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, Huntington's disease, and others.

[0003] In addition, significant progress has been made in the research and development of PDE4 inhibitors. In the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease, 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 shown 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.

[0004] 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.

[0005] 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.

[0006] A selective PDE4B inhibitor with good activity, high safety, few side effects and better pharmacokinetic properties has been discovered. It has good clinical development prospects and can be used to treat COPD, cancer or other proliferative diseases or conditions.

[0007] Summary of the Invention

[0008] 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):

[0009] Wherein, Cy is selected from Cy1, Cy2, 5-membered monocyclic heteroaryl or 8-10-membered bicyclic heteroaryl, and the monocyclic heteroaryl and bicyclic heteroaryl are optionally further substituted by 1-3 R; in some embodiments, Cy is selected from Cy1 or Cy2; in some embodiments, Cy is selected from Cy1; in some embodiments, Cy is selected from 5-membered monocyclic heteroaryl, 5-membered heteroaryl and benzo ring, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl , 5-membered heteroaryl and 6-membered cycloalkyl, 5-membered heteroaryl and 4-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heterocycloalkyl, 6-membered heteroaryl and benzocyclic ring, 6-membered heteroaryl and 5-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 6-membered heteroaryl and 6-membered cycloalkyl, 6-membered heteroaryl and 4-membered heterocycloalkyl, 6-membered heteroaryl and 5-membered heterocycloalkyl, 6-membered heteroaryl and 6-membered heterocycloalkyl; in some embodiments, Cy is selected from the following structures:

[0010] In some embodiments, Cy is selected from the following structures:

[0011] Cy2 is optionally substituted with 1-3 R; in some embodiments, Cy2 is unsubstituted;

[0012] L is -(L1)n-(L2)m-;

[0013] In all embodiments of the present invention, the connection site between L and Cy is arbitrary; in some embodiments, the L2 end is the connection site with Cy; in some embodiments, the L1 end is the connection site with Cy;

[0014] L1 is -NR1-, -CR2=N-, -CR2=CR2- or -CR2R2-;

[0015] In all embodiments of the present invention, the connection site of L1 is arbitrary, for example, as -CR2=N- connected to L2, its N atom and C atom can serve as the connection site with L2;

[0016] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 、C 3-5 cycloalkyl, 6-9 membered aryl, 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, cycloalkyl, aryl, heteroaryl, 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, L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 、C 3-5cycloalkyl, 6-9 membered aryl, 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, cycloalkyl, aryl, heteroaryl, 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; 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, 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, In some embodiments, each L2 can also be independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0017] 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,

[0018] In all embodiments of the present invention, the connection sites of L2 and the left and right groups are arbitrary, for example, L2 as a terminal Both N atoms and C atoms can serve as sites for attachment to Cy;

[0019] R L2 H, C 1-4Alkyl 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;

[0020] L is selected from one of the following structures:

[0021] In some embodiments, L is selected from In some embodiments, L is selected from

[0022] In some embodiments, L is selected from In some embodiments, L is selected from

[0023] In some embodiments, Selected from the following structures:

[0024] Or selected from

[0025] X1 and X2 are independently CR X1 or N; in some embodiments, X1, X2 are CR X1 ; In some embodiments, X1 and X2 are N;

[0026] Each R X1 are independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -SO2NH2, or R X1 With R1, R X1 With R2, or R X1 Together with R3 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, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 are independently H, halogen, C 1-4 Alkyl or C1-4 Haloalkyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-7 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 are independently H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-7 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkoxy, OH and NH2; in some embodiments, each R X1 are independently H, F, Cl, Br, I, methyl, ethyl, propyl, or halomethyl, haloethyl, halopropyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms a C5 cycloalkyl, a C6 cycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, or a pyrrolyl, imidazolyl, furyl, pyranyl, morpholinyl, etc., and is 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 are independently H, F, Cl, methyl, ethyl, or R X1 Together with R3 and the atoms to which it is attached, it forms a C5 cycloalkyl group, a C6 cycloalkyl group, a 5-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a 6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0027] Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHCONH2, -NHCOC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; or two adjacent R, R and R X1 and its connected atoms together form C 3-8 Cycloalkyl, 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, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 In certain embodiments, each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHCONH2, -NHCOC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; or two adjacent R, R and R X1 and its connected atoms together form C 3-8Cycloalkyl, 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, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 In certain embodiments, each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(C 1-2 Alkyl)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; or two adjacent R, R and R X1 and its connected atoms together form 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 In certain embodiments, each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(CH3)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; or two adjacent R, R and R X1 and its connected atoms together form C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C1-4 In certain embodiments, each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SO2NH2, -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 Halogenated alkyl, or two adjacent R, R and R X1 and its connected atoms together form C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups or -C(O)C 1-4 In some embodiments, each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SO2NH2, -NHSO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Halogenated alkyl, or two adjacent R, R and R X1 and its connected atoms together form 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 substituted with alkoxy, OH, and NH2; in some embodiments, each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, -SO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Halogenated alkyl, or two adjacent R, R and R X1 and its connected atoms together form C 3-6Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 In some embodiments, each R is independently H, F, Cl, Br, I, methyl, ethyl, propyl, methynyl, ethynyl, propynyl, -SO2NH2, -NHSO2C 1-4 Alkyl (such as methyl, ethyl, propyl), -SO2NHC 1-4 Alkyl (such as methyl, ethyl, propyl), SO2C 1-4 Alkyl (such as methyl, ethyl, propyl), SCF3, SF5 or C 1-4 Halogenated alkyl (such as methyl, ethyl, propyl), or two adjacent R, R and R X1 and the atoms to which they are attached together form cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, etc., and are optionally substituted by 1-3 atoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups or -C(O)C 1-4 Alkyl substitution;

[0028] R1 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 In some embodiments, R1 is H, C 1-4 Alkyl or C 1-4 Haloalkyl; in some embodiments, R1 is H, methyl, ethyl, propyl, isopropyl, or halogenated methyl, ethyl, propyl, isopropyl, and halogen includes F, Cl, Br, I;

[0029] R2 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, R2 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 In some embodiments, R2 is H, C 1-4 Alkyl or C 1-4 Haloalkyl; in some embodiments, R2 is H, methyl, ethyl or propyl;

[0030] R3 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 Alkoxy; in some embodiments, R3 is H, F, Cl, ═O, CN, C 1-3 Alkyl or C1-3 Alkoxy; in some embodiments, R3 is H, halogen, =O, CN or C 1-4 Alkyl; In some embodiments, R3 is H, halogen, =O, CN, methyl, ethyl, or propyl; In some embodiments, R3 is H, F, Cl, =O, CN, C 1-3 alkyl;

[0031] n is 0, 1, 2, 3, or 4; in some embodiments, n is 0, 1, 2, or 3; in some embodiments, n is 0, 1, or 2;

[0032] m is 0, 1, 2, or 3; in some embodiments, m is 0, 1, or 2; in some embodiments, n is 0 or 1;

[0033] The condition is,

[0034] The compound is not

[0035] The present invention provides a specific solution 1, a compound shown in Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

[0036] wherein Cy is selected from Cy1, Cy2, a 5-membered monocyclic heteroaryl or an 8-10-membered bicyclic heteroaryl, wherein the monocyclic heteroaryl or bicyclic heteroaryl is optionally further substituted with 1-3 R; further, Cy is selected from Cy1 or Cy2;

[0037] Cy2 is optionally substituted with 1-3 R;

[0038] L is -(L1)n-(L2)m-;

[0039] L1 is -NR1-, -CR2=N-, -CR2=CR2- or -CR2R2-;

[0040] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 、C 3-5cycloalkyl, 6-9 membered aryl, 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, cycloalkyl, aryl, heteroaryl, 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;

[0041] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0042] X1 and X2 are independently CR X1 or N;

[0043] Each R X1 are independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -SO2NH2, or R X1 With R1, R X1 With R2, or R X1 Together with R3 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, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0044] Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHCONH2, -NHCOC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHSO2C 1-4Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; or two adjacent R, R and R X1 and its connected atoms together form C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups or -C(O)C 1-4 Alkyl substituted; or, each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SO2NH2, -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 Halogenated alkyl, or two adjacent R, R and R X1 and its connected atoms together form C 3-8 Cycloalkyl, 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, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups or -C(O)C 1-4 Alkyl substitution;

[0045] R1 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0046] R2 is H, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0047] R3 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0048] n is 0, 1, 2, 3 or 4;

[0049] m is 0, 1, 2, or 3;

[0050] The condition is,

[0051] The compound is not

[0052] Furthermore, the compound represented by formula I, its stereoisomers or pharmaceutically acceptable salts,

[0053] wherein Cy is selected from Cy1 or Cy2;

[0054] Cy2 is optionally substituted with 1-3 R;

[0055] L is -(L1)n-(L2)m-;

[0056] L1 is -NR1-, -CR2=N-, -CR2=CR2- or -CR2R2-;

[0057] L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 、C 3-5 cycloalkyl, 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, cycloalkyl, heteroaryl, 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 、C 3-5 cycloalkyl, 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, cycloalkyl, heteroaryl, 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;

[0058] R L2 H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0059] X1 and X2 are independently CR X1 or N;

[0060] Each R X1 are independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -SO2NH2, or R X1 With R1, R X1 With R2, or R X1 Together with R3 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, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0061] Each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SO2NH2, -NHSO2NH2, -NHCONH2, -NHCOC 1-4Alkyl, -CONHC 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; or two adjacent R, R and R X1 and its connected atoms together form C 3-8 Cycloalkyl, 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, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups or -C(O)C 1-4 Alkyl substitution;

[0062] R1 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0063] R2 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0064] R3 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy;

[0065] n is 0, 1, 2, 3 or 4;

[0066] m is 0, 1, 2, or 3;

[0067] The condition is,

[0068] The compound is not

[0069] Scheme 2 of the present invention, the compound described in Scheme 1, its stereoisomer or pharmaceutically acceptable salt,

[0070] Wherein, each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C2-4 Alkenylene, C 2-4 Alkynylidene,

[0071] Alternatively, 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,

[0072] Alternatively, each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

[0073] or each L2 is independently selected from CO, O, NR L2 、C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene,

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

[0075] Each R X1 are independently H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-7 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0076] Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(C 1-2 Alkyl)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; or two adjacent R, R and R X1 and its connected atoms together form 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; or, each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SO2NH2, -NHSO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 Halogenated alkyl, or two adjacent R, R and R X1 and its connected atoms together form 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 groups; or two adjacent R, R and R X1 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, which 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;

[0077] R1 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0078] R2 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 alkoxy;

[0079] R3 is H, halogen, =O, CN or C 1-4 alkyl;

[0080] n is 0, 1, 2, 3 or 4;

[0081] m is 0, 1 or 2.

[0082] Scheme 3 of the present invention, such as the compound of Scheme 1 or 2, its stereoisomer or pharmaceutically acceptable salt, wherein the compound has the structure of the following Formula II,

[0083] Wherein, L is selected from one of the following structures:

[0084] Alternatively, L is selected from one of the following structures:

[0085] Alternatively, L is selected from one of the following structures:

[0086] Alternatively, L is selected from one of the following structures:

[0087] Or L is selected from one of the following structures:

[0088] Alternatively, L is selected from one of the following structures:

[0089] X1 and X2 are independently CR X1 or N;

[0090] Each R X1 are independently H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-7 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution;

[0091] Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(CH3)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; or two adjacent R, R and R X1 and its connected atoms together form 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 groups; or each R is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkynyl, -SO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 groups; or two adjacent R, R and R X1 and its connected atoms together form 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 groups; or two adjacent R, R and R X1 and the atoms to which they are attached together form a 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, which 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;

[0092] R1 is H or C 1-4 Alkyl or C 1-4 alkyl halide;

[0093] R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0094] R3 is H, halogen, =O, CN or C 1-4 alkyl.

[0095] Scheme 4 of the present invention, such as the compound of Scheme 1 or 2, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0096] Cy is selected from the group consisting of a 5-membered monocyclic heteroaryl, a 5-membered heteroaryl acene ring, a 5-membered heteroaryl and 5-membered heteroaryl, a 5-membered heteroaryl and 6-membered heteroaryl, a 5-membered heteroaryl and 4-membered cycloalkyl, a 5-membered heteroaryl and 5-membered cycloalkyl, a 5-membered heteroaryl and 6-membered cycloalkyl, a 5-membered heteroaryl and 4-membered heterocycloalkyl, a 5-membered heteroaryl and 5-membered heterocycloalkyl, a 5-membered heteroaryl and 6-membered heterocycloalkyl, a 6-membered heteroaryl acene ring, a 6-membered heteroaryl and 5-membered heteroaryl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-membered cycloalkyl, a 6-membered heteroaryl and 5-membered cycloalkyl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-membered cycloalkyl, a 6-membered heteroaryl and 5-membered cycloalkyl, a 6-membered heteroaryl and 6-membered heterocycloalkyl, a 6-membered heteroaryl and 4-membered heterocycloalkyl;

[0097] Alternatively, Cy is selected from the following structures optionally further substituted with 1-3 R:

[0098] Further, the compound of Scheme 1 or 2, its stereoisomers or pharmaceutically acceptable salts, wherein,

[0099] Cy is selected from the group consisting of a 5-membered monocyclic heteroaryl, a 5-membered heteroaryl acene ring, a 5-membered heteroaryl and 5-membered heteroaryl, a 5-membered heteroaryl and 6-membered heteroaryl, a 5-membered heteroaryl and 4-membered cycloalkyl, a 5-membered heteroaryl and 5-membered cycloalkyl, a 5-membered heteroaryl and 6-membered cycloalkyl, a 5-membered heteroaryl and 4-membered heterocycloalkyl, a 5-membered heteroaryl and 5-membered heterocycloalkyl, a 5-membered heteroaryl and 6-membered heterocycloalkyl, a 6-membered heteroaryl acene ring, a 6-membered heteroaryl and 5-membered heteroaryl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-membered cycloalkyl, a 6-membered heteroaryl and 5-membered cycloalkyl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-membered cycloalkyl, a 6-membered heteroaryl and 5-membered cycloalkyl, a 6-membered heteroaryl and 6-membered heterocycloalkyl, a 6-membered heteroaryl and 4-membered heterocycloalkyl;

[0100] or,

[0101] Scheme 5 of the present invention is a compound according to Scheme 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0102] L is selected from

[0103] X1 and X2 are independently CR X1 or N;

[0104] Each R X1 are independently H, F, Cl, methyl, ethyl, or R X1 Together with R3 and the atoms to which it is attached, it forms a C5 cycloalkyl group, a C6 cycloalkyl group, a 5-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a 6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;

[0105] R3 is H, F, Cl, =O, CN, C 1-3 alkyl;

[0106] Each R is independently H, F, Cl, methyl, ethyl, acetylene, propyne, or two adjacent Rs and the atoms to which they are connected together form a cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group, wherein the cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group is optionally substituted with 1 to 3 groups selected from F, Cl, =O, CN, methyl, ethyl, methoxy, ethoxy, OH, and NH2;

[0107] Further, the compound of Scheme 3, its stereoisomers or pharmaceutically acceptable salts, wherein L is selected from

[0108] X1 and X2 are independently CR X1 or N;

[0109] Each R X1 are independently H, F, Cl, methyl, ethyl;

[0110] Each R is independently H, F, Cl, methyl, ethyl, acetylene, propyne, or two adjacent Rs and the atoms to which they are connected together form a cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group, and the cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group is optionally substituted with 1-3 groups selected from F, Cl, =O, CN, methyl, ethyl, methoxy, ethoxy, OH, and NH2.

[0111] Further, the compound of Scheme 3, its stereoisomers or pharmaceutically acceptable salts, wherein,

[0112] L is selected from

[0113] X1 and X2 are independently CR X1 or N;

[0114] Each R X1 are independently H, F, Cl, methyl, ethyl;

[0115] Each R is independently H, F, Cl, methyl, ethyl, acetylene, propyne, or two adjacent Rs and the atoms to which they are connected together form a cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group, and the cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group is optionally substituted with 1-3 groups selected from F, Cl, =O, CN, methyl, ethyl, methoxy, ethoxy, OH, and NH2.

[0116] Scheme 6 of the present invention is a compound according to Scheme 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Selected from the following structures:

[0117] Or selected from

[0118] In scheme 7 of the present invention, the compound of the present invention is selected from the following compounds with one of the structures in Table 1, stereoisomers or pharmaceutically acceptable salts thereof:

[0119] Table 1

[0120] In scheme 8 of the present invention, the compound of the present invention is selected from one of the compounds of the following Table 2, its stereoisomers or pharmaceutically acceptable salts,

[0121] Table 2

[0122] 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").

[0123] 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.

[0124] 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.

[0125] The present invention also provides a method for treating a disease in a mammal, 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 preceding 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 of the present invention includes a human.

[0126] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to 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 a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising 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, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 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, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 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;

[0127] 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;

[0128] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the main drug in the unit dosage form 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, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 0 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0129] 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, and the disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0130] A method for treating a disease in a mammal, comprising 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, wherein the daily dose can 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.

[0131] 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.

[0132] 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.

[0133] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0134] Synthesis route

[0135] 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.

[0136] 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.

[0137] the term

[0138] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0139] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0140] "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.

[0141] "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.

[0142] "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.

[0143] "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.

[0144] "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, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, etc.

[0145] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", non-limiting examples of which include cyclopropylene, cyclobutylene, and the like.

[0146] "Heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted aromatic ring, a substituted or unsubstituted, saturated or partially unsaturated non-aromatic ring, and unless otherwise specified, contains 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, including 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 to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ... hydrofuranyl, 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]heptanyl, wait.

[0147] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0148] "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.

[0149] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0150] "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.

[0151] "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.

[0152] "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.

[0153] "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 1-4 Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0154] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0155] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

[0156] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furyl, and the like.

[0157] "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, and O as ring members. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, etc.

[0158] "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.

[0159] "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.

[0160] "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.

[0161] 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.

[0162] "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.

[0163] "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.

[0164] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0165] "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.

[0166] 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. DETAILED DESCRIPTION

[0167] 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.

[0168] Dess-Martin reagent; 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxyl-3-(1H)-one

[0169] DIPEA: N,N-diisopropylethylamine

[0170] NMP; N-methylpyrrolidone

[0171] TBDMSCl: tert-butyldimethylsilyl chloride

[0172] DMAP: 4-dimethylaminopyridine

[0173] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0174] T3P: Propylphosphonic acid tricyclic anhydride

[0175] Example 1:

[0176] Step 1: To a 250 mL single-necked flask, add substrate 1A (5.0 g, 26.11 mmol) and dissolve in dioxane (40 mL). Then, add sodium carbonate solution (2 M, 40 mL), 1B (9.7 g, 31.33 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.1 g, 2.61 mmol). Stir overnight at 100°C under nitrogen. The reaction mixture was diluted with water (40 mL) and filtered through celite. The filtrate was extracted with ethyl acetate (2 × 50 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 1C (7.2 g, 94%).

[0177] LC-MS(ESI):m / z=238.1[M-56+H] + .

[0178] Step 2: Substrate 1C (0.6 g, 2.04 mmol) was added to a 50 mL single-necked bottle, and methanol (5 mL) and dioxane hydrochloride (4 M, 5 mL) were dissolved. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated to obtain the title compound 1D (0.47 g, 100%).

[0179] LC-MS (ESI): m / z = 194.1 [M+H] + .

[0180] Step 3: Substrate 1E (0.15 g, 0.52 mmol) (Compound 1E was synthesized according to the method of patent WO2013026797) was added to a 50 mL single-necked bottle, and dioxane (10 mL) was dissolved. 1C (0.14 g, 0.62 mmol) and diisopropylethylamine (0.2 g, 1.55 mmol) were added, and the reaction was carried out at 100 °C overnight. The reaction solution was concentrated, purified by HPLC, and freeze-dried to obtain the title compound 1 (120 mg, 52%).

