is selected from: R6 is H; -L3-Selected from: -L4-Selected from: Select any 1-3 R R One of the following structures: R R Each independently selected from F, Cl, Br, methyl, isopropyl, ethoxy, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, dimethylamino, R X1 is H; or R X1 Together with R6 and the atom to which it is attached, it forms a morpholinyl, furyl, pyrrolyl or thienyl group.

6. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, in, L4 is 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, 5-membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the monoheterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, spirocyclic heterocycloalkyl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are independently CR X1 , S or N; R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl; R6 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy; Each R X1 , R are independently H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkynyl, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 a halogenated alkyl group or a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R, and R on adjacent ring atoms; X1 , or R X1 Together with R6 and the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, phenyl, or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O The cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R1 and R2 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, B, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; R 12 is selected from 4-10 membered heterocycloalkylene, 3-10 membered cycloalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, hydroxy-C 1-6 Alkyl, C 1-4 Alkyl -CN, -CRaRb=NOC 1-4 Alkyl, -C(NRaRb)=N-CN, -C(C 1-4 alkyl)=N-CN, -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 alkyl), -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)-(4-6 membered heterocycloalkyl), wherein the heterocycloalkylene, cycloalkylene, arylene, heteroarylene groups are optionally further substituted by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, -(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, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb, -(CH2) t -C(O)NRaRb, -(CH2) t -NRa-C(O)CH3 group substitution; Ra and Rb are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O; p is selected from 0 or 1.

7. The compound according to claim 6, its stereoisomer or pharmaceutically acceptable salt, in, L4 is R 12 Selected from -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.

8. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein The compound is selected from one of the structures in Table 1.

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

10. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

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

12. Use of the compound according to any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts in the preparation of a medicament for treating / preventing a PDE4B-mediated disease.

13. A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 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.

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