[0181] 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 80%; c. Flow rate: 15 mL / min; d. Elution time: 15 min; Retention time: 7.0 min.

[0182] 1 H NMR(400MHz,DMSO-d6)δ7.49-7.46(m,2H),7.42-7.37(m,2H),7.35(s,1H),6.31(t,1H),4.83(t,1H),4.35(s,2H),3.97(t,2H),3.75(d,2 H),3.45-3.39(m,1H),3.26-3.16(m,1H),2.99-2.81(m,2H),2.51-2.49(m,2H),2.43-2.27(m,2H),2.23-2.16(m,2H),1.87-1.71(m,2H).

[0183] LC-MS (ESI): m / z = 445.2 [M+H] + .

[0184] Example 2

[0185] Step 1: Add sodium borohydride (1.9 g, 51.05 mmol) and anhydrous tetrahydrofuran (50 mL) to a 500 mL single-necked flask. Add boron trifluoride etherate (7.25 g, 51.05 mmol) dropwise in an ice-water bath. Stir in an ice-water bath for 0.5 h. Continue adding a solution of 2A (5.0 g, 17.02 mmol) in tetrahydrofuran (20 mL) dropwise in an ice-water bath. Warm the mixture to room temperature and stir overnight. Water (19 mL), ethanol (19 mL), and sodium hydroxide solution (10%, 103 mL) are added sequentially to the reaction mixture. Finally, hydrogen peroxide (9.4 mL, 51.05 mmol) is added and stirred at 70°C overnight. The reaction solution was adjusted to pH 5-6 with HCl (2M), extracted with dichloromethane (3×100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to give the title compound ±2B (± represents a racemate of the configuration shown) (4.0 g, 75%).

[0186] LC-MS(ESI):m / z=256.1[M-56+H] + .

[0187] Step 2: Add ±2B (1.9 g, 6.09 mmol) to a 100 mL single-necked flask and dissolve in anhydrous dichloromethane (20 mL). Add bis(2-methoxyethyl)aminosulfur trifluoride (1.48 g, 6.67 mmol) dropwise in an ice bath. Slowly warm to room temperature and stir overnight. The reaction mixture is washed with saturated sodium bicarbonate solution (20 mL). The aqueous phase is extracted with dichloromethane (2 x 20 mL). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford the title compound ±2C (1.56 g, 82%).

[0188] LC-MS(ESI):m / z=258.1[M-56+H] + .

[0189] Step 3: Add ±2C (1.56 g, 4.97 mmol) to a 100 mL single-necked bottle, dissolve in anhydrous methanol (10 mL), add dioxane hydrochloride (10 mL), stir at room temperature for 2 h, and concentrate to obtain the title compound ±2D (1.24 g, 100%).

[0190] LC-MS (ESI): m / z = 214.1 [M+H] + .

[0191] Step 4: 1E (0.30 g, 1.04 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (10 mL). ±2D (0.32 g, 1.26 mmol) and diisopropylethylamine (0.4 g, 3.14 mmol) were added and reacted at 100°C overnight. The reaction solution was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1-8:1). The mixture was then chirally prepared to give the title compound 2 (0.11 g, 23%) and the title compound 3 (90 mg, 19%).

[0192] Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phase: 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: 2.9 min.

[0193] Compound 2, retention time 1.94 min, 1 H NMR(400MHz,DMSO-d6)δ7.43(s,1H),7.40-7.33(m,4H),5.04-5.01(d,1H),4.82(t,1H),4.71-4.63(m,1H),4.57-4.51(m,1H),3.7 7-3.66(m,2H),3.47-3.39(m,1H),3.27-3.19(m,1H),3.09-2.81(m,5H),2.46-2.25(m,2H),2.20-2.14(m,2H),1.91-1.55(m,4H).

[0194] Compound 3, retention time 2.23 min, 1 H NMR(400MHz,DMSO-d6)δ7.43(s,1H),7.39-7.34(m,4H),5.05-5.02(m,1H),4.82(t,1H),4.69-4.52(m,2H),3.71(d,2 H),3.48-3.39(m,1H),3.27-3.19(m,1H),3.08-2.81(m,5H),2.41-2.29(m,2H),2.21-2.10(m,2H),1.89-1.55(m,4H).

[0195] LC-MS (ESI): m / z = 465.2 [M+H] + .

[0196] Example 3

[0197] Step 1: To a 100 mL single-necked flask, 4A (2.0 g, 9.38 mmol) was added and dissolved in anhydrous tetrahydrofuran (10 mL). 4B (10.3 mL, 1 M, 10.32 mmol) was added dropwise in an ice bath. The mixture was warmed to room temperature and stirred for 3 h. The mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to give the title compound 4C (2.6 g, 85%).

[0198] LC-MS(ESI):m / z=252.1[M-56-18+H] + .

[0199] Step 2: Substrate 4C (1.0 g, 3.07 mmol) was added to a 50 mL single-necked flask and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added and stirred at room temperature overnight. The pH was adjusted to 8-9 with NaOH (2 M) solution and extracted with dichloromethane (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a mixture of the title compounds 4D and 4E (0.6 g, 94%).

[0200] LC-MS (ESI): m / z = 208.1 [M+H] + .

[0201] Step 3: 1E (0.20 g, 0.69 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (5 mL). A mixture of 4D and 4E (0.21 g, 1.01 mmol) and diisopropylethylamine (0.26 g, 2.05 mmol) were added and reacted at 100°C overnight. The reaction solution was concentrated and separated by column chromatography (dichloromethane:methanol = 20:1-10:1) to obtain 0.5 g of the crude product. Purification by HPLC afforded the title compound 4 (0.13 g, 42%) and the title compound 5 (50 mg, 16%).

[0202] Preparation method: Instrument: Waters 2767 preparative liquid phase; 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 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 70%; c. Flow rate: 15 mL / min. d. Elution time: 15 min; Retention time: 4.0 min for compound 4 and 7.0 min for compound 5.

[0203] Compound 4, 1H NMR(400MHz,DMSO-d6)δ7.33(brs,4H),7.24(s,1H),6.17(t,1H),4.82(t,1H),4.30-4.32(m,2H),4.09-3.85(m,2H),3.71(d,2H), 3.44-3.36(m,1H),3.24-3.16(m,1H),2.98-2.78(m,2H),2.66-2.56(m,2H),2.44-2.27(m,2H),2.17(brs,2H),1.93-1.69(m,4H).

[0204] Compound 5, 1 H NMR(400MHz,DMSO-d6)δ7.34(brs,4H),7.25(s,1H),6.03(t,1H),4.82(t,1H),4.05-3.80(m,4H),3.72(d,2H),3.45-3.37(m,1H),3 .24-3.15(m,1H),2.98-2.80(m,2H),2.77-2.65(m,2H),2.53-2.45(m,2H),2.42-2.25(m,2H),2.20-2.07(m,2H),1.82-1.68(m,2H).

[0205] LC-MS (ESI): m / z = 459.1 [M+H] + .

[0206] Example 4

[0207] Step 1: Weigh tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.12 g, 10 mmol), 1-chloro-4-iodobenzene (2.61 g, 11 mmol), Pd2(dba)3 (915 mg, 1 mmol), Xphos (952 mg, 2 mmol), and sodium tert-butoxide (1.15 g, 12 mmol) into a 250 mL three-necked flask. Add toluene (50 mL) and tert-butanol (10 mL). After nitrogen substitution, the mixture was reacted at 100°C for 16 h. After completion of the reaction as monitored by LCMS, the system was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated and separated by silica gel column chromatography (PE:EA = 20:1 to 5:1) to obtain the target compound 6A (2.76 g, 85.2%).

[0208] LC-MS (ESI): m / z = 323.2 [M+H] + .

[0209] Step 2: Dissolve 6A (2.76 g, 0.85 mmol) in methanol (30 mL), add dioxane hydrochloride solution (5 mL, 4 M), react at room temperature for four hours, and spin dry to obtain the title compound 6B (2.56 g, crude product).

[0210] LC-MS (ESI): m / z = 223.2 [M+H] + .

[0211] Step 3: 1E (287 mg, 1 mmol) and 6B (300 mg) were dissolved in 1,4-dioxane (20 mL), and DIPEA (1 mL) was added. The mixture was kept at 90°C overnight. LCMS detected that the reaction of the raw materials was complete. The system was concentrated, water (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 20:1 (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through a column (DCM:MeOH = 1:0 to 0:1) to obtain compound 6 (289 mg, 60.9%).

[0212] 1 H NMR (400MHz, DMSO-d6) δ7.33-7.07(m,3H),6.66-6.38(m,2H),4.85-4.76(m,1H),3.82-3.74(m,2H),3.74-3.67(m,2H),3.52- 3.34(m,5H),3.26-3.13(m,3H),3.13-3.04(m,2H)2.96-2.79(m,2H),2.43-2.27(m,2H),2.19-2.09(m,2H),1.86-1.65(m,2H).

[0213] LC-MS (ESI): m / z = 474.2 [M+H] + .

[0214] Example 5

[0215] Step 1: Under a nitrogen atmosphere, compound 7A (1 g, 4.2 mmol) was dissolved in 50 mL of tetrahydrofuran and the mixture was cooled to 0°C. 4.6 mL of 4-chlorophenylmagnesium bromide (1 M in THF) was slowly added dropwise, and the mixture was allowed to warm to room temperature and reacted for 3 h. The reaction was quenched by adding saturated aqueous ammonium chloride. After concentrating the reaction, the mixture was extracted three times with 50 mL of ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated to afford crude compound 7B, which was used directly in the next step.

[0216] LCMS m / z=296.1[M-55] + .

[0217] Step 2: Dissolve the crude compound 7B in a mixed solvent (DCM:TFA = 50 mL:4 mL) and react at room temperature for 2 h. After the reaction is complete, concentrate the system to obtain the crude compound 7C, which is used directly in the next step.

[0218] LCMS m / z=234.2[M+1] + .

[0219] Step 3: Dissolve the crude compound 7C in 50 mL of methanol, add 300 mg of palladium carbon (10%), react overnight under a hydrogen atmosphere, remove the solid residue in the system by suction, and concentrate the filtrate to obtain the crude compound 7D, which is directly used in the next reaction.

[0220] LCMS m / z=236.1[M+1] + .

[0221] Step 4: Under nitrogen, crude compound 7D, compound 1E (150 mg, 0.52 mmol), and DIPEA (0.86 mL, 5.2 mmol) 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 compound 7 (98 mg, 38%).

[0222] LCMS m / z=487.1[M+1] + .

[0223] 1 H NMR(400MHz,DMSO-d6)δ7.34-7.26(m,5H),4.87-4.84(m,1H),3.85-3.59(m,6H), 3.44-3.34(m,1H),3.26-3.15(m,1H),2.95-2.81(m,2H),2.54-2.46(m,1H),2.41-2.27(m,2 H),2.15(s,2H),1.99-1.93(m,2H),1.86-1.68(m,4H),1.64-1.57(m,2H),1.50-1.41(m,2H).

[0224] Example 6

[0225] Step 1: Compound 8A (2.00 g, 10.91 mmol) and compound 1B (3.31 g, 10.91 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (15 mL) was added to dissolve the mixture. Sodium carbonate solution (2N, 15 mL) and Pd(dppf)Cl2 (0.66 g, 1.1 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100°C for 4 h. The reaction was complete as shown by TLC (petroleum ether:ethyl acetate = 5:1). 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 8B (2.50 g, 80%).

[0226] LCMS m / z=286.1[M+1] + .

[0227] Step 2: Compound 8B (1.00 g, 3.50 mmol) was weighed into a 100 mL single-necked flask, and then ethyl acetate (20 mL) was added to dissolve it. Palladium carbon (0.19 g, 1.74 mmol) was added to the reaction solution. After the addition was completed, the mixture was stirred under hydrogen atmosphere for 1 h. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the target compound 8C (1.00 g, 99%).

[0228] LCMS m / z=288.1[M+1] + .

[0229] Step 3: Compound 8C (1.00 g, 3.48 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (20 mL). A 4 N solution of dioxane hydrochloride (20 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure to afford the target compound 8D (0.60 g, 92% yield).

[0230] LCMS m / z=188.2[M+1] + .

[0231] Step 4: To a 100 mL single-necked flask, add compound 8D (0.20 g, 1.04 mmol) and compound 1E (0.30 g, 1.04 mmol). Dissolve the mixture in 1,4-dioxane (10 mL). Finally, add N,N-diisopropylethylamine (0.40 g, 3.12 mmol). After the addition is complete, stir the mixture at 100°C under nitrogen for 16 h. The reaction mixture is concentrated under reduced pressure to yield the crude title compound. Preparative HPLC yields the title compound 8 (190 mg, 62%).

[0232] 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: 10.38 min.

[0233] LCMS m / z=439.2[M+1] + .

[0234] 1 H NMR(400MHz,DMSO-d6)δ7.26(s,1H),7.02-7.04(m,1H),6.94-6.97(m,1H),4.75-4.82(m,3H),3.71(d,3H),3.36-3.45(m,1H), 3.17-3.25(m,1H),3.07(s,4H),2.74-2.96(m,5H),2.27-2.41(m,2H),2.12-2.19(m,2H),1.70-1.80(m,4H),1.44-1.54(m,2H).

[0235] Example 7

[0236] Step 1: Compound 9A (2.00 g, 10.05 mmol) and compound 1B (3.11 g, 10.05 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (15 mL) was added to dissolve the mixture. Sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.66 g, 1.01 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100°C for 4 h. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1). 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 9B (2.50 g, 80%).

[0237] LCMS m / z=300.1[M+1] + .

[0238] Step 2: Weigh compound 9B (3.00 g, 9.95 mmol) into a 100 mL single-necked flask, then add ethyl acetate (20 mL) to dissolve it. Add palladium carbon (0.50 g, 4.97 mmol) to the reaction solution. After the addition is complete, stir under hydrogen for 1 h. After the reaction is completed, filter the reaction solution, and concentrate the filtrate under reduced pressure until no liquid drips out to obtain the target compound 9C (3.00 g, 99%).

[0239] LCMS m / z=302.1[M+1] + .

[0240] Step 3: Compound 9C (3.00 g, 9.89 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (20 mL). A 4N solution of dioxane hydrochloride (20 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure to yield the target compound 9D (2.00 g, 99%).

[0241] LCMS m / z=202.2[M+1] + .

[0242] Step 4: To a 100 mL single-necked flask, add compound 9D (0.20 g, 1.03 mmol) and compound 1E (0.29 g, 1.03 mmol). Dissolve the mixture in 1,4-dioxane (10 mL). Finally, add N,N-diisopropylethylamine (0.26 g, 2.05 mmol). After the addition is complete, stir the mixture at 100°C under nitrogen for 16 h. The reaction mixture is concentrated under reduced pressure to yield the crude title compound. Preparative HPLC yields the title compound 9 (190 mg, 64%).

[0243] 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 45% to 80%; c. Flow rate: 20 mL / min; d. Elution time: 20 min; Retention time: 8.11 min.

[0244] LCMS m / z=453.2[M+1] + .

[0245] 1H NMR(400MHz,DMSO-d6)δ7.26(s,1H),7.07-7.12(m,2H),6.96-6.97(m,1H),4.75-4.82(m,3H),3.72(d,2H),3.36-3.45(m,1H),3.1 8-3.25(m,1H),2.75-2.97(m,9H),2.28-2.41(m,2H),2.11-2.20(m,2H),1.93-2.01(m,2H),1.72-1.80(m,4H),1.44-1.54(m,2H).

[0246] Example 8

[0247] Step 1: Compound 10A (2.00 g, 9.47 mmol) was weighed and placed in a 100 mL single-necked flask. Tetrahydrofuran (30 mL) was then added to dissolve the mixture. 4-Chlorophenylmagnesium chloride (18.94 mL, 18.94 mmol) was added to the reaction solution. After the addition was complete, the mixture was stirred at room temperature for 4 h. TLC (petroleum ether:ethyl acetate = 3:1) 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 10B (1.50 g, 48%).

[0248] LCMS m / z=324.1[M+1] + .

[0249] Step 2: Compound 10B (0.50 g, 1.54 mmol) was weighed into a 100-mL single-necked flask, and then dichloromethane (15 mL) was added to dissolve it. Trifluoroacetic acid (5 mL) was added to the reaction solution. After the addition was complete, the mixture was stirred at room temperature for 16 h. After the reaction was completed, the filtrate was concentrated under reduced pressure to obtain the target compound 10C (0.40 g, crude product).

[0250] LCMS m / z=206.1[M+1] + .

[0251] Step 3: Compound 10C (0.40 g, 1.94 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (20 mL). Palladium on carbon (0.10 g, 0.97 mmol) was added and stirred for 2 h. After completion of the reaction, the reaction mixture was filtered, and the organic phase was concentrated under reduced pressure to obtain the target compound 10D (0.40 g, crude product).

[0252] LCMS m / z=208.2[M+1] + .

[0253] Step 4: To a 100 mL single-necked flask, add compound 10D (0.40 g, 1.91 mmol) and compound 1E (0.55 g, 1.91 mmol). Dissolve the mixture in 1,4-dioxane (10 mL). Finally, add N,N-diisopropylethylamine (0.74 g, 5.73 mmol). After the addition is complete, stir at 100°C under nitrogen for 16 h. The reaction mixture is concentrated under reduced pressure to yield the crude title compound. Preparative HPLC yields the title compound 10 (25 mg, 4%).

[0254] 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 50% to 90%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 6.45 min.

[0255] LCMS m / z=459.2[M+1] + .

[0256] 1 H NMR(400MHz,DMSO-d6)δ7.34-7.36(m,2H),7.25-7.30(m,3H),4.86(t,1H),4.14(s,2H),3.92(s,2H),3.70(d,2H),3.35-3.4 4(m,2H),3.17-3.24(m,1H),2.82-2.95(m,2H),2.54-2.61(m,2H),2.24-2.34(m,4H),2.10-2.16(m,2H),1.69-1.85(m,2H).

[0257] Example 9

[0258] Step 1: Compound 11A (2.00 g, 7.78 mmol) and compound 1B (2.89 g, 9.34 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (15 mL) was added to dissolve the mixture. Sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.57 g, 0.78 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100°C for 4 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 11B (2.60 g, 93%).

[0259] LCMS m / z=360.1[M+1] + .

[0260] Step 2: Compound 11B (0.50 g, 1.39 mmol) was weighed into a 100 mL single-necked flask, and then ethanol (20 mL) was added to dissolve it. Palladium carbon (0.15 g, 1.39 mmol) was added to the reaction solution. After the addition was completed, the mixture was stirred under hydrogen atmosphere for 16 h. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the target compound 11C (0.50 g, 99%).

[0261] LCMS m / z=362.1[M+1] + .

[0262] Step 3: Compound 11C (0.50 g, 1.38 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (20 mL). A 4N solution of dioxane hydrochloride (20 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure to yield the target compound 11D (0.40 g, crude product).

[0263] LCMS m / z=262.2[M+1] + .

[0264] Step 4: To a 100 mL single-necked flask, add compound 11D (0.20 g, 0.76 mmol) and compound 1E (0.22 g, 0.76 mmol). Dissolve the mixture in 1,4-dioxane (10 mL). Finally, add N,N-diisopropylethylamine (0.29 g, 2.28 mmol). After the addition is complete, stir at 100°C under nitrogen for 16 h. The reaction mixture is concentrated under reduced pressure to yield the crude title compound. Preparative HPLC yields the title compound 11 (240 mg, 61%).

[0265] 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: 12.08 min.

[0266] LCMS m / z=513.2[M+1] + .

[0267] 1 H NMR(400MHz,DMSO-d6)δ7.62(d,2H),7.43(d,2H),7.29(s,1H),4.77-4.84(m,3H),3.71(d,2H),3.37-3.45(m,1H), 3.18-3.26(m,1H),2.82-2.98(m,5H),2.28-2.41(m,2H),2.12-2.19(m,2H),1.70-1.85(m,4H),1.48-1.58(m,2H).

[0268] Example 10

[0269] Step 1: (4-Bromophenyl)sulfide pentafluoride (1.0 g, 3.55 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (12A, 1.65 g, 5.33 mmol) were dissolved in 1,4-dioxane (10 mL). Aqueous sodium carbonate solution (2 mol / L, 10 mL) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (200 mg) were added. The mixture was refluxed under nitrogen for 4 hours, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:10) to obtain the product (12B) (700 mg, yield 51%).

[0270] LCMS m / z=330.1[M+1-56] + .

[0271] Step 2: Compound 12B (700 mg, 1.8 mmol) was dissolved in methanol (10 mL), palladium on carbon (100 mg) was added, and hydrogenation was performed at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to obtain a crude product (12C) (700 mg, 100% yield).

[0272] LCMS m / z=332.1[M+1-56] + .

[0273] Step 3: Add hydrogen chloride-dioxane (10 mL) to compound 12C (700 mg, 1.8 mmol), react at room temperature for 1 hour, and concentrate to obtain a crude product (12D) (400 mg, yield 72%).

[0274] LCMS m / z=288.1[M+1] + .

[0275] Step 4: Compound 12D (0.1 g, 0.31 mmol) and intermediate 1E (89 mg, 0.31 mmol) were dissolved in 1,4-dioxane (10 mL) and N,N-diisopropylethylamine (120 mg, 0.93 mmol). The mixture was stirred under reflux overnight and concentrated before direct separation and purification using a liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase: deionized water containing 0.1% ammonia (A), acetonitrile (B), gradient elution, B content = 5% to 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30°C); the title compound 12 (50 mg, yield 29%, retention time approximately 9.0 min) was obtained.

[0276] 1 H NMR(400MHz,DMSO-d6)δ7.79(d,2H),7.50(d,2H),7.30(s,1H),4.91-4.72(m,3H),3.72(d,2H), 3.47-3.36(m,1H),3.27-3.17(m,1H),3.02-2.80(m,5H),2.44-2.26(m,2H),2.22-2.09(m,2H), 1.87-1.69(m,4H),1.60-1.47(m,2H).

[0277] MS M / Z(ESI): m / z=539.1[M+1] + .

[0278] Example 11

[0279] 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 and the mixture was allowed to react for 2 h. A solution of 12A (5 g, 22.19 mmol) in tetrahydrofuran (20 mL) was then added dropwise and the mixture was allowed to react 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 13B (4 g, 53.36%).

[0280] LC-MS (ESI): m / z = 338.1 [M+H] + .

[0281] Step 2: Add 13B (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 directly concentrated under reduced pressure and then used for the next reaction.

[0282] LC-MS (ESI): m / z = 220.1 [M+H] + .

[0283] Step 3: 13C (4 g, 11.99 mmol), methanol (50 mL), and 10% palladium on carbon (0.8 g) were added to a 100 mL single-necked vial. The mixture was reacted at room temperature under hydrogen atmosphere for 1 h. The filtrate was filtered, concentrated under reduced pressure, and purified by HPLC to yield the target compound 13D (1.5 g, 37.26%).

[0284] LC-MS (ESI): m / z = 222.1 [M+H] + .

[0285] Preparative HPLC separation method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Dissolve the sample in DMF and filter 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% acetic acid). b. Gradient elution, mobile phase A content from 5% to 40%. c. Flow rate: 12 mL / min. d. Elution time: 20 min.

[0286] Step 4: Compound 1E (0.15 g, 0.52 mmol), 13D (0.21 g, 0.63 mmol), dioxane (5 mL), and DIPEA (0.27 g, 2.05 mmol) were added sequentially to a 50 mL single-necked flask and 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 220 mg of the mixture.

[0287] Chiral preparations yielded the title compound 13 (0.14 g, 56%, retention time: 0.787 min) and the title compound 14 (20 mg, 8%, retention time: 0.995 min). Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% ammonia in water); 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.

[0288] Compound 13 1 H NMR(400MHz,DMSO-d6)δ7.34-7.25(m,4H),7.22(s,1H),4.83(t,1H),3.73(d, 2H),3.66-3.62(m,2H),3.52-3.50(m,2H),3.45-3.33(m,1H),3.25-3.08(m,2H),2.97-2 .74(m,4H),2.44-2.23(m,4H),2.17-2.13(m,2H),1.84-1.67(m,2H),1.45-1.38(m,2H).

[0289] LC-MS (ESI): m / z = 473.2 [M+H] + .

[0290] Compound 14 1 H NMR(400MHz,DMSO-d6)δ7.35-7.28(m,4H),7.22(s,1H),4.84(t,1H),3.84-3.80(m,2H),3.74(d,2H),3.45- 3.33(m,3H),3.24-3.17(m,2H),2.95-2.82(m,4H),2.42-2.30(m,2H),2.18-2.13(m,2H),1.94-1.72(m,6H).

[0291] LC-MS (ESI): m / z = 473.2 [M+H] +.

[0292] Example 12

[0293] Step 1: Compound 15A (5 g, 45 mmol) was dissolved in 200 mL of dichloromethane, and triethylamine (17 mL, 122 mmol) and di-tert-butyl carbonate (11.5 mL, 50 mmol) were added. The mixture was reacted at room temperature for 5 h. After the starting material disappeared, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted three times with 200 mL of dichloromethane and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain compound 15B (8 g, 95%).

[0294] LCMS m / z=127.2[M-55] + .

[0295] Step 2: Under a nitrogen atmosphere, compound 15C (15 g, 53.2 mmol) was dissolved in 200 mL of tetrahydrofuran and the mixture was cooled to 0°C. Borane tetrahydrofuran solution (133 mL, 1 M in THF) was slowly added. After warming to room temperature, the mixture was heated under reflux for 3 h. The reaction was cooled to 0°C and quenched by the addition of 1N hydrochloric acid. The mixture was concentrated and extracted three times with 200 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 15 g of crude compound 15D, which was used directly in the next reaction.

[0296] 1 H NMR (400MHz, CDCl3) δ7.82-7.81(m,1H),7.41-7.33(m,2H),4.64(s,2H),1.92(s,1H).

[0297] Step 3: Dissolve triphenylphosphine (22 g, 83.8 mmol) in 250 mL of dichloromethane and cool the mixture to 0°C. Slowly add bromine (4.5 mL, 83.5 mmol). Stir for 10 min, then add imidazole (7.6 g, 111 mmol) and 15 g of crude compound 15D. Warm the mixture to room temperature for 3 h. Sodium thiosulfate is added to quench the reaction, followed by extraction with 200 mL of dichloromethane. After drying over anhydrous sodium sulfate, the concentrated organic phase is separated by column chromatography to afford compound 15E (12 g, 68%).

[0298] 1 H NMR (400MHz, CDCl3) δ7.86-7.84(m,1H),7.42-7.29(m,2H),4.55(s,2H).

[0299] Step 4: Under a nitrogen atmosphere, compound 15B (2 g, 11 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -40°C. Sodium bis(trimethylsilyl)amide (11 mL, 2 M in THF) was added and stirred for 30 min. Compound 15E (3.6 g, 10.8 mmol) was dissolved in a small amount of tetrahydrofuran and added to the system. The reaction was maintained at -40°C for 2 h. After the reaction was complete, saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was warmed to room temperature. Extraction was performed three times with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to yield compound 15F (2 g, 41%).

[0300] LCMS m / z=376.9[M-55] + .

[0301] Step 5: Under nitrogen, compound 15F (1.9 g, 4.4 mmol) was dissolved in 20 mL of tetrahydrofuran and the system was cooled to -78°C. n-Butyl lithium (9.5 mL, 2.5 M) was slowly added dropwise and the reaction was maintained at -78°C for 15 min. After the starting material disappeared, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, and the concentrated organic phase was separated by column chromatography to obtain compound 15G (800 mg, 59%).

[0302] LCMS m / z=252.0[M-55] + .

[0303] Step 6: Under a nitrogen atmosphere, compound 15G (400 mg, 1.3 mmol) was dissolved in 20 mL of dichloromethane. Boron trifluoride etherate (1.5 mL, 11.4 mmol) and triethylsilane (3 mL, 23 mmol) were added, and the reaction temperature was raised to 45°C for 10 h. After the starting material disappeared, the reaction system was cooled to room temperature and poured into saturated sodium bicarbonate aqueous solution. Extraction was performed with 50 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 280 mg of crude compound 15H, which was used directly in the next reaction.

[0304] LCMS m / z=194.1[M+H] + .

[0305] Step 7: Under nitrogen, 280 mg of crude compound 15H, 150 mg of compound 1E (0.52 mmol), and DIPEA (0.86 mL, 5.2 mmol) 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 yield compound 15 (71 mg, 31%).

[0306] LCMS m / z=445.1[M+H] + .

[0307] 1 H NMR(400MHz,DMSO-d6)δ7.33-7.17(m,4H),4.85-4.81(m,1H),3.95(s,4H),3.74-3.61(m,2H),3.44-3.3 4(m,1H),3.26-3.10(m,5H),2.97-2.81(m,2H),2.40-2.25(m,2H),2.16-2.06(m,2H),1.83-1.63(m,2H).

[0308] Example 13

[0309] Step 1: 4C (0.5 g, 1.53 mmol) was added to a 50 mL single-necked flask and dissolved in dichloromethane (10 mL). Triethylsilane (0.53 g, 4.59 mmol) was then added dropwise. Boron trifluoride etherate (0.43 g, 3.06 mmol) was added dropwise in an ice bath and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the title compound 16A (0.35 g, crude product).

[0310] LC-MS (ESI): m / z = 210.1 [M+H] + .

[0311] Step 2: 1E (0.40 g, 1.39 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (10 mL). 16A (0.35 g, 1.67 mmol) and diisopropylethylamine (0.54 g, 4.18 mmol) were then added and reacted at 100°C overnight. The reaction solution was concentrated and separated by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford 0.2 g of the crude product. Chiral preparations were then performed to afford the title compounds 16 (40 mg, 6%) and 17 (35 mg, 5%).

[0312] Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phase: A: carbon dioxide and B: isopropanol (0.1% ammonia); Isocratic elution: 25% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 2.8 min.

[0313] Compound 16, retention time 2.16 min, 1H NMR(400MHz,DMSO-d6)δ7.29(d,2H),7.22(d,2H),7.16(s,1H),4.85-4.74(m,1H),4.09-3.87(m,2H),3.73-3.61(m,3H),3.45-3.36(m,2 H),3.26-3.19(m,1H),3.00-2.77(m,2H),2.71-2.62(m,1H),2.42-2.34(m,2H),2.15-2.10(m,2H),1.98-1.91(m,2H),1.75-1.60(m,6H).

[0314] Compound 17, retention time 2.47 min, 1 H NMR(400MHz,DMSO-d6)δ7.32-7.27(m,2H),7.25-7.13(m,3H),4.86-4.76 (m,1H),4.06-3.96(m,1H),3.83-3.64(m,4H),3.58-3.55(m,1H),3.50-3 .36(m,1H),3.26-3.18(m,1H),2.98-2.80(m,2H),2.69-2.66(m,1H),2.4 2-2.32(m,2H),2.21-2.06(m,2H),1.98-1.95(m,2H),1.89-1.53(m,6H).

[0315] LC-MS (ESI): m / z = 461.2 [M+H] + .

[0316] Example 14

[0317] Step 1: Place p-chloroiodobenzene (2.5 g, 10.42 mmol) and anhydrous tetrahydrofuran (20 mL) in a 100 mL three-necked flask. The atmosphere was replaced with nitrogen. n-Butyllithium (12 mmol, 4.8 mL) was added dropwise at -78°C, and the mixture was allowed to react for 2 h. A solution of 18A (2 g, 9.5 mmol) in tetrahydrofuran (10 mL) was then added dropwise, and the mixture was allowed to react for 1 h at -78°C. Water (100 mL) was added, and the mixture 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, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA / PE = 0-35%) to yield the target compound 18B (2.4 g, 78%).

[0318] LC-MS (ESI): m / z = 324.1 [M+H] + .

[0319] Step 2: To a 100ml single-necked flask were added 18B (2g, 6.18mmol), dichloroethane (30mL), triethylsilane (3.59g, 30.9mmol), and boron trifluoride etherate (4.4g, 3.81mmol) in sequence. The mixture was reacted at 80°C for 3h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified on a C18 reverse-phase column using mobile phases A and B (A / B = 30% / 70%): acetonitrile; water (containing 0.1% TFA). The title compound 18C (450mg, 22%) was obtained.

[0320] LC-MS (ESI): m / z = 208.1 [M+H] + .

[0321] Step 3: To a 50 mL single-necked flask were added 1E (0.15 g, 0.52 mmol), 18C (0.14 g, 0.68 mmol), dioxane (5 mL), and DIPEA (0.27 g, 2.05 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 220 mg of the mixture.

[0322] Chiral preparation yielded the title compound 18 (80 mg, 33%, retention time: 1.253 min) and the title compound 19 (78 mg, 32%, retention time: 1.392 min). Chiral preparation method: Instrument: Waters 150 MGM; 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: 2.7 min.

[0323] Compound 18:

[0324] 1 H NMR(400MHz,DMSO-d6)δ7.37-7.31(m,2H),7.21(d,1H),7.15(d,1H),7.09(d ,1H),4.89-4.78(m,1H),4.65(d,1H),3.79-3.69(m,1H),3.65-3.57(m,1H), 3.52-3.44(m,1H),3.43-3.33(m,1H),3.27-3.03(m,3H),3.01-2.68(m,3H), 2.46-2.22(m,2H),2.21-2.09(m,2H),2.04-1.93(m,1H),1.91-1.58(m,5H).

[0325] LC-MS (ESI): m / z = 459.2 [M+H] + .

[0326] Compound 19:

[0327] 1 H NMR(400MHz,DMSO-d6)δ7.35-7.25(m,3H),7.15-7.11(m,2H),4.84(d,1H) ,4.66(d,1H),3.78-3.71(m,1H),3.66-3.57(m,1H),3.48-3.42(m,2H),3.2 4-3.19(m,1H),3.18-3.04(m,2H),3.00-2.69(m,3H),2.45-2.32(m,1H),2 .30-2.11(m,3H),2.05-1.93(m,1H),1.92-1.83(m,2H),1.81-1.59(m,3H).

[0328] LC-MS (ESI): m / z = 459.2 [M+H] + .

[0329] Example 15

[0330] Step 1: To a dichloromethane (200 mL) solution of 20A (2.00 g, 10.70 mmol, synthesis reference: Chemistry-A European Journal, 2019, 25 (14), 3521-3524) and rhodium acetate (190 mg, 0.4 mmol) was slowly added dropwise under nitrogen at room temperature. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 20B (1.10 g, yield: 37.67%).

[0331] 1 H NMR(400MHz, CDCl3)δ7.19(d,2H),6.97(d,2H),4.20-4.13(m,2H),3.96-3.91(m,1H),3.81 -3.76(m,1H),2.60-2.57(m,1H),2.14-2.10(m,1H),2.02-1.96(m,1H),1.27-1.22(m,3H).

[0332] Step 2: Compound 20B (1.00 g, 3.66 mmol) was dissolved in 7N methanolic ammonia (40 mL) and heated to 80°C with stirring for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 1:1) to afford the target compound 20C (400 mg, yield: 52.62%).

[0333] LC-MS (ESI): m / z = 208.0 [M+H] + .

[0334] 1 H NMR (400MHz, CDCl3) δ7.27-7.23(m,2H),6.99-6.96(m,2H),5.58(br s,1H),3.67-3.63(m,1H),3.55-3.49(m,1H),2.23-2.20(m,1H),2.13-2.09(m,2H).

[0335] Step 3: Compound 20C (400 mg, 1.93 mmol) was dissolved in 20 mL of tetrahydrofuran. Lithium aluminum tetrahydride (220 mg, 5.79 mmol) was added portionwise at 0°C, and the mixture was warmed to room temperature and stirred for 16 h. 0.3 mL of water, 0.3 mL of 15% aqueous sodium hydroxide solution, and 0.9 mL of water were added. After stirring for 1 h, the solid was removed by filtration. The filtrate was dried to give compound 20D (310 mg, 83.10%), which was used directly in the next reaction.

[0336] 1 H NMR (400MHz, CDCl3) δ7.22-7.19(m,2H),6.99-6.95(m,2H),3.12(d,2H),2.99(d,2H),1.69-1.64(m,3H).

[0337] Step 4: Compound 1E (200 mg, 0.70 mmol) and compound 20D (150 mg, 0.78 mmol) were dissolved in 1,4-dioxane (8 mL), and then DIPEA (270 mg, 2.09 mmol) was added. After the addition was complete, the mixture was heated to 100°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: DCM:MeOH = 100:1 to 9:1) and further purified by prep.HPLC (preparative method: instrument: Waters 2767 preparative liquid phase; 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 20% to 85%; c. flow rate: 15 mL / min; d. elution time: 15 min; retention time: 6.0 min) to obtain the target compound 20 (120 mg, 38.80%).

[0338] LCMS m / z=445.1[M+1] + .

[0339] 1 H NMR (400MHz, CDCl3) δ7.22(d,2H),6.95(d,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),2.37-2.25(m,4H),1.99-1.85(m,4H),1.69-1.62(m,1H).

[0340] Example 16

[0341] Step 1: Under nitrogen, (1R,5S)-3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (3.00 g, 14.9 mmol) was dissolved in dry tetrahydrofuran (80 mL). The mixture was cooled to 0°C and a solution of 4-chlorophenylmagnesium bromide in tetrahydrofuran (22.4 mL, 22.4 mmol) was added dropwise. The reaction was maintained at 0°C for approximately 1 hour. After completion of the reaction, saturated aqueous ammonium chloride (80 mL) was added. The mixture was warmed to room temperature and the aqueous and organic phases were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford compound 21B (3.69 g, 78.8%).

[0342] LC-MS (ESI): m / z = 314.2 [M+H] + .

[0343] Step 2: Compound 21B (3.00 g, 9.58 mmol) was dissolved in 1,2-dichloroethane (80 mL). Boron trifluoride etherate (4.08 g, 28.8 mmol) and triethylsilane (5.57 g, 47.9 mmol) were added at room temperature. The temperature was raised to 80°C and the reaction was continued overnight. After completion of the reaction, the temperature was lowered to room temperature, and saturated aqueous sodium bicarbonate (80 mL) and water (80 mL) were added. The aqueous and organic phases were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford compound 21C (1.38 g, 48.5%).

[0344] LC-MS (ESI): m / z = 298.1 [M+H] + .

[0345] Step 3: Compound 21C (700 mg, 2.35 mmol) was added to a microwave reaction tube and dissolved in dry 1,2-dichloroethane (12 mL). 1-Chloroethyl chloroformate (1.68 g, 11.7 mmol) was then added. The mixture was heated to 140°C in a microwave reactor for 100 minutes. After completion of the reaction, the reaction mixture was transferred to a round-bottom flask and drained. Methanol (30 mL) was added to redissolve the mixture and allowed to react at 70°C for approximately 3 hours. The reaction mixture was concentrated again and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1 to 5:1) to yield compound 21D (280 mg, 57.4%).

[0346] LC-MS (ESI): m / z = 208.0 [M+H] + .

[0347] Step 4: Dissolve 1E (300 mg, 1.04 mmol), compound 21D (238 mg, 1.15 mmol), and N,N-diisopropylethylamine (673 mg, 5.21 mmol) in 1,4-dioxane (15 mL). Heat to 100°C and react for approximately 3 hours. After completion of the reaction, monitor by TLC. Cool to room temperature, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to yield compound 21.

[0348] LC-MS (ESI): m / z = 459.2 [M+H] + .

[0349] Compound 21-1 (80.5 mg, 16.8%) and compound 21-2 (87.4 mg, 18.3%) were then prepared by chiral chromatography. Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% ammonia solution); Isocratic elution: 35% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 2.9 min.

[0350] Compound 21-1, retention time 1.78 min, 1 H NMR(400MHz, Methanol-d4)δ7.26(d,2H),7.06(d,2H),3.93(d,2H),3.81(q,1H),3.70-3.49(m,3H),3.42-3.29(m ,2H),3.22-3.10(m,2H),3.09-2.96(m,2H),2.58(q,1H),2.44-2.16(m,3H),2.13-1.99(m,2H),1.94-1.67(m,3H);

[0351] Compound 21-2, retention time 1.94 min, 1 H NMR(400MHz,Methanol-d4)δ7.26(d,2H),7.06(d,2H),4.02-3.87(m,2H),3.81(q,1H),3.75-3.47(m,3H),3 .42-3.29(m,2H),3.21-2.94(m,4H),2.58(q,1H),2.44-2.16(m,3H),2.13-1.98(m,2H),1.95-1.68(m,3H).

[0352] Example 17

[0353] Step 1: Under nitrogen, 22A (2.0 g, 9.29 mmol) was dissolved in dry tetrahydrofuran (80 mL). The temperature was cooled to 0°C, and a solution of 4-chlorophenylmagnesium bromide in tetrahydrofuran (18.6 mL, 18.6 mmol) was added dropwise. The reaction was maintained at 0°C for approximately 1 hour. After completion of the reaction, as monitored by TLC, saturated aqueous ammonium chloride (80 mL) was added. The reaction was allowed to warm to room temperature, and the aqueous and organic phases were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford compound 22B (2.89 g, 94.8%).

[0354] LC-MS (ESI): m / z = 328.1 [M+H] + .

[0355] Step 2: Compound 22B (710 mg, 2.16 mmol) was dissolved in 1,2-dichloroethane (30 mL). Boron trifluoride etherate (920 mg, 6.48 mmol) and triethylsilane (1.26 g, 10.8 mmol) were added at room temperature. The temperature was raised to 80°C and the reaction was continued for 3 hours. After completion of the reaction, the temperature was lowered to room temperature and saturated aqueous sodium bicarbonate (30 mL) and water (30 mL) were added. The aqueous and organic phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford compound 22C (560 mg, 75.6%).

[0356] LC-MS (ESI): m / z = 312.1 [M+H] + .

[0357] Step 3: Compound 22C (560 mg, 1.80 mmol) was added to a microwave reaction tube and dissolved in dry 1,2-dichloroethane (12 mL). 1-Chloroethyl chloroformate (1.28 g, 8.98 mmol) was then added. The mixture was heated to 140°C in a microwave reactor for 100 minutes. After completion of the reaction, the reaction mixture was transferred to a round-bottom flask and drained. Methanol (30 mL) was added to redissolve the mixture and allowed to react at 70°C for approximately 3 hours. The reaction mixture was concentrated again and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1 to 5:1) to yield 22D (340 mg, 85.4%).

[0358] LC-MS (ESI): m / z = 222.1 [M+H] + .

[0359] Step 4: 1E (300 mg, 1.04 mmol), compound 22D (255 mg, 1.15 mmol), and N,N-diisopropylethylamine (673 mg, 5.21 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was heated to 100°C and reacted for approximately 3 hours. After completion of the reaction, the temperature was cooled to room temperature, monitored by TLC. The reaction solution was directly concentrated and initially purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 22, which was then purified by HPLC to afford compound 22 (450 mg, 91.1%).

[0360] HPLC preparation method: instrument: Waters 150 MGM; chromatographic column: Chiralpak Column; mobile phase: A: carbon dioxide and B: methanol (0.1% ammonia solution); isocratic elution: 30% mobile phase B; flow rate: 100 mL / min; back pressure: 100 bar; column temperature: 25°C; wavelength: 220 nm; elution time: 2.9 min; retention time: 1.81 min.

[0361] 1 H NMR(400MHz,Methanol-d4)δ7.44-7.20(m,4H),4.26(d,2H),3.91(dd,2H),3.52(dt,1H),3.38-3.27(m,1H,overlappe d),3.20-3.07(m,3H),3.07-2.97(m,2H),2.85-2.76(m,2H),2.38-2.21(m,4H),2.03-1.83(m,4H),1.74-1.61(m,2H).

[0362] LC-MS (ESI): m / z = 473.5 [M+H] + .

[0363] Example 18

[0364] Step 1: Under nitrogen, p-chloroiodobenzene (6.19 g, 26.0 mmol) was dissolved in dry tetrahydrofuran (150 mL). The mixture was cooled to -78°C and then added dropwise with a solution of n-butyllithium in n-hexane (10.4 mL, 26.0 mmol). The reaction was continued for approximately 1 hour. 23A (4.5 g, 20.0 mmol) in dry tetrahydrofuran (80 mL) was then added dropwise. After the addition was complete, the mixture was heated to -10°C and stirred for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride (200 mL) was added. The mixture was allowed to warm to room temperature and the aqueous and organic phases were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford compound 23B (5.70 g, 84.4%).

[0365] LC-MS (ESI): m / z = 338.2 [M+H] + .

[0366] Step 2: Compound 23B (3.00 g, 15.1 mmol) was dissolved in dichloromethane (50 mL). Trifluoroacetic acid (10 mL) was added at room temperature and the reaction was continued for 1 hour. After completion of the reaction, the mixture was concentrated to afford the trifluoroacetate salt of 23C, which was used directly in the next reaction without further purification.

[0367] LC-MS (ESI): m / z = 220.1 [M+H] + .

[0368] Step 3: The crude trifluoroacetate salt of compound 23C (4.10 g) was added to a round-bottom flask and dissolved in methanol (80 mL). Palladium-on-carbon catalyst (615 mg, 0.580 mmol) was then added. A hydrogen balloon was introduced and the reaction was maintained at room temperature for 20 minutes. After TLC monitoring of the disappearance of the starting material, the reaction solution was filtered and washed with methanol. The filtrate was then dried under reduced pressure and directly purified by preparative liquid chromatography to afford the trifluoroacetate salt of compound 23D (312 mg, 10.5% yield over two steps).

[0369] Preparative HPLC separation and purification 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 0.5% trifluoroacetic acid); b. Gradient elution, mobile phase A content ranging from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 10 min.

[0370] LC-MS (ESI): m / z = 222.1 [M+H] + .

[0371] Step 4: Dissolve 1E (266 mg, 0.923 mmol), the trifluoroacetic acid salt of compound 23D (310 mg, 0.923 mmol), and N,N-diisopropylethylamine (595 mg, 4.62 mmol) in 1,4-dioxane (15 mL). Heat to 100°C and react for approximately 3 hours. After completion of the reaction, monitor the reaction by TLC. Cool to room temperature, concentrate the reaction solution, and perform preliminary separation and purification by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). After concentration, the solution was purified by HPLC to yield compound 23 (252 mg, 57.7%).

[0372] HPLC preparation method: instrument: Waters 150 MGM; chromatographic column: Chiralpak Column; mobile phase: A: carbon dioxide and B: methanol (0.1% ammonia solution); isocratic elution: 30% mobile phase B; flow rate: 100 mL / min; back pressure: 100 bar; column temperature: 25°C; wavelength: 220 nm; elution time: 2.9 min; retention time: 1.62 min.

[0373] 1 H NMR(400MHz, Methanol-d4)δ7.23(q,4H),4.81-4.76(m,1H),4.75–4.68(m,1H),4.01-3.87(m,2H),3.66-3.53(m,1H),3.44-3.33(m, 1H),3.16-3.02(m,2H),2.57-2.43(m,3H),2.43-2.23(m,4H),2.13-2.00(m,2H),2.01-1.84(m,2H),1.79(d,2H),1.75-1.61(m,2H).

[0374] LC-MS (ESI): m / z = 473.3 [M+H] + .

[0375] Example 19

[0376] Step 1: 1-Bromo-4-chlorobenzene (15.0 g, 78.3 mmol), 1,4-dioxo-8-azaspiro[4.5]decane (11.8 g, 82.2 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (2.9 g, 4.7 mmol), and tris(dibenzylideneacetone)dipalladium (2.2 g, 2.4 mmol) were dissolved in 150 mL of dioxane and stirred at room temperature for 15 minutes. Sodium tert-butoxide (0.75 g, 7.8 mmol) was added. The reaction mixture was heated to 80°C and allowed to react for 2 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The organic phases were combined, dried, and the solvent removed by rotary evaporation. Purification by silica gel column chromatography using a mobile phase of PE:EA = 20:1 afforded the target compound 24B (3.5 g, 19% yield).

[0377] LCMS (ESI): m / z = 254.2 [M+H] + .

[0378] Step 2: Dissolve 24B (3.5 g, 13.8 mmol) in 30 mL of tetrahydrofuran, add 120 mL of 10% sulfuric acid, and heat to 90°C for 12 h. After TLC confirms the reaction is complete, cool to room temperature and adjust the pH to neutral with saturated sodium bicarbonate. Wash with 100 mL of ethyl acetate (3 times), then wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to yield 24C (2.2 g, 76% yield), which is used directly in the next step.

[0379] LCMS (ESI): m / z = 210.1 [M+H] + .

[0380] Step 3: The raw material 24C (2.2 g, 10.5 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (3.82 g, 12.6 mmol) were dissolved in 25 mL of tetrahydrofuran, and DBU (1.92 g, 12.6 mmol) was added. After stirring at room temperature for 4 h, the reaction was completed after TLC monitoring. After concentration, the product was purified by silica gel column chromatography using a mobile phase system of PE:EA = 50:1 to obtain 24D (3.9 g, yield 75%).

[0381] LCMS (ESI): m / z = 492.1 [M+H] + .

[0382] Step 4: 24D (3.9 g, 8.0 mmol), pinacol diboron (2.42 g, 9.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (173 mg, 0.24 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (132 mg, 0.24 mmol) were suspended in dioxane (100 mL). The mixture was stirred at room temperature for 15 min. Potassium acetate (2.4 g, 24.5 mmol) was added, and the mixture was reacted at 90°C for 16 h. TLC and LCMS (ESI) were used to monitor the reaction. After completion of the reaction, the sample was directly subjected to silica gel column chromatography using a mobile phase of PE:EA = 20:1 to obtain the title compound 24E (0.9 g, 38% yield).

[0383] LCMS (ESI): m / z = 320.1 [M+H] + .

[0384] Step 5: Compound 24E (900 mg, 2.8 mmol) was suspended with XphosPd G2 (443 mg, 0.56 mmol), Xphos (538 mg, 1.12 mmol), and potassium phosphate (1.50 g, 7.0 mmol) 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 dropped into 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 using DCM:MeOH (15:1) as the mobile phase to obtain the target compound 24 (280 mg, 22%).

[0385] 1 H NMR(400MHz,DMSO-d6)δ7.84-7.82(s,1H),7.28-7.19(m,3H),7.03-6.94(m,2H),4.87-4.83(m,1H),3.94-3.90 (m,2H),3.77-3.73(m,2H),3.56(m,1H),3.46-3.40(m,2H),3.35-3.30(m,1H),3.20-3.07(m,1H),3.03-2.96(m 1H),2.68-2.64(s,2H),2.44-2.18(m,4H),1.88-1.72(m,2H).

[0386] LCMS (ESI): =445.1[M+H] + .

[0387] Example 20

[0388] Step 1: Weigh (3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2.12 g, 10 mmol), 2,5- Toluene (50 mL) and tert-butanol (10 mL) were added to a 250 mL three-necked flask containing dichloropyrimidine (1.64 g, 11 mmol), tris(dibenzylideneacetone)dipalladium (915 mg, 1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (952 mg, 2 mmol), and sodium tert-butoxide (1.15 g, 12 mmol). The atmosphere was replaced with nitrogen and the mixture was reacted at 100°C for 2 h. After completion of the reaction as monitored by LCMS, the system was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated and separated by silica gel column chromatography (PE:EA = 10:1 to 5:1) to obtain the target compound 25A (2.86 g, 88.2%).

[0389] LC-MS (ESI): m / z = 325.1 [M+H] + .

[0390] Step 2: 25A (2.86 g, 0.85 mmol) was dissolved in methanol (30 mL), and dioxane hydrochloride (5 mL, 4 M) solution was added. The mixture was reacted at room temperature for four hours and dried to give the title compound 25B (2.01 g, crude product).

[0391] LC-MS (ESI): m / z = 225.1 [M+H] + .

[0392] Step 3: 1E (287 mg, 1 mmol) and 25B (300 mg) were dissolved in 1,4-dioxane (20 mL), and DIPEA (1 mL) was added. The mixture was kept at 90°C overnight. LCMS detected that the reaction of the raw materials was complete. The system was concentrated, water (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 20:1 (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through a column (DCM:MeOH = 1:0 to 0:1) to obtain compound 25 (262 mg, 55.1%).

[0393] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,2H),7.22(s,1H),4.84-4.71(m,1H),3.82-3.69(m,6H),3.47-3.34(m,5H),3.2 5-3.15(m,1H),3.12-3.03(m,2H),2.96-2.79(m,2H),2.42-2.27(m,2H),2.19-2.10(m,2H),1.85-1.67(m,2H).

[0394] LC-MS (ESI): m / z = 476.5 [M+H] + .

[0395] Example 21

[0396] Step 1: Compound 8B (0.50 g, 1.75 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). A 4 N dioxane hydrochloride solution (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 26A (0.40 g, 100% yield).

[0397] LCMS m / z=186.1[M+1] + .

[0398] Step 2: Compound 1E (0.20 g, 0.69 mmol), compound 26A (0.15 g, 0.83 mmol), and N,N-dimethylethylamine (0.27 g, 2.07 mmol) were added to a 100 mL single-necked flask. After the addition was complete, the system was stirred at 90°C for 16 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yielded the title compound 26 (170 mg, 56%).

[0399] 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: 11.25 min.

[0400] LCMS m / z=437.2[M+1] + .

[0401] 1H NMR(400MHz,DMSO-d6)δ7.31(s,1H),7.25(d,1H),7.16(s,1H),7.04(s,1H),6.13(s,1H),4.82(t ,1H),4.33(s,2H),3.96(t,2H),3.74(d,2H),3.46-3.38(m,1H),3.30(s,2H),3.18-3.25(m,1H), 3.12(s,4H),2.83-2.98(m,2H),2.30-2.42(m,2H),2.15-2.23(m,2H),1.75-1.85(m,2H).

[0402] Example 22

[0403] Step 1: Weigh compound 27A (2.00 g, 10.91 mmol) and compound 27B (3.52 g, 10.91 mmol, synthesis method refer to patent WO2021158829) in a 100 mL single-necked bottle, then add 1,4-dioxane (15 mL) to dissolve, add sodium carbonate solution (2N, 15 mL), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.71 g, 1 0.09 mmol). After the addition was complete, the mixture was stirred at 100°C for 4 h. TLC analysis (petroleum ether:ethyl acetate = 5:1) indicated that the reaction was complete. Water (20 mL) was added to the reaction solution, which was stirred for 5 min. 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 27C (0.50 g, yield: 15%).

[0404] LCMS m / z=300.1[M+1] + .

[0405] Step 2: Compound 27C (0.50 g, 1.67 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). A 4 N dioxane hydrochloride solution (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 27D (0.40 g, 100% yield).

[0406] LCMS m / z=200.2[M+1] + .

[0407] Step 3: Add compound 1E (0.20 g, 0.69 mmol), compound 27D (0.17 g, 0.83 mmol), and N,N-dimethylethylamine (0.27 g, 2.07 mmol) to a 100 mL single-necked flask. After the addition is complete, the system is protected by nitrogen and stirred at 100°C for 4 h. The reaction solution is concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yields the title compound 27 (12 mg, 3.9%).

[0408] 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 ranging from 40% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 15 min; Retention time: 9.0 min.

[0409] LCMS m / z=451.6[M+1] + .

[0410] 1 H NMR(400MHz,DMSO-d6)δ7.24(s,1H),7.11(d,1H),6.97-7.00(m,2H),5.84(t,1H),5.82(t,1H),3.77-4.03(m,4H),3.71(d,2H),3.37- 3.45(m,1H),3.17-3.25(m,1H),3.09(s,4H),2.83-2.96(m,2H),3.72(m,2H),2.29-2.47(m,4H),2.12-2.18(m,2H),1.69-1.81(m,2H).

[0411] Example 23

[0412] Step 1: In a 250 mL single-necked flask, substrate 28A (5.0 g, 20.77 mmol) was dissolved in dioxane (100 mL) and water (20 mL). Sodium carbonate (6.6 g, 62.31 mmol), 1B (7.1 g, 22.85 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.5 g, 2.08 mmol) were added and stirred overnight at 100°C under nitrogen. The reaction mixture was diluted with water (50 mL) and filtered through celite. The filtrate was extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford the title compound 28B (5.0 g, 81%).

[0413] LC-MS(ESI):m / z=240.1[M-56+H] + .

[0414] Step 2: Substrate 28B (1.0 g, 3.38 mmol) was added to a 50 mL single-necked bottle, and methanol (5 mL) and dioxane hydrochloride (4 M, 5 mL) were dissolved. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated to obtain the title compound 28C (0.79 g, 100%).

[0415] LC-MS (ESI): m / z = 196.2 [M+H] + .

[0416] Step 3: Substrate 1E (0.20 g, 0.69 mmol) was added to a 50 mL single-necked bottle and dissolved in dioxane (10 mL). 28C (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 28 (130 mg, 42%).

[0417] 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.

[0418] 1H 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).

[0419] LC-MS (ESI): m / z = 447.1 [M+H] + .

[0420] Example 24

[0421] Step 1: Compound 29A (7.3 g, 40.0 mmol) was dissolved in tetrahydrofuran (100 mL). Methylmagnesium chloride solution (20.0 mL, 3.0 M in THF, 60.0 mmol) was slowly added under ice-cooling. After addition, the temperature was slowly raised to room temperature and the reaction was allowed to react for 2 h. Saturated ammonium chloride solution was added to quench the reaction. The product was extracted with ethyl acetate (50.0 mL × 3), dried, filtered, and concentrated to afford compound 29B (8.0 g, 100%), which was directly used for the next step.

[0422] LC-MS (ESI): m / z = 181.0 [M-OH] + .

[0423] Step 2: Compound 29B (8.0 g, 40.0 mmol) was dissolved in methanol (100 mL), and p-toluenesulfonic acid (350.0 mg, 2.0 mmol) was added. The mixture was heated to 70°C for 2 h, cooled to room temperature, and concentrated to remove the solvent. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 29C (2.6 g, 36%).

[0424] LC-MS (ESI): m / z = 181.0 [M+H] + .

[0425] Step 3: Compound 29C (1.8 g, 10.0 mmol) was dissolved in glacial acetic acid (3.5 mL), and then formaldehyde aqueous solution (37% in H2O, 43.0 mmol) and ammonium chloride (1.1 g, 20.0 mmol) were added. The mixture was heated to 100°C for 18 h, and then sodium hydroxide solution was added to adjust to alkalinity. The mixture was extracted with dichloromethane (50 mL × 3), dried, and concentrated to obtain compound 29D (1.9 g, 80%), which was used directly in the next step.

[0426] Step 4: Compound 29D (1.9 g, 8.0 mmol) was dissolved in concentrated hydrochloric acid (30.0 mL), heated under reflux for 3 h, cooled to room temperature, and adjusted to alkalinity by addition of sodium hydroxide solution. The mixture was extracted with ethyl acetate (50 mL × 3), dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound 29E (0.6 g, 27%).

[0427] LC-MS (ESI): m / z = 222.0 [M+H] + .

[0428] Step 5: Compound 29E (110.0 mg, 0.5 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (140.0 mg, 0.5 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 = 15 / 1) to give compound 29 (0.05 g, 21%).

[0429] LC-MS (ESI): m / z = 473.1 [M+H] + .

[0430] 1 H NMR(400MHz,DMSO-d6)δ7.39(s,1H),7.14(d,1H),6.98-6.95(m,1H),6.88(d,1H),4.85-4.82(m,1H),4.74(s,2H),4.20(s,2H),4.01- 3.98(m,2H),3.74(d,2H),3.50-3.35(m,1H),3.26-3.18(m,1H),2.97-2.84(m,2H),2.46-2.26(m,4H),2.19(s,2H),1.91-1.70(m,2H).

[0431] Example 25

[0432] Step 1: Compound 30A (7.2 g, 40.0 mmol) was dissolved in tetrahydrofuran (100 mL). Methylmagnesium chloride solution (20.0 mL, 3.0 M in THF, 60.0 mmol) was slowly added under ice-cooling. After addition, the temperature was slowly raised to room temperature and the reaction was allowed to react for 2 h. Saturated ammonium chloride solution was added to quench the reaction. The product was extracted with ethyl acetate (50.0 mL × 3), dried, filtered, and concentrated to afford compound 30B (8.0 g, 99%), which was directly used for the next step.

[0433] LC-MS (ESI): m / z = 179.0 [M-OH] + .

[0434] Step 2: Compound 30B (8.0 g, 40.0 mmol) was dissolved in methanol (100 mL), and p-toluenesulfonic acid (350.0 mg, 2.0 mmol) was added. The mixture was heated to 70°C for 2 h, cooled to room temperature, and concentrated to remove the solvent. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 30C (5.6 g, 80%).

[0435] LC-MS (ESI): m / z = 179.0 [M+H] + .

[0436] Step 3: Compound 30C (3.6 g, 20.0 mmol) was dissolved in glacial acetic acid (7.0 mL), and then formaldehyde aqueous solution (37% in H2O, 86.0 mmol) and ammonium chloride (2.2 g, 40.0 mmol) were added. The mixture was heated to 100°C for 18 h, and then sodium hydroxide solution was added to adjust to alkalinity. The mixture was extracted with dichloromethane (50 mL × 3), dried, and concentrated to obtain compound 30D (5.0 g, 89%), which was used directly in the next step.

[0437] Step 4: Compound 30D (5.0 g, 21.0 mmol) was dissolved in concentrated hydrochloric acid (50.0 mL), heated under reflux for 3 h, cooled to room temperature, and adjusted to alkalinity by addition of sodium hydroxide solution. The mixture was extracted with ethyl acetate (50 mL × 3), dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound 30E (1.0 g, 22%).

[0438] LC-MS (ESI): m / z = 220.0 [M+H] + .

[0439] Step 5: Compound 30E (110.0 mg, 0.5 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (140.0 mg, 0.5 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 = 15 / 1) to give compound 30 (0.04 g, 19%).

[0440] LC-MS (ESI): m / z = 471.1 [M+H] + .

[0441] 1H NMR(400MHz,DMSO-d6)δ7.33(s,1H),7.22(s,2H),7.20-7.13(m,1H),4.85-4.83(m,1H),4.27(s,2H),3.99(s,2H),3.75(s,2H ),3.45-3.38(m,1H),3.27-3.16(m,1H),2.97-2.83(m,2H),2.79-2.75(t,2H),2.45-2.34(m,4H),2.20(d,4H),1.79(d,,2H).

[0442] Example 26

[0443] Step 1: Compound 33A (3.00 g, 19.40 mmol) and compound 1B (7.20 g, 23.28 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (15 mL) was added to dissolve the mixture. Sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.42 g, 1.94 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100°C for 4 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, 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 33B (4.0 g, yield: 68%).

[0444] LCMS m / z=302.1[M+1] + .

[0445] 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),7.10(s,1H),4.16(s,2H),3.62(t,2H),2.92-3.00(m,4H),2.73(s,2H),2.11-2.19(m,2H),1.49(s,9H).

[0446] Step 2: Compound 33B (1.00 g, 3.32 mmol) was weighed into a 100-mL single-necked flask and dissolved in ethyl acetate (20 mL). Palladium on carbon (0.18 g, 1.66 mmol) was added to the reaction solution. After the addition was complete, the mixture was stirred under normal pressure of hydrogen for 2 h. After the reaction was completed, the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain the target compound 33C (0.90 g, yield: 89%).

[0447] LCMS m / z=304.2[M+1] + .

[0448] Step 3: Compound 33C (0.90 g, 2.97 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 to yield the target compound 33D (0.70 g, crude product).

[0449] LCMS m / z=204.1[M+1] + .

[0450] Step 4: To a 100 mL single-necked flask, add compound 1E (0.20 g, 0.69 mmol), compound 33D (0.17 g, 0.83 mmol), and N,N-diisopropylethylamine (0.26 g, 2.05 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 33 (120 mg, 38%).

[0451] 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: 10.38 min.

[0452] LCMS m / z=455.2[M+1] + .

[0453] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.29(s,1H),4.84(s,1H),4.71(d,2H),3.72(t,2H),3.37-3.45(m,1H),3.18-3.25(m,1H),2. 94-3.15(m,4H),2.82-2.89(m,5H),2.27-2.38(m,2H),2.12-2.19(m,2H),2.00-2.11(m,2H),1.86-1.93(m,2H),1.61-1.80(m,4H).

[0454] Example 27

[0455] Step 1: To a 100 mL single-necked flask, substrate 28A (1.1 g, 4.55 mmol) was dissolved in dioxane (20 mL) and water (5 mL). Sodium carbonate (1.5 g, 13.70 mmol), 34B (2.1 g, 4.55 mmol, containing 50% regioisomers, synthesis method referenced in patent WO2021158829), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.33 g, 0.45 mmol) were added. The mixture was stirred overnight at 100°C under nitrogen. The reaction mixture was diluted with water (50 mL) and filtered through celite. The filtrate was extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford the title compound 34C (1.0 g, 71%, containing 50% regioisomers).

[0456] LC-MS(ESI):m / z=254.3[M-56+H] + .

[0457] Step 2: Substrate 34C (1.0 g, 3.23 mmol) was added to a 50 mL single-necked flask, dissolved in methanol (10 mL) and dioxane hydrochloride (4 M, 10 mL), and stirred at room temperature for 3 h. The reaction solution was concentrated to obtain the title compound 34D (0.80 g, 100%, containing 50% regioisomers).

[0458] LC-MS (ESI): m / z = 210.2 [M+H] + .

[0459] Step 3: Substrate 1E (0.10 g, 0.35 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (10 mL). 34D (0.11 g, 0.52 mmol) and diisopropylethylamine (0.14 g, 1.05 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 34 (16 mg, 10%).

[0460] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@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 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 30% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 15 min; Retention time: 7.5 min.

[0461] 1H NMR(400MHz,DMSO-d6)δ8.84(s,2H),7.39(s,1H),7.24(s,1H),4.83(t,1H),3.93-3.88(m,4H),3.73-3.7 2(m,2H),3.23-3.20(m,1H),3.06-2.79(m,5H),2.60(s,2H),2.42-2.25(m,2H),2.17(s,2H),1.79(s,2H).

[0462] LC-MS (ESI): m / z = 461.2 [M+H] + .

[0463] Example 28

[0464] Step 1: Compound 35A (2.00 g, 8.79 mmol) and compound 1B (3.26 g, 10.55 mmol) were weighed into a 100 mL single-necked flask, and 1,4-dioxane (20 mL) was added to dissolve the mixture. Sodium carbonate solution (2N, 20 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.64 g, 0.88 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100°C for 4 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 35B (2.0 g, yield: 69%).

[0465] LCMS m / z=330.1[M+1] + .

[0466] 1 H NMR (400MHz, CDCl3) δ6.93(s,1H),6.91(s,1H),5.81(s,1H),4.06(d,2H),3.62(t,2H),2.38(s,2H),1.49(s,9H).

[0467] Step 2: Compound 35B (0.30 g, 1.02 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 hours. The organic phase was concentrated under reduced pressure to afford the target compound 35C (0.20 g, crude product).

[0468] LCMS m / z=230.1[M+1] + .

[0469] Step 3: Compound 1E (0.20 g, 0.69 mmol), compound 35C (0.19 g, 0.83 mmol), and N,N-diisopropylethylamine (0.26 g, 2.05 mmol) were added to a 100 mL single-necked flask. After the addition was complete, the system was protected with nitrogen and stirred at 90°C for 16 h. The reaction solution was concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yielded the title compound 35 (220 mg, 66%).

[0470] 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 ranging from 40% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 11.20 min.

[0471] LCMS m / z=481.1[M+1] + .

[0472] 1 H NMR(400MHz,DMSO-d6)δ7.35-7.40(m,3H),6.00(s,1H),4.83(t,1H),4.34(s,2H),3.96(t,2H),3.73(d,2H),3. 39-3.47(m,1H),3.19-3.26(m,1H),2.84-2.98(m,2H),2.27-2.40(m,4H),2.15-2.21(m,2H),1.69-1.82(m,2H).

[0473] Example 29

[0474] Step 1: Compound 36A (2.00 g, 9.39 mmol) was weighed into a 100 mL single-necked flask, and tetrahydrofuran (40 mL) was added to dissolve the mixture. 4-Chlorophenylmagnesium chloride (11.27 mL, 11.27 mmol) was added to the reaction solution and stirred at room temperature for 4 h. TLC (petroleum ether:ethyl acetate = 3:1) indicated complete reaction. Water (40 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 36B (2.0 g, yield: 65%).

[0475] LCMS m / z=326.1[M+1] + .

[0476] Step 2: Compound 36B (0.30 g, 0.97 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 36C (0.20 g, crude product).

[0477] LCMS m / z=208.1[M+1] + .

[0478] Step 3: Compound 1E (0.20 g, 0.69 mmol), compound 36C (0.17 g, 0.83 mmol), and N,N-diisopropylethylamine (0.26 g, 2.05 mmol) were added to a 100 mL single-necked flask. After the addition was complete, the system was protected with nitrogen and stirred at 90°C for 16 h. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to obtain the title compound 36 (88 mg, 27%).

[0479] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@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 chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonium acetate); b. Gradient elution, mobile phase A content from 30% to 90%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 12.82 min.

[0480] LCMS m / z=459.2[M+1] + .

[0481] 1 H NMR(400MHz,DMSO-d6)δ7.40(d,2H),7.32(s,1H),7.24(d,2H),4.84(t,1H),4.20(s,2H),3.94(t,2H),3.73(d,2H),3.39- 3.47(m,1H),3.19-3.27(m,1H),2.84-2.99(m,2H),2.29-2.42(m,4H),2.14-2.19(m,2H),1.73-1.84(m,2H),1.63(s,3H).

[0482] Example 30

[0483] Step 1: Compound 37A (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 atmosphere was purged with nitrogen three times, heated to 45°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 37B (1.7 g, 99%).

[0484] LC-MS (ESI): m / z = 284.1 [M-56] + .

[0485] Step 2: Compound 37B (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, and the mixture was heated to 50°C for 14 h. 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 37C (240.0 mg, 72%).

[0486] LC-MS (ESI): m / z = 302.1 [M-56] + .

[0487] Step 3: Compound 37C (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 37D (150.0 mg, 87%), which was used directly in the next step.

[0488] LC-MS (ESI): m / z = 258.1 [M+H] + .

[0489] Step 4: Compound 37D (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 37E (70.0 mg, 65%).

[0490] LC-MS (ESI): m / z = 186.1 [M+H]+ .

[0491] Step 5: Compound 37E (70.0 mg, 0.38 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (115.0 mg, 0.4 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 37 (20.0 mg, 12%).

[0492] LC-MS (ESI): m / z = 437.1 [M+H] + .

[0493] 1 H 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).

[0494] Example 31

[0495] Step 1: Under nitrogen, 38A (2.50 g, 21.5 mmol) was dissolved in dry tetrahydrofuran (80 mL). The temperature was cooled to 0°C, and a solution of 4-chlorophenylmagnesium bromide in tetrahydrofuran (32.3 mL, 32.3 mmol) was added dropwise. The temperature was maintained at 0°C for approximately 1 hour. After completion of the reaction, as monitored by TLC, saturated aqueous ammonium chloride (100 mL) was added. The reaction was allowed to warm to room temperature, and the aqueous and organic phases were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford compound 38B (4.51 g, 91.7%).

[0496] LC-MS (ESI): m / z = 229.1 [M+H] + .

[0497] Step 2: Compound 38B (4.00 g, 17.5 mmol) was dissolved in 1,2-dichloroethane (200 mL). Triethylsilane (10.2 g, 87.4 mmol) and trifluoroacetic acid (5.98 g, 52.5 mmol) were added sequentially at room temperature. The reaction was allowed to continue overnight at room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate (80 mL) and water (80 mL) were added. The aqueous and organic phases were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was initially purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford crude compound 38C. This was then purified by preparative HPLC to afford compound 38C (950 mg, 25.5%).

[0498] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 preparative liquid phase; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min. Compound 38C, retention time: 17.2 min.

[0499] 1 H NMR (400MHz, Chloroform-d) δ7.27(d,2H),7.12(d,2H),2.83(ddd,2H),2.75-2.65(m,2H),2.50(tt,1H),2.11(dq,2H),1.82(qd,2H).

[0500] Step 3: Compound 38C (600 mg, 2.82 mmol) and ammonium carbamate (418 mg, 5.36 mmol) were added to methanol (15 mL) and stirred until uniform. Iodophenyl diacetic acid (2.27 g, 7.05 mmol) was added and the mixture was allowed to react overnight in an air atmosphere at room temperature. After completion of the reaction, saturated aqueous ammonium chloride (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL x 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford compounds 38D (250 mg, 36.4%) and 38E (240 mg, 34.9%).

[0501] LC-MS (ESI): m / z = 244.1 [M+H] + .

[0502] Step 4: Under nitrogen, compound 38D (150 mg, 0.615 mmol), (R)-2-chloro-4-(1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide (230 mg, 0.800 mmol), palladium acetate (27.6 mg, 0.123 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (153 mg, 0.246 mmol), and potassium phosphate (327 mg, 1.54 mmol) were dissolved in toluene (10 mL) and heated to 110°C for approximately 5 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and initially purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). The mixture was then purified by preparative HPLC to afford compound 38-1 (95 mg, 31.2%).

[0503] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 preparative liquid phase; 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 chromatographic conditions: a. Mobile phase A and B composition: Mobile phase A: methanol; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min.

[0504] Compound 38-1, retention time 20.2 min, 1 H NMR(400MHz,DMSO-d6)δ7.42-7.32(m,3H),7.29-7.21(m,2H),4.88(t,1H),4.00-3.87(m,2H),3.77-3.63(m,2H), 3.58-3.39(m,3H),3.30-3.22(m,1H),3.12-2.83(m,3H),2.40-2.17(m,4H),2.16-2.00(m,4H),1.87-1.67(m,2H).

[0505] LC-MS (ESI): m / z = 495.1 [M+H] + ;

[0506] Referring to the above synthesis method, compound 38E (150 mg, 0.615 mmol) was used as the starting material to synthesize compound 38-2 (107 mg, 35.1%).

[0507] Compound 38-2, retention time 16.3 min, 1H NMR(400MHz,DMSO-d6)δ7.45-7.36(m,2H),7.36-7.26(m,3H),4.90(t,1H),3.89-3.75(m,2H),3.75-3.63(m,2H), 3.58-3.37(m,3H),3.29-3.22(m,1H),3.10-2.83(m,3H),2.39-2.24(m,2H),2.24-2.09(m,6H),1.86-1.65(m,2H).

[0508] LC-MS (ESI): m / z = 495.1 [M+H] + .

[0509] Example 32

[0510] Step 1: 18B (500 mg, 1.55 mmol) and dichloromethane (20 mL) were added to a 100 mL three-necked flask. The atmosphere was replaced with nitrogen. Bis(2-methoxyethyl)aminosulfur trifluoride (685 mg, 3.1 mmol) was added dropwise at -78°C and allowed to warm to room temperature for 1 h. Saturated aqueous sodium bicarbonate (50 mL) and dichloromethane (50 mL x 2) were added. 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 = 0-20%) to yield the title compound (0.5 g, 99%).

[0511] LC-MS(ESI):m / z=270.1[M-56+H] + .

[0512] Step 2: To a 50 mL single-necked flask, add 39A (0.5 g, 1.54 mmol) and hydrogen chloride-dioxane (4 M, 20 mL) in sequence. React at room temperature for 1 h. Concentrate the reaction mixture under reduced pressure to obtain the title compound (400 mg, 100%).

[0513] LC-MS (ESI): m / z = 226.1 [M+H] + .

[0514] Step 3: To a 50 mL single-necked flask were added 1E (287 mg, 1 mmol), 39B (261 mg, 1 mmol), dioxane (5 mL), and DIPEA (645 mg, 5 mmol) in sequence. The mixture was reacted at 100°C for 8 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 400 mg of the mixture.

[0515] Chiral preparations were performed to obtain the title compound 39-1 (160 mg, 33%, retention time: 1.311 min) and the title compound 39-2 (101 mg, 21%, retention time: 1.501 min). Chiral preparation method: Instrument: Waters 150 MGM; 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: 2.0 min.

[0516] Compound 39-1:

[0517] 1 H NMR (400MHz, DMSO-d6) δ7.49-7.41(m,2H),7.38-7.25(m,2H),4.91-4.79(m,2H),3.80-3.69(m,1H),3.66-3.53(m,1H),3.47-3 .31(m,2H),3.30-3.05(m,3H),3.02-2.93(m,1H),2.88-2.77(m,2H),2.49-2.14(m,6H),2.08-1.89(m,2H),1.86-1.52(m,2H).

[0518] LC-MS (ESI): m / z = 477.1 [M+H] + .

[0519] Compound 39-2:

[0520] 1 H NMR(400MHz,DMSO-d6)δ7.48-7.46(m,1H),7.38-7.32(m,2H),7.20-7.17(m,1H),7.07-7.04(m,1H),4.84-4.71(m,1H),3.81-3 .71(m,1H),3.61-3.09(m,5H),3.08-2.65(m,4H),2.49-2.11(m,6H),2.05-1.90(m,2H),1.88-1.70(m,1H),1.71-1.45(m,1H).

[0521] LC-MS (ESI): m / z = 477.1 [M+H] + .

[0522] Example 33

[0523] Step 1: To a 50 mL single-necked flask were added 40A (0.15 g, 0.52 mmol), 13C (0.21 g, 0.62 mmol), dioxane (5 mL), and DIPEA (0.34 g, 2.59 mmol) in sequence. The mixture was reacted at 100°C for 5 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH / DCM = 0-10%) to yield 220 mg of the mixture.

[0524] The title compound 40-1 (42 mg, 17%, retention time: 0.786 min) and the title compound 40-2 (82 mg, 33%, retention time: 0.993 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; 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.

[0525] Compound 40-1:

[0526] 1 H NMR (400MHz, DMSO-d6) δ7.50-7.48(m,2H),7.39-7.37(m,2H),7.18(s,1H),6.26(s,1H),4.82(s,1H),3.87(s,1H),3.79-3.54(m,5H),3.4 4-3.34(m,1H),3.22-3.12(m,2H),3.12-3.05(m,1H),2.98-2.77(m,3H),2.62(d,1H),2.40-2.29(s,2H),2.15(s,2H),1.85-1.70(m,2H).

[0527] LC-MS (ESI): m / z = 471.2 [M+H] + .

[0528] Compound 40-2:

[0529] 1H NMR (400MHz, DMSO-d6) δ7.50-7.48(m,2H),7.39-7.37(m,2H),7.18(s,1H),6.26(s,1H),4.82(s,1H),3.90-3.83(m,1H),3.79-3.54(m,5H),3.4 6-3.32(m,1H),3.24-3.13(m,2H),3.12-3.05(m,1H),2.97-2.78(m,3H) ,2.65-2.58(m,1H),2.43-2.28(m,2H),2.14(s,2H),1.85-1.68(m,2H).

[0530] LC-MS (ESI): m / z = 471.2 [M+H] + .

[0531] Example 34

[0532] Step 1: To a 50 mL single-necked flask, add 18B (0.5 g, 1.55 mmol) and hydrogen chloride-dioxane (4 M, 20 mL) in sequence. Allow to react at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to yield the title compound (400 mg, 100%).

[0533] LC-MS (ESI): m / z = 224.1 [M+H] + .

[0534] Step 2: To a 50 mL single-necked flask were added 1E (287 mg, 1.0 mmol), 41A (233 mg, 1.0 mmol), dioxane (5 mL), and DIPEA (645 mg, 5.0 mmol) in sequence. The mixture was reacted at 100°C for 8 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 410 mg of the mixture.

[0535] The title compound 41-1 (150 mg, 32%, retention time: 1.302 min) and the title compound 41-2 (100 mg, 21%, retention time: 1.488 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; 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: 2.0 min.

[0536] Compound 41-1:

[0537] 1 H NMR(400MHz,DMSO-d6)δ7.53(d,2H),7.42-7.33(m,2H),7.20(s,1H),5.43(d,1H),4.87(s,1H),4.55(d,1H),4.12-3.97(m,1H),3. 90-3.62(m,2H),3.46-3.38(m,1H),3.30-3.16(m,2H),3.01-2.81(m,2H),2.79-2.67(m,1H),2.46-2.07(m,5H),1.87-1.54(m,5H).

[0538] LC-MS (ESI): m / z = 475.2 [M+H] + .

[0539] Compound 41-2:

[0540] 1 H NMR(400MHz,DMSO-d6)δ7.55(d,2H),7.43-7.38(m,2H),5.60(d,2H),4.71-4.48(m,1H ),4.05(d,1H),3.99-2.93(m,8H),2.84(d,1H),2.44-2.13(m,5H),1.91-1.67(m,5H).

[0541] LC-MS (ESI): m / z = 475.2 [M+H] + .

[0542] Example 35

[0543] Step 1: Compound 42A (1 g, 4.44 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the nitrogen atmosphere was purged 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 42B (1.3 g, 82%).

[0544] LCMS (ESI): m / z=302.2[M+H-56].

[0545] Step 2: To compound 42B (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 42C (0.89 g, 73%).

[0546] LCMS (ESI): m / z=280.2[M+H-56].

[0547] Step 3: To compound 42C (0.89 g, 2.65 mmol) dissolved in 1,4-dioxane / water (10 ml / 2 ml) under nitrogen was added 5-chloro-2-iodopyrimidine (578 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, washed with ethyl acetate, and the filtrate was concentrated and directly purified by rapid column chromatography (eluent ratio: EA / PE = 0% to 10%) to afford the desired compound 42D (0.44 g, 52%).

[0548] LCMS (ESI): m / z=266.1 [M+H-56].

[0549] Step 4: Compound 42D (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 salt of compound 42E (170 mg).

[0550] LCMS (ESI): m / z = 222.1 [M+H] + .

[0551] Step 5: Dissolve intermediate 1E (198 mg, 0.69 mmol) in 1,4-dioxane (5 ml), add 42E (170 mg, 0.69 mmol) and diisopropylethylamine (267 mg, 2.07 mmol), and react 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. Spin dry and transfer to preparative HPLC. Separation method: 1. Apparatus: 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 and 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. The compound 42 (240 mg, 74%) was obtained at a retention time of 7.0 min.

[0552] LCMS (ESI): m / z = 473.2 [M+H] + .

[0553] Compound 42 splitting:

[0554] Compound 42 (240 mg) was used for separation to obtain compound 42-1 (retention time: 1.257 min, 74 mg, ee% = 100%) and compound 42-2 (retention time: 1.553 min, 77 mg, ee% = 100%).

[0555] Separation conditions: Instrument: Waters 150 MGM; Column: DAICEL CHIRALPAK AD; Mobile phase: A for CO2 and B for EtOH (0.1% NH3·H2O); Gradient: B 40%; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 13 min;

[0556] Compound 42-1:

[0557] 1H NMR (400MHz, CDCl3) δ = 8.61 (s, 2H), 6.85 (s, 1H), 5.91 (s, 1H), 5.11 (s, 1H), 3.99 (d, 1H), 3.84 (s, 2H), 3.78 (s, 1H), 3.70 (d, 1H), 3.64-3 .51(m,1H),3.39(d,1H),3.30(d,1H),3.24-3.12(m,1H),3.11-2.91(m,3H),2.85(d,1H),2.45-2.12(m,4H),1.91(d,2H),1.67(s,1H).

[0558] Compound 42-2:

[0559] 1 H NMR (400MHz, CDCl3) δ = 8.62 (s, 2H), 6.85 (s, 1H), 5.88 (s, 1H), 5.10 (d, 1H), 4.10-3.92 (m, 1H), 3.81 (d, 3H), 3.68 (s, 1H) ),3.58(d,1H),3.43-3.28(m,2H),3.17(s,1H),3.12-2.92(m,3H),2.85(d,1H),2.29(t,4H),1.91(d,2H),1.69(d,1H).

[0560] Example 36

[0561] Step 1: Compound 27A (1.00 g, 5.45 mmol) and compound 31A (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 4-[4-[[4-(4-[4-(4-oxo-3-nitropropene]-1-yl)propene]-4-nitro ...

[0562] LCMS m / z=315.1[M+1] + .

[0563] Step 2: Compound 31B (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 31C (0.20 g, crude product).

[0564] LCMS m / z=215.1[M+1] + .

[0565] Step 3: Compound 1E (0.20 g, 0.69 mmol), compound 31C (0.15 g, 0.69 mmol), and N,N-diisopropylethylamine (0.26 g, 2.05 mmol) were added to a 100 mL single-necked flask. After the addition was complete, the system was stirred at 90°C for 16 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to obtain the crude target compound. Preparative HPLC yielded the title compound 31 (120 mg, 37%).

[0566] 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: 10.20 min.

[0567] LCMS m / z=466.2[M+1] + .

[0568] 1 H NMR(400MHz,DMSO-d6)δ7.21(s,1H),6.85(d,1H),6.34-6.37(m,2H),4.81(t,1H),3.75-3.80(m,2H),3.72(d,2H), 3.35-3.45(m,5H),2.97-3.24(m,9H),2.81-2.94(m,2H),2.29-2.42(m,2H),2.11-2.17(m,2H),1.69-1.81(m,2H).

[0569] Example 37

[0570] Step 1: Dissolve 2,5-dichloropyrimidine (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 using a mobile phase of PE:EA = 20:1 affords the target compound 32B (8.5 g, 99% yield).

[0571] LCMS (ESI): m / z = 256.2 [M+H] + .

[0572] Step 2: 32B (8.5 g, 33.2 mmol) was dissolved in 30 mL of tetrahydrofuran, and 120 mL of 10% sulfuric acid was added. The mixture was heated to 90°C and refluxed for 12 h. After TLC confirmed the reaction was complete, the mixture was cooled to room temperature and the pH was adjusted to neutral with saturated sodium bicarbonate. The mixture was washed with 100 mL of ethyl acetate (3 x 100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The resulting solid 32C (6.2 g, 88% yield) was used directly in the next step.

[0573] LCMS (ESI): m / z = 212.3 [M+H] + .

[0574] Step 3: The raw material 32C (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 DBU (5.3 g, 35.0 mmol) was added. After stirring at room temperature for 4 h, the reaction was completed after TLC monitoring. After concentration, the product was purified by silica gel column chromatography using a mobile phase system of PE:EA = 50:1 to obtain an oily product 32D (10.6 g, yield 73%).

[0575] LCMS (ESI): m / z = 494.0 [M+H] + .

[0576] Step 4: 32D (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) were suspended in dioxane (65 mL) and stirred at room temperature for 15 min. Potassium acetate (2.58 g, 26.4 mmol) was added and the mixture was reacted at 90°C for 16 h. After completion of the reaction, the reaction was monitored by TLC and LCMS. The mixture was then purified by silica gel column chromatography using a mobile phase of PE:EA = 20:1 to afford the title compound 32E (3.37 g, 79% yield) as a white product.

[0577] LCMS (ESI): m / z = 322.4 [M+H] + .

[0578] Step 5: Compounds 32E (500 mg, 1.55 mmol) and 1E (405 mg, 1.40 mmol) were suspended with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol), and sodium carbonate (493 mg, 4.65 mmol) 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 dropwise poured into ice water and extracted three times with 20 mL of dichloromethane. The organic phases were combined, concentrated, and purified by silica gel column chromatography using a mobile phase of DCM:MeOH (15:1) to afford the title compound 32 (142 mg, 23%).

[0579] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,2H),7.84(s,1H),7.32-7.16(m,1H),4.87(t,1H),4.39(q,2H),3.94(t,2H),3.80-3.70(m,2H),3. 61-3.55(m,1H),3.35-3.29(m,1H),3.18-3.09(m,1H),3.03-2.95(m,1H),2.65-2.57(m,2H),2.49-2.12(m,4H),1.86-1.72(m,2H).

[0580] LCMS (ESI): m / z=447.6[M+H]-.

[0581] Example 38

[0582] Step 1: Dissolve starting material ±2B (1.5 g, 4.81 mmol) and Dess-Martin periodinane (5.1 g, 12.0 mmol) in 15 mL of dichloromethane and react for 4 h. After TLC confirmation of reaction completion, the reaction mixture was filtered, and the filter cake was sonicated with 15 mL of dichloromethane. The combined filtrates were then removed from the solvent using a rotary evaporator and purified by silica gel column chromatography (PE:EA = 5:1) to afford the target compound 43B (970 mg, 66% yield).

[0583] LCMS (ESI): m / z=254.2[M+H-tBu] + .

[0584] Step 2: Dissolve raw material 43B (970 mg, 3.13 mmol) in 10 mL of tetrahydrofuran and slowly add diethylaminosulfur trifluoride (2.53 g, 15.69 mmol) dropwise at -20°C for 4 h. After TLC confirmation of reaction completion, quench the reaction by adding 20 mL of saturated sodium bicarbonate in an ice bath. Extract with 20 mL x 2 of dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent removed using a rotary evaporator. The mixture is then purified by silica gel column chromatography (PE:EA = 40:1) to afford the target compound 43C (126 mg, 13% yield).

[0585] LCMS (ESI): m / z=256.3[M+H-tBu] + .

[0586] Step 3: The raw material 43C (126 mg, 0.41 mmol) was dissolved in a mixed solution of 0.5 mL of 4N dioxane hydrochloride and 0.5 mL of methanol. After stirring at room temperature for 4 h, the reaction was completed after LCMS monitoring, and the target compound 43D (84 mg, yield 98%) was obtained by concentration.

[0587] LCMS (ESI): m / z = 212.1 [M+H] + .

[0588] Step 4: Compound 43D (84 mg, 0.40 mmol) and 1E (104 mg, 0.37 mmol), and DIPEA (258 mg, 2.00 mmol) were dissolved in 2 mL of dioxane and reacted at 80°C for 4 h. After the reaction, the reaction solution was added dropwise to 10 mL of ice water and extracted three times with 10 mL x 3 dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The target compound 43 (39 mg, 23%) was obtained by HPLC.

[0589] 1H NMR(400MHz,DMSO-d6)δ7.50(s,1H),7.49-7.40(m,4H),4.86(s,1H),4.42(s,2H),3.99-3.93(m,2H),3.76-3.70(m,2H),3.51- 3.40(m,1H),3.27-3.19(m,1H),3.02-2.85(m,2H),2.61-2.51(m,2H),2.43-2.27(m,2H),2.24-2.15(m,2H),1.78-1.73(m,2H).

[0590] LCMS (ESI): =463.1[M+H] + .

[0591] 19 F NMR (376MHz, DMSO) δ-116.81.

[0592] Example 39

[0593] Step 1: Compound 44A (4.00 g, 20.67 mmol) was weighed and placed in a 100 mL single-necked flask. Anhydrous toluene (50 mL) was then added to dissolve the mixture. n-Butyl lithium (1.32 g, 20.67 mmol) was added to the reaction mixture at -78°C and stirred for 0.5 h. Compound 10A (5.24 g, 24.80 mmol) was then added. The mixture was warmed to 0°C and stirred for 2 h. TLC analysis (petroleum ether:ethyl acetate = 3:1) indicated the reaction was complete. Saturated ammonium chloride solution (50 mL) was added to the reaction mixture, stirred for 5 min, and extracted with ethyl acetate (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 44B (1.0 g, 15%).

[0594] LCMS m / z=326.1[M+1] + .

[0595] Step 2: Compound 44B (1.00 g, 3.01 mmol) was weighed into a 100 mL single-necked flask and dissolved in pyridine (15 mL). Thionyl chloride (0.22 mL) was added to the reaction solution and stirred at room temperature for 16 h. After the reaction, the filtrate was concentrated under reduced pressure until no liquid was seen. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 44C (0.26 g, 27%).

[0596] LCMS m / z=308.1[M+1] + .

[0597] Step 3: Compound 44C (0.10 g, 0.32 mmol) was weighed into a 100 mL single-necked flask and dissolved in ethyl acetate (5 mL). Palladium on carbon (0.10 g, 0.97 mmol) was added and stirred for 2 h. After completion of the reaction, the reaction mixture was filtered, and the organic phase was concentrated under reduced pressure until no liquid remained, yielding the target compound 44D (0.09 g, crude product).

[0598] LCMS m / z=310.1[M+1] + .

[0599] Step 4: Compound 44D (0.09 g, 0.29 mmol) was weighed into a 50 mL single-necked flask and dissolved in methanol (5 mL). A 4 N solution of dioxane hydrochloride (5 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid remained, yielding the target compound 44E (0.07 g, crude product).

[0600] LCMS m / z=210.2[M+1] + .

[0601] Step 5: To a 100 mL single-necked flask, add compound 1E (0.10 g, 0.35 mmol) and compound 44E (0.07 g, 0.35 mmol). Dissolve the mixture in 1,4-dioxane (10 mL). Finally, add N,N-diisopropylethylamine (0.13 g, 1.03 mmol). After the addition is complete, stir the mixture at 100°C under nitrogen for 16 h. The reaction mixture is concentrated under reduced pressure to yield the crude title compound. Preparative HPLC yields the title compound 44 (3.3 mg, 2%).

[0602] 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 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 10.20 min.

[0603] LCMS m / z=461.2[M+1] + .

[0604] 1H NMR(400MHz,DMSO-d6)δ8.86(s,2H),7.29(s,1H),4.87(t,1H),4.13(s,2H),3.95(s,2H),3.62-3.72(m,3H),3.36-3.43(m,2H), 3.14-3.25(m,1H),2.82-2.95(m,2H),2.59-2.65(m,2H),2.51-2.54(m,1H),2.23-2.41(m,2H),2.13(t,2H),1.69-1.85(m,2H).

[0605] Example 40

[0606] Step 1: Dissolve compound 42D (1 g, 3.11 mmol) in 150 ml of ethyl acetate, add palladium on carbon (100 mg), replace the hydrogen atmosphere three times, and stir overnight at room temperature under a hydrogen atmosphere. After the reaction, filter and spin-dry the mixture, and send to preparative HPLC for separation: 1. Apparatus: 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 and 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. Retention time: 10.0 min to obtain compound 45A (300 mg, 30%).

[0607] LCMS (ESI): m / z = 268.3 [M+H-56] + .

[0608] Step 2: Compound 45A (300 mg, 0.93 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 45B (242 mg).

[0609] LCMS (ESI): m / z = 224.1 [M+H] + .

[0610] Step 3: Dissolve intermediate 1E (267 mg, 0.93 mmol) in 1,4-dioxane (5 mL), add the hydrochloride salt of compound 45B (242 mg, 0.93 mmol) and diisopropylethylamine (360 mg, 2.79 mmol), and place the reaction system 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 was then spin-dried and sent for preparative HPLC separation. Method: 1. Apparatus: 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 and 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. The residue was purified by eluting with a residue of 45 (300 mg, 68%) at a retention time of 7.0 min.

[0611] LCMS (ESI): m / z = 475.2 [M+H] + .

[0612] Compound 45 splitting:

[0613] Compound 45 (130 mg) was used for separation to obtain compound 45-1 (retention time: 1.344 min, 254 mg, ee% = 100%) and compound 45-2 (retention time: 1.621 min, 20 mg, ee% = 100%).

[0614] Split conditions:

[0615] Instrument: Waters 150 MGM; Column: DAICEL CHIRALPAK AD;

[0616] 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;

[0617] Column temperature: 35°C; wavelength: 220 nm; cycle: 13 min;

[0618] Compound 45-1:

[0619] 1H NMR (400MHz, CDCl3) δ = 8.58 (s, 2H), 5.94 (s, 1H), 5.17 (s, 1H), 3.85 (s, 2H), 3.75-3.70 (m, 2H), 3.68-3.48 (m, 4H) ),3.43-3.36(m,1H),3.09-2.94(m,2H),2.88(s,2H),2.44-2.37(m,2H),2.36-2.17(m,4H),2.02-1.81(m,4H).

[0620] Compound 45-2:

[0621] 1 H NMR (400MHz, CDCl3) δ = 8.60 (s, 2H), 5.93 (s, 1H), 3.92-3.85 (m, 4H), 3.64-3.58 (m, 2H), 3.53-3.39 (m, 3H), 3 .15-2.96(m,4H),2.33(s,2H),2.33-2.23(m,5H),2.09-2.01(m,2H),2.00-1.94(m,1H),1.94-1.87(m,1H).

[0622] Example 41

[0623] Step 1: To compound 42C (1 g, 2.99 mmol) dissolved in 1,4-dioxane / water (10 ml / 2 ml) under nitrogen was added 4-bromophenylcyclobutane (497 mg, 2.71 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (220 mg, 0.3 mmol), and sodium carbonate (951 mg, 8.97 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 46A (0.44 g, 52%).

[0624] LCMS (ESI): m / z = 256.2 [M+H-56] + .

[0625] Step 2: Compound 46A (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 46B (170 mg).

[0626] LCMS (ESI): m / z = 212.1 [M+H] + .

[0627] Step 3: Dissolve intermediate 1E (200 mg, 0.69 mmol) in 1,4-dioxane (5 mL). Add the hydrochloride salt of compound 46B (170 mg) and diisopropylethylamine (267 mg, 2.07 mmol). The reaction system was 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 was then spin-dried and sent for preparative HPLC separation. Method: 1. Apparatus: 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 and 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. The retention time was 7.0 min to obtain compound 46 (200 mg, 63%).

[0628] LCMS (ESI): m / z = 463.3 [M+H] + .

[0629] Compound 46 splitting:

[0630] Compound 46 (200 mg) was used for separation to obtain compound 46-1 (retention time: 1.214 min, 73 mg, ee% = 100%) and compound 46-2 (retention time: 1.541 min, 68 mg, ee% = 100%).

[0631] Split conditions:

[0632] Instrument: Waters 150 MGM; Column: DAICEL CHIRALPAK AD;

[0633] 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;

[0634] Column temperature: 35°C; wavelength: 220 nm; cycle: 13 min;

[0635] Compound 46-1:

[0636] 1H NMR (400MHz, CDCl3) δ = 7.24 (s, 1H), 7.11 (s, 1H), 6.99 (d, 1H), 5.95 (s, 1H), 5. 89(s,1H),4.08-3.87(m,1H),3.88-3.78(m,3H),3.80-3.65(m,2H),3.64-3.5 2(m,2H),3.44-3.33(m,1H),3.32-3.19(m,1H),3.15(s,4H),3.13-3.05(m,1H ),3.06-2.92(m,3H),2.72-2.58(m,1H),2.36-2.21(m,4H),1.98-1.85(m,2H).

[0637] Compound 46-2:

[0638] 1 H NMR (400MHz, CDCl3) δ = 7.24 (s, 1H), 7.12 (s, 1H), 6.99 (d, 1H), 5.95 (s, 1H), 5.88 (s, 1H), 4.04-3.91 (m, 1H), 3.84 (d, J = 14.1, 2H), 3.80-3.6 6(m,2H),3.60(s,2H),3.44-3.20(m,2H),3.15(s,4H),3.13-3.06(m, 1H),3.00(t,3H),2.64(d,1H),2.43-2.14(m,4H),1.98-1.80(m,2H).

[0639] Example 42

[0640] Step 1: To a 250 mL single-necked flask were added 47A (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 47B (10.0 g, 64.5% yield).

[0641] LC-MS (ESI): m / z = 336.2 [M+H] + .

[0642] Step 2: To a 250 mL single-necked flask were added 47B (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 47C (7.0 g, 76.9% yield).

[0643] LC-MS (ESI): m / z = 306.2 [M+H] + .

[0644] 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 chloride (1.2 g, 11.8 mmol) in sequence. The mixture was heated to 65°C, and a solution of 47C (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 heating was stopped, 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 47D (0.4 g, 12.6% yield).

[0645] LC-MS(ESI):m / z=269.2[M-56+H] + .

[0646] Step 4: To a 50 mL single-necked flask were added 47D (0.4 g, 1.2 mmol) and hydrogen chloride-dioxane solution (4N, 10 mL) in sequence. The mixture was reacted at room temperature for 1 h and concentrated under reduced pressure to afford 47E (0.4 g, 100.0% yield).

[0647] LC-MS (ESI): m / z = 225.1 [M+H] + .

[0648] Step 5: To a 50 mL single-necked flask, 1E (344 mg, 1.2 mmol), 47E (400 mg, 1.2 mmol), dioxane (5 mL), and DIPEA (774 mg, 6.0 mmol) were added sequentially and 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.

[0649] The title compound 47-1 (90 mg, 31.6%, retention time: 1.897 min) and the title compound 47-2 (80 mg, 28.0%, retention time: 2.355 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: isopropanol (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: 20 min.

[0650] (Compound 47-1)

[0651] 1 H NMR(400MHz,DMSO-d6)δ7.45(s,1H),6.92(d,1H),6.86-6.81(m,1H),6.77(d,1H), 4.93-4.80(m,1H),4.77-4.58(m,2H),4.45-4.30(m,1H),4.05-3.92(m,1H),3.88- 3.78(m,1H),3.77-3.65(m,2H),3.52-3.39(m,1H),3.26-3.17(m,1H),3.14-2.84( m,4H),2.77-2.57(m,2H),2.40-2.25(m,2H),2.23-2.14(m,2H),1.89-1.66(m,2H).

[0652] LC-MS (ESI): m / z = 476.2 [M+H] + .

[0653] (Compound 47-2)

[0654] 1 H NMR(400MHz,DMSO-d6)δ7.45(s,1H),6.92(d,1H),6.86-6.80(m,1H),6.77(d,1H), 4.90-4.78(m,1H),4.80-4.58(m,2H),4.43-4.31(m,1H),4.07-3.93(m,1H),3.89- 3.80(m,1H),3.76-3.68(m,2H),3.52-3.38(m,1H),3.27-3.17(m,1H),3.13-2.83( m,4H),2.76-2.57(m,2H),2.44-2.25(m,2H),2.24-2.12(m,2H),1.86-1.66(m,2H).

[0655] LC-MS (ESI): m / z = 476.2 [M+H] + .

[0656] Example 43

[0657] Step 1: Add tert-butyl nitrite (3.55 g, 34.38 mmol) and cuprous iodide (5.24 g, 27.50 mmol) to acetonitrile (70 mL). Heat the mixture to 65°C, then add a solution of 48A (7 g, 22.92 mmol) in acetonitrile (20 mL) dropwise. Maintain the reaction at 65°C for 4 h. Cool the mixture to room temperature, concentrate the reaction mixture under reduced pressure, add water (50 mL), wash with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by silica gel column chromatography (eluent: EA / PE = 0-25%) to afford crude product 48B (5 g). Use directly in the next step.

[0658] LC-MS(ESI):m / z=361.3[M+H-56] + .

[0659] Step 2: 48B (5 g), trimethylethynylsilane (1.42 g, 14.41 mmol), bistriphenylphosphine palladium dichloride (0.84 g, 1.20 mmol), cuprous iodide (0.46 g, 2.40 mmol), and triethylamine (3.65 g, 36.03 mmol) were added to tetrahydrofuran (40 mL). After nitrogen replacement, the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA / PE = 0-25%) to afford 3.5 g of the crude product. The product was then purified using a C18 reverse phase column with mobile phases A: acetonitrile and B: water (containing 0.1% TFA) (A / B = 25% / 75%) to afford 48C (2 g, 43%).

[0660] LC-MS (ESI): m / z = 387.2 [M+H] + .

[0661] Step 3: 48C (1.5 g, 3.88 mmol) and potassium carbonate (1.07 g, 7.76 mmol) were added to methanol (15 mL) and reacted at room temperature for 3 h. LC-MS monitored the reaction for completion. Most of the methanol was concentrated under reduced pressure, and water (20 mL) was added. The product was extracted with ethyl acetate (20 mL x 2). 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 to yield 48D (1.1 g, 90.18%).

[0662] LC-MS (ESI): m / z = 315.5 [M+H] + .

[0663] Step 4: 48D (0.35 g, 1.11 mmol) and triethylamine (1.12 g, 11.11 mmol) were added to dichloromethane (15 mL), followed by the dropwise addition of trimethylsilyl iodide (1.34 g, 6.69 mmol). The mixture was allowed to react at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to yield crude product 48E (1.7 g). This was then used directly in the next reaction.

[0664] LC-MS (ESI): m / z = 215.5 [M+H] + .

[0665] Step 5: Crude 48E (1.7 g), 1E (0.32 g, 1.1 mmol), and N,N-diisopropylethylamine (0.57 g, 4.41 mmol) were added to 1,4-dioxane (15 mL). The mixture was heated to 100°C and reacted 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 0.4 g of the mixture. Chiral preparation afforded 48-1 (120 mg, 23.4%, retention time: 1.249 min) and 48-2 (130 mg, 25.4%, retention time: 1.586 min). Chiral preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Chromatographic column: ChiralPak AD, 250×30 mm ID, 10 μm; Mobile phase: A: carbon dioxide and B: isopropanol (0.1% ammonia); Isocratic elution: 40% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 38°C; Wavelength: 220 nm; Elution time: 3.4 min.

[0666] (Compound 48-1)

[0667] 1 H NMR(400MHz, CDCl3)δ7.02-7.00(m,1H),6.92(d,1H),6.72(d,1H),6.13(s,1H),4.86 -4.65(m,2H),4.31-4.25(m,1H),4.14-3.93(m,2H),3.90-3.80(m,2H),3.79-3.72(m, 1H),3.65-3.53(m,1H),3.45-3.36(m,1H),3.24-3.12(m,2H),3.10-2.97(m,2H),2.9 6(s,1H),2.85-2.72(m,2H),2.39-2.29(m,2H),2.28-2.19(m,2H),2.01-1.83(m,2H).

[0668] LC-MS (ESI): m / z = 466.6 [M+H] + .

[0669] (Compound 48-2)

[0670] 1 H NMR(400MHz, CDCl3)δ7.04-6.99(m,1H),6.92(d,1H),6.72(d,1H),6.12(s,1H),4.88 -4.62(m,2H),4.33-4.25(m,1H),4.15-3.95(m,2H),3.90-3.79(m,2H),3.78-3.72(m, 1H),3.65-3.54(m,1H),3.45-3.35(m,1H),3.23-3.13(m,2H),3.10-2.96(m,2H),2.9 6(s,1H),2.85-2.73(m,2H),2.39-3.00(m,2H),2.29-2.18(m,2H),2.01-1.84(m,2H).

[0671] LC-MS (ESI): m / z = 466.6 [M+H] + .

[0672] Example 44

[0673] Step 1: Compound 49A (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 with stirring and reacted overnight. The mixture was cooled to room temperature, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness to obtain compound 49B (24 g, crude product), which was used directly in the next step without isolation and purification.

[0674] LCMS(ESI):=235.1,237.1[M+H] + .

[0675] Step 2: The crude product 49B (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 column chromatography (DCM:MeOH, v / v = 10:1) to obtain compound 49C (8 g, two-step yield 48.7%).

[0676] LCMS (ESI): =172.1[M+H]+ .

[0677] Step 3: Compound 49C (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 off. The solvent was dried to obtain compound 49D (3.25 g, 36%).

[0678] LCMS (ESI): =140.0 [M+H] + .

[0679] Step 4: 49D (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. 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 49E (4.45 g, 79.6%).

[0680] LCMS (ESI): =184.1 [M+H] + .

[0681] Step 5: Dissolve 49E (4.45 g, 18.60 mmol) in tetrahydrofuran (50 mL) under nitrogen atmosphere and cool with ice-water. 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-water, 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 49F (2.26 g, 53.9%).

[0682] LCMS (ESI): =170.1[M+H] + .

[0683] Step 6: 49F (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 4-dimethylaminopyridine (123 mg, 1.00 mmol) were added. 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 h, and the mixture was directly spin-dried. The mixture was separated by silica gel column chromatography (EA:PE = 1:3) to give 49G (2.26 g, 74.1%).

[0684] LCMS(ESI):=248.1,250.1[M+H] + .

[0685] Step 7: 49G (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 49H (640 mg, 58.0%).

[0686] LCMS(ESI):=280.1,282.1[M+H] + .

[0687] Step 8: 49H (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 49I (300 mg, crude product), which was used directly in the next step.

[0688] LCMS(ESI):=236.1,238.1[M+H] + .

[0689] Step 9: Compound 49I (0.28 g, 1.18 mmol) and 1E (0.34 g, 1.18 mmol) were dissolved in 1,4-dioxane (10 ml), and N,N-diisopropylethylamine (0.46 g, 3.54 mmol) was added. The temperature was raised to 100°C and the reaction was allowed to proceed for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was heated to 70°C with acetonitrile / water (v / v = 9 / 1, 5 mL) and hot-beaten for 1 hour. The mixture was then hot-filtered. The filter cake was rinsed with a small amount of acetonitrile and dried to obtain the title compound 49 (350.0 mg, 60.9%).

[0690] 1 H NMR(400MHz,DMSO-d6)δ7.69-7.64(m,2H),7.51-7.47(m,3H),4.92-4.70(m,4H),3.81(s,2H), 3.67-3.62(m,1H),3.39-3.32(m,2H),3.07-3.03(m,1H),2.39-2.30(m,4H),1.87-1.84(m,2H).

[0691] MS M / Z(ESI): m / z=487.1[M+1] + .

[0692] Example 45

[0693] Step 1: Compound 37B (2.0 g, 5.9 mmol) was dissolved in N,N-dimethylformamide (50 ml), and zinc cyanide (0.7 g, 5.9 mmol) and tetrakis(triphenylphosphine)palladium (0.7 g, 5.9 mmol) were added. The nitrogen atmosphere was evacuated three times, and the temperature was raised to 90°C. After reacting for 3 h, the mixture was passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 9) to give compound 50A (1.5 g, 89%).

[0694] LC-MS (ESI): m / z = 287.4 [M+H] + .

[0695] Step 2: Compound 50A (1.5 g, 5.2 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (6.0 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 50B (0.9 g, 92%), which was used directly in the next step.

[0696] LC-MS (ESI): m / z = 187.2 [M+H] + .

[0697] Step 3: Compound 50B (0.9 mg, 4.8 mmol) was dissolved in 1,4-dioxane (50.0 mL), and compound 1E (1.4 g, 4.8 mmol) and N,N-diisopropylethylamine (0.7 g, 5.3 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 50 (0.3 g, 14%).

[0698] LC-MS (ESI): m / z = 438.5 [M+H] + .

[0699] 1 H NMR(400MHz, CDCl3)δ8.92(s,1H),7.52(s,1H),6.21(s,1H),4.55(s,1H),4.05(t,2H),3.93-3.82(m,2H),3.65-3.57 (m,1H),3.43-3.35(m,1H),3.08-2.99(m,2H),2.78(s,2H),2.39-2.31(m,2H),2.31-2.25(m,2H),1.97-1.84(m,2H).

[0700] Example 46

[0701] Step 1: Compound 51A (0.9 g, 3.2 mmol) was dissolved in 1,4-dioxane (40 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (0.2 mg, 0.3 mmol), cesium carbonate (2.1 g, 6.3 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 g, 3.5 mmol), and water (10 mL) were added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 90°C for 4 h. The mixture was passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 51B (0.7 g, 57%).

[0702] LC-MS (ESI): m / z = 386.4 [M+H] + .

[0703] Step 2: Compound 51B (0.7 g, 1.8 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.8 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 51C (0.5 g, 96%), which was used directly in the next step.

[0704] Step 3: Compound 50C (0.5 mg, 1.8 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (0.5 g, 1.8 mmol) and N,N-diisopropylethylamine (1.8 g, 14.5 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 51 (0.5 g, 53%).

[0705] LC-MS (ESI): m / z = 537.1 [M+H] + .

[0706] 1H NMR(400MHz, CDCl3)δ7.74(s,1H),7.64(d,1H),7.51(d,1H),7.43(t,1H),6.34(s,1H),6.18(s,1H),4.43(s,2H),4.07(s,2H),3.90–3.8 1(m,2H),3.67–3.59(m,1H),3.42-3.34(m,1H),3.08-3.04(m,2H),2.61(s,2H),2.40-2.33(m,2H),2.27-2.22(m,2H),1.96-1.83(m,2H).

[0707] 19 F NMR (377MHz, CDCl3) δ64.91(s), 64.62(s).

[0708] Example 47

[0709] Step 1: Compound 52A (1.0 g, 3.8 mmol) was dissolved in 1,4-dioxane (40 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (0.3 mg, 0.4 mmol), cesium carbonate (2.5 g, 7.7 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.3 g, 4.3 mmol) and water (10 mL) were added. The atmosphere was purged with nitrogen three times, heated to 90°C for 3 h, and then passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 52B (1.3 g, 94%).

[0710] LC-MS (ESI): m / z = 360.4 [M+H] + .

[0711] Step 2: Compound 52B (1.3 g, 3.6 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.8 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 52C (0.8 g, 85%), which was used directly in the next step.

[0712] Step 3: Compound 52C (0.7 mg, 2.7 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (0.78 g, 2.7 mmol) and N,N-diisopropylethylamine (1.1 g, 8.1 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 52 (0.55 g, 40%).

[0713] LC-MS (ESI): m / z = 511.1 [M+H] + .

[0714] 1 H NMR(400MHz, CDCl3)δ7.66(s,1H),7.55(d,1H),7.50(d,1H),7.39(t,1H),6.18(s,1H),6.13(s,1H),4.41(s,2H),4.35(s,1H),4.0 5(s,2H),3.87(s,2H),3.65–3.57(m,1H),3.43–3.35(m,1H),3.08-2.96(m,2H),2.60(s,2H),3.35-3.25(m,4H),2.00-1.85(m,2H).

[0715] 19 F NMR (377MHz, CDCl3) δ-40.50 (s).

[0716] Example 48

[0717] Step 1: Compound 37B (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, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 53A (820.0 mg, 91%).

[0718] LC-MS (ESI): m / z = 302.1 [M+H] + .

[0719] Step 2: Compound 53A (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 53B (1.0 g, 99%), which was used directly in the next step.

[0720] LC-MS (ESI): m / z = 202.1 [M+H] + .

[0721] Step 3: Compound 53B (400.0 mg, 2.0 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (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 53 (180.0 mg, 20%).

[0722] LC-MS (ESI): m / z = 453.1 [M+H] + .

[0723] 1 H NMR(400MHz,DMSO-d6)δ8.54(s,2H),7.35(s,1H),7.18(s,1H),4.86-4.83(m, 1H),4.43(s,2H),3.97-3.94(m,2H),3.75(d,2H),3.45-3.38(m,1H),3.23-3.1 8(m,1H),3.00-2.78(m,2H),2.64(s,2H),2.43-2.29(m,2H),2.22-2.18(m,2H ),2.02-1.89(m,1H),1.89-1.69(m,2H),1.13-0.96(m,2H),0.89-0.77(m,2H).

[0724] Example 49

[0725] Step 1: Compound 37B (1.0 g, 2.9 mmol) was dissolved in toluene (50 mL), and tris(dibenzylideneacetone)dipalladium (266.1 mg, 0.29 mmol), 2-(di-tert-butylphosphino)biphenyl (179.0 mg, 0.6 mmol), and sodium tert-butoxide (576.0 mg, 6.0 mmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C for 3 h. The mixture was then passed through a silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 9) to give compound 54A (258.0 mg, 23%).

[0726] LC-MS (ESI): m / z = 389.2 [M+H] + .

[0727] Step 2: Compound 54A (258.0 mg, 0.66 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (3.0 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 54B (218.0 mg, 99%), which was used directly in the next step.

[0728] LC-MS (ESI): m / z = 289.2 [M+H] + .

[0729] Step 3: Compound 54B (218.0 mg, 0.66 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (190.0 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.35 g, 2.6 mmol) were added. The mixture was heated to 90°C for 3 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 54 (0.06 g, 17%).

[0730] LC-MS (ESI): m / z = 540.2 [M+H] + .

[0731] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,2H),7.30(s,1H),6.86(s,1H),4.80-4.78(m,1H),4.31(s,2H),3.87(s,2H),3.76-3.47(m,6H),3.37-3.31(m,1 H),3.17-3.09(m,1H),2.90-2.76(m,2H),2.55(s,2H),2.34-2.21(m,2H ),2.15-2.10(m,2H),1.83-1.60(m,2H),0.76-0.53(m,4H),0.00(s,6H).

[0732] Example 50

[0733] Step 1: Compound 55A (750 mg, 4.6 mmol) was dissolved in 1,4-dioxane (12 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (340 mg, 0.46 mmol), cesium carbonate (4.5 g, 13.8 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.1 g, 6.89 mmol) and water (3 mL) were added. The atmosphere was purged with nitrogen three times, heated to 90°C for 16 h, and then passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 55B (0.8 g, 66%).

[0734] LC-MS (ESI): m / z = 266.1 [M+H] + .

[0735] Step 2: Compound 55B (400 mg, 1.51 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. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried and concentrated to obtain compound 55C (240 mg, 96%), which was used directly in the next step.

[0736] LC-MS (ESI): m / z = 166.1 [M+H] + .

[0737] Step 3: Compound 55C (390 mg, 1.36 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (220 mg, 1.33 mmol) and N,N-diisopropylethylamine (530 mg, 4.08 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 55 (440 mg, 78%).

[0738] LC-MS (ESI): m / z = 417.2 [M+H] + .

[0739] 1 H NMR(400MHz, CDCl3)δ6.75-6.70(m,1H),6.24(s,1H),4.46(s,2H),4.03(s,2H),3.95-3.79(m,2H),3.67-3.53(m, 1H),3.44-3.34(m,1H),3.10-2.96(m,2H),2.76-2.68(m,2H),2.54(s,3H),2.42-2.20(m,4H),2.00-1.78(m,2H).

[0740] Example 51

[0741] Step 1: Compound 56A (2.00 g, 7.67 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.84 mg, 9.19 mmol) were suspended in 50 mL of a 4:1 dioxane:water mixture at 80°C for 16 h. After completion of the reaction, the reaction solution was added dropwise to 100 mL of ice water and filtered. The filtrate was extracted with dichloromethane (100 mL x 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 40:1) to afford the target compound 56B (420 mg, 17%).

[0742] LCMS (ESI): m / z = 317.1 [M+H] + .

[0743] Step 2: Compound 56B (420 mg, 1.33 mmol) was dissolved in 2 mL of methanol, and 2 mL of hydrochloric acid / dioxane was added. The mixture was stirred at room temperature for 1.5 h and filtered. The filter cake was the target compound 56C (260 mg, 77%), which was used directly in the next step without purification.

[0744] LCMS (ESI): m / z = 217.1 [M+H] + .

[0745] Step 3: Compound 56C (200 mg, 1.02 mmol) and intermediate 1E (355 mg, 1.23 mmol) were suspended in 2 mL of dioxane and reacted at 80°C for 16 h. After completion of the reaction, the mixture was filtered. The filter cake was slurried with 5 mL of methanol, stirred at room temperature for 0.5 h, and filtered. The filter cake yielded the target compound 56 (190 mg, 51%).

[0746] LCMS (ESI): m / z = 468.1 [M+H] + .

[0747] 1 H NMR(400MHz,DMSO-d6)δ8.07(d,1H),7.97(d,1H),7.53-7.47(m,1H),7.46-7.37(m,2H),6.92-6.89(m,1H),4.84(t,1H),4.47(s,2H),4.01(t,2 H),3.76(d,2H),3.50-3.39(m,1H),3.29-3.17(m,1H),3.02-2.83(m,2H ),2.76(s,2H),2.44-2.29(m,2H),2.29-2.17(m,2H),1.91-1.61(m,2H).

[0748] Example 52

[0749] Step 1: Compound 57A (3.00 g, 16.92 mmol) and tert-butyl piperazine-1-carboxylate (3.78 g, 20.30 mmol) were weighed into a 100-mL single-necked flask, 1,4-dioxane (30 mL) was dissolved, and N,N-diisopropylethylamine (6.56 g, 50.76 mmol) was added. After the addition was complete, the mixture was stirred at 80°C for 16 h. The reaction was complete as determined by TLC (petroleum ether:ethyl acetate = 5:1). Water (20 mL) was added and stirred for 5 min. The mixture was extracted with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 57B (2.8 g, yield: 48%).

[0750] LCMS m / z=343.1[M+1] + .

[0751] Step 2: Compound 57B (1.0 g, 2.92 mmol) and trimethylethynylsilane (1.43 g, 14.61 mmol) were weighed into a 100 mL stew pot and dissolved in tetrahydrofuran (20 mL). Triethylamine (1.21 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.24 g, 0.29 mmol), and cuprous iodide (56 mg, 0.29 mmol) were added. After addition, the mixture was stirred at 80°C for 12 h. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). Water (20 mL) was added, stirred for 5 min, and extracted with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 57C (0.50 g, 47%).

[0752] LCMS m / z=361.1[M+1] + .

[0753] Step 3: Compound 57C (0.5 g, 1.39 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (10 mL). Potassium carbonate (0.58 g, 4.2 mmol) was added and stirred at room temperature for 2 h. TLC (petroleum ether:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction mixture was filtered, the filtrate concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the target compound 57D (0.40 g, 100%).

[0754] LCMS m / z=289.2[M+1] + .

[0755] Step 4: Compound 57D (0.2 g, 0.69 mmol) was weighed into a 100 mL single-necked flask and dissolved in methanol (5 mL). A dioxane hydrochloride solution (4N, 5 mL) was added. After the addition was complete, the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to obtain the target compound 57E (0.15 g, crude product).

[0756] LCMS m / z=189.1[M+1] + .

[0757] Step 5: To a 100 mL single-necked flask, add compound 1E (200 mg, 0.66 mmol), dissolve in 1,4-dioxane (8 mL), and then add compound 57E (131 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.26 g, 1.98 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, which is then separated by preparative HPLC to afford the title compound 57 (100 mg, 33%).

[0758] 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: 10.50 min.

[0759] LCMS m / z=440.2[M+1] + .

[0760] 1 H NMR(400MHz,DMSO-d6)δ8.51(s,2H),7.46(s,1H),4.85(t,1H),4.31(s,1H),3.83(s,8H),3.72(d,2H),3.33- 3.45(m,1H),3.15-3.25(m,1H),2.84-2.98(m,2H),2.26-2.40(m,2H),2.13-2.17(m,2H),1.71-1.82(m,2H).

[0761] Example 53

[0762] Step 1: Under nitrogen, 58A (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, then cooled to -78°C. A solution of iodine (2.56 g, 10.07 mmol) in tetrahydrofuran (10 mL) was added. The system was 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 obtain the crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 58B (700 mg, yield: 34.03%).

[0763] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.73(m,2H),7.38-7.36(m,2H).

[0764] Step 2: Compound 58B (700 mg, 2.86 mmol), [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (910 mg, 4.00 mmol), potassium carbonate (990 mg, 7.14 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg, 0.14 mmol) were added to a reaction flask. 20 mL of tetrahydrofuran and water (5 mL) were added. After nitrogen was replaced, the temperature was raised to 85°C and the reaction mixture was reacted for 16 h. The starting material disappeared after spotting on a microplate reader. The mixture was diluted 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 obtain the crude product. The crude product was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 58C (850 mg, yield: 99.06%).

[0765] LC-MS (ESI): m / z = 301.2 [M+H] + .

[0766] 1 H NMR (400MHz, CDCl3) δ7.72-7.70(m,1H),7.51-7.48(m,1H),7.33-7.31(m,2H) ,6.97(s,1H),4.21-4.20(m,2H),3.68-3.65(m,2H),2.76(s,2H),1.50(s,9H).

[0767] Step 3: Dissolve compound 58C (850 mg, 2.83 mmol) in 20 mL of dichloromethane, add dioxane hydrochloride (4 mL), and stir at 0°C for 30 min. After the disappearance of the starting material by spot plate detection, the reaction solution was concentrated at room temperature to obtain crude product 58D (850 mg), which was used directly in the next reaction.

[0768] Step 4: Compound 1E (300 mg, 1.04 mmol) and compound 58D (320 mg, 1.36 mmol) were dissolved in 1,4-dioxane (8 mL), and then DIPEA (405 mg, 3.13 mmol) was added. After the addition was complete, the temperature was raised 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: DCM:MeOH = 100:1 to 9:1) and further purified by preparative HPLC (preparative method: instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@PrepC18 (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 90%; c. flow rate: 15 mL / min; d. elution time: 15 min; retention time: 6.0 min) to obtain the title compound 58 (105 mg, 22.30%).

[0769] LCMS m / z=452.2[M+H] + .

[0770] 1 H NMR (400MHz, CDCl3) δ7.73-7.70(m,1H),7.52-7.50(m,1H),7.34-7.31(m,2H),7.05(s,1H),6.24(s,1H),4.52(s,2H),4.08(s,2H ),3.92-3.84(m,2H),3.67-3.58(m,1H),3.43-3.35(m,1H),3.09-2.99(m,2H),2.83(s,2H),2.42-2.23(m,5H),1.99-1.84(m,2H).

[0771] Example 54

[0772] Step 1: 37B (1.1 g, 3.23 mmol) was added to a 100 mL single-necked flask and dissolved in dioxane (20 mL). Dimethylphosphine oxide (0.38 g, 4.88 mmol), anhydrous potassium phosphate (0.75 g, 3.53 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g, 0.65 mmol), and tris(dibenzylideneacetone)dipalladium (0.30 g, 0.32 mmol) were added sequentially. The mixture was reacted at 100 °C under nitrogen for 7 h. The mixture was concentrated and purified by column chromatography (DCM:MeOH = 10:1) to give the title compound 59A (0.8 g, 73%).

[0773] LC-MS(ESI):m / z=282.4[M-56+H] + .

[0774] Step 2: In a 50 mL single-necked bottle, 59A (0.5 g, 1.48 mmol) was added, methanol (10 mL) and dioxane hydrochloride (4 M, 10 mL) were dissolved, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated to obtain the title compound 59B (0.40 g, 100%).

[0775] LC-MS (ESI): m / z = 238.1 [M+H] + .

[0776] Step 3: 1E (0.15 g, 0.52 mmol) was added to a 50 mL single-necked bottle and dissolved in dioxane (10 mL). 59B (0.25 g, 1.06 mmol) and diisopropylethylamine (0.27 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 59 (23 mg, 7%).

[0777] 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 0.1% TFA); b. Gradient elution, mobile phase A content from 5% to 60%; c. Flow rate: 15 mL / min; d. Elution time: 15 min; Retention time: 8.0 min.

[0778] 1H NMR(400MHz,DMSO-d6)δ9.08(d,2H),8.29-8.14(m,1H),7.46-7.38(m,1H),4.50(s,2H),3.99(t,2H),3.80-3.74(m,2H),3.6 1-3.49(m,1H),3.34-3.24(m,1H),3.15-3.09(m,1H),3.04-2.92(m,1H),2.74(s,2H),2.42-2.19(m,4H),1.85-1.76(m,8H).

[0779] LC-MS (ESI): m / z = 489.5 [M+H] + .

[0780] Example 55

[0781] Step 1: Compound 60A (800 mg, 4.94 mmol) was dissolved in 1,4-dioxane (20 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (360 mg, 0.49 mmol), cesium carbonate (4.83 g, 14.82 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.29 g, 7.41 mmol) and water (4 mL) were added. The atmosphere was purged with nitrogen three times, heated to 90°C for 16 h, and then passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 60B (0.9 g, 69%).

[0782] LC-MS (ESI): m / z = 265.1 [M+H] + .

[0783] Step 2: Compound 60B (5800 mg, 1.89 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. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried and concentrated to obtain compound 60C (300 mg, 97%), which was used directly in the next step.

[0784] LC-MS (ESI): m / z = 165.1 [M+H] + .

[0785] Step 3: Compound 60C (300 mg, 1.04 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (170 mg, 1.04 mmol) and N,N-diisopropylethylamine (400 mg, 3.12 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 60 (340 mg, 79%).

[0786] LC-MS (ESI): m / z = 416.2 [M+H] + .

[0787] 1 H NMR(400MHz, CDCl3)δ7.30(d,1H),6.71-6.67(m,1H),6.30(s,1H),4.42(s,2H),4.01(s,2H),3.93-3.77(m,2H),3.67-3 .54(m,1H),3.42-3.32(m,1H),3.09-2.96m,2H),2.72-2.64(m,2H),2.45-2.20(m,4H),2.18(d,3H),1.97-1.79(m,2H).

[0788] Example 56

[0789] Step 1: Methanol (10 mL), 48B (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 61A (0.3 g, 86.1% yield).

[0790] LC-MS(ESI):m / z=235.2[M-56+H] + .

[0791] Step 2: 61A (0.3 g, 1.03 mmol) and hydrogen chloride-dioxane solution (4N, 15 mL) were added sequentially to a 50 mL single-necked bottle. The mixture was reacted at room temperature for 1 hour and concentrated under reduced pressure to obtain 61B (0.27 g, 99.6% yield).

[0792] LC-MS (ESI): m / z = 191.2 [M+H] + .

[0793] Step 3: To a 50 mL single-necked flask were added 1E (287 mg, 1.0 mmol), 61B (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.

[0794] The title compound 61-1 (62 mg, 14.1%, retention time: 1.733 min) and the title compound 61-2 (51 mg, 11.5%, retention time: 1.884 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; 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.

[0795] (Compound 61-1)

[0796] 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).

[0797] LC-MS (ESI): m / z = 442.2 [M+H] + .

[0798] (Compound 61-2)

[0799] 1H 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),4.02-3.81(m,2H),3.79-3.68(m,2H),3.51-3.39(m,1H ),3.26-3.16(m,1H),3.14-2.83(m,4H),2.76-2.55(m,2H),2.43-2.25(m,2H),2.26-2.13(m,2H),1.89-1.69(m,2H).

[0800] LC-MS (ESI): m / z = 442.2 [M+H] + .

[0801] Example 57

[0802] Step 1: Compound 62A (1.0 g, 4.5 mmol) was dissolved in DMF (30 mL), and cesium carbonate (2.2 g, 6.7 mmol) and 4-chlorobenzyl bromide (1.4 g, 6.7 mmol) were added. The atmosphere was purged with nitrogen three times and heated to 50°C for 5 h. The mixture was then passed through a silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give a mixture of 62B-1 and 62B-2 (0.5 g, 32%).

[0803] LC-MS (ESI): m / z = 348.8 [M+H] + .

[0804] Step 2: Dissolve the mixture of compounds 62B-1 and 62B-2 (0.5 g, 1.4 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (2.5 mL), react at room temperature for half an hour, and concentrate to obtain a mixture of compounds 62C-1 and 62C-2 (0.3 g, 85%), which is directly used in the next step.

[0805] Step 3: Dissolve the mixture of compounds 62C-1 and 62C-2 (0.3 g, 1.2 mmol) in 1,4-dioxane (30.0 mL), add compound 1E (0.35 g, 1.2 mmol) and N,N-diisopropylethylamine (0.47 g, 3.7 mmol), heat back to 90 ° C for 12 h, cool to room temperature, concentrate, and column chromatography (dichloromethane / methanol = 10 / 1) to obtain a crude mixture of compounds 62-1 and 62-2.

[0806] The crude mixture of compound 62-1 and 62-2 (380 mg) was subjected to chiral resolution to give compound 62-1 (175 mg) and compound 62-2 (45 mg).

[0807] Preparation method: Instrument: Waters 150 SFC, column: Chiralpak AS, mobile phase: (A for CO2 and B for MeOH (0.1% NH3·H2O); gradient: 35% phase B elution; flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25°C, wavelength: 220 nm, cycle time: 2.2 min. Sample preparation: sample concentration 10 mg / mL, acetonitrile solution injection: 3.5 mL each time. After separation, the fractions were dried by rotary evaporation at a bath temperature of 35°C to obtain P1 (retention time: 1.905 minutes, set as compound 62-1) and P2 (retention time: 2.072 minutes, set as compound 62-2).

[0808] LC-MS (ESI): m / z = 499.6 [M+H] + .

[0809] 1 H NMR (400MHz, DMSO-d6) δ7.64(s,1H),7.4-7.38(m,2H),7.34(s,1H),7.25-7.23(m,2H),5.22(s,1H),4.82(t,2H),4.76(s,2H),4.03-3.98(m,2H ),3.73(d,2H),3.45-3.36(m,1H),3.22-2.18(m,1H),2.95-2.82(m,2H) ,2.67(t,2H),2.37-2.27(m,2H),2.22-2.14(m,2H),1.82-1.73(m,2H).

[0810] LC-MS (ESI): m / z = 499.7 [M+H] + .

[0811] 1H NMR(400MHz, CDCl3)δ7.38(s,1H),7.29–7.27(m,2H),7.07(s,1H),7.05(s,1H),5.98(s,1H),5.19(s,2H),4.79(s,2H),4.07(s,2H ),3.91-3.83(m,2H),3.62–3.54(m,2H),3.41–3.32(m,2H),3.07-2.94(m,2H),2.62(t,2H),2.34-2.23(m,2H),1.97-1.86(m,2H).

[0812] Example 58

[0813] Step 1: Under nitrogen, 63A (5.00 g, 17.67 mmol) was dissolved in N,N-dimethylformamide (60 mL). Dimethylphosphine oxide (1.70 g, 21.20 mmol), palladium acetate (0.43 g, 1.77 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (2.00 g, 3.53 mmol), and potassium phosphate (10.00 g, 47.11 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the reaction mixture was heated to 100°C and stirred for 16 h. The mixture was then cooled to room temperature and concentrated under reduced pressure using an oil pump. The reaction mixture was diluted 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 obtain a crude product, which was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain the target compound 63B (2.00 g, yield: 48.56%).

[0814] 1 H NMR (400MHz, CDCl3) δ7.89-7.85(m,1H),7.69-7.64(m,2H),7.40-7.29(m,1H),1.76(s,3H),1.73(s,3H).

[0815] Step 2: Under nitrogen, compound 63B (2.00 g, 8.58 mmol) was added to a mixture of 1,4-dioxane (40 mL) and water (8 mL). [1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (2.34 g, 10.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (630 mg, 0.86 mmol), and potassium carbonate (3.56 g, 25.75 mmol) were added sequentially with stirring at room temperature. After the additions were complete, the reaction mixture was heated to 85°C and stirred under nitrogen for 16 h. The disappearance of the starting material was confirmed by spotting the reaction mixture, which was then cooled to room temperature. The mixture was concentrated under reduced pressure, diluted with water (100 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain the target compound 63C (2.50 g, yield: 86.86%).

[0816] LC-MS(ESI):m / z=280.60[M+H-56] + .

[0817] 1 H NMR (400MHz, CDCl3) δ7.80-7.77(m,1H),7.53-7.51(m,1H),7.48-7.44(m,2H),6.11(s,1H) ,4.09-4.08(m,2H),3.66-3.60(m,2H),2.55(s,2H),1.76(s,3H),1.73(s,3H),1.48(s,9H).

[0818] Step 3: Dissolve compound 63C (1.10 g, 3.28 mmol) in 20 mL of dichloromethane, add dioxane hydrochloride (4 mL), and stir at 0°C for 30 min. After TLC analysis confirmed the disappearance of the starting material, the reaction solution was concentrated at room temperature to afford crude product 63D (800 mg), which was used directly in the next reaction.

[0819] Step 4: Compound 1E (500 mg, 1.74 mmol) and compound 63D (800 mg, 2.94 mmol) were dissolved in 1,4-dioxane (8 mL), followed by the addition of DIPEA (675 mg, 5.21 mmol). After the addition was complete, the mixture was heated to 85°C and stirred for 16 hours under nitrogen. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 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 obtain the target compound 63 (320 mg, 37.85%).

[0820] LCMS m / z=487.3[M+H] + .

[0821] 1 H NMR(400MHz,DMSO-d6)δ7.82-7.79(m,1H),7.68-7.61(m,2H),7.51-7.47(m,1H),7.39 (s,1H),6.35(s,1H),4.87-4.85(m,1H),4.38(s,2H),4.00-3.98(m,2H),3.76-3.75(m,2H),3.48-2.39(m,1H),3.26-3.18( m,1H),2.98-2.84(m,2H),2.57(s,2H),2.43-2.30(m,2H),2.23-2.17(m,2H),1.86-1.73(m,2H),1.67(s,3H),1.64(s,3H).

[0822] Example 59

[0823] Step 1: Compound 37B (3.4 g, 10 mmol) was dissolved in N,N-dimethylformamide (100 mL), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (725 mg, 1.0 mmol), potassium fluoride (1.7 g, 30 mmol), 4-isoxazoleboronic acid pinacol ester (2.4 g, 12 mmol), and water (30 mL) were added. The atmosphere was purged with nitrogen three times, heated to 90°C for 4 h, and then passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 64A (1.3 g, 39%).

[0824] LC-MS (ESI): m / z = 329.1 [M+H] + .

[0825] Step 2: Compound 64A (1.3 g, 4.0 mmol) was dissolved in methanol (40 mL), and potassium fluoride (0.7 g, 12 mmol) and water (12 mL) were added. The mixture was heated to 90°C for 4 h, passed through a short silica gel column, washed with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 64B (1.0 g, 84%).

[0826] LC-MS (ESI): m / z = 301.2 [M+H] + .

[0827] Step 3: Compound 64B (1.0 g, 3.3 mmol) was dissolved in water (5 mL), and tetrabutylammonium bromide (96 mg, 0.3 mmol), 1,2-dibromoethane (751 mg, 4 mmol) and potassium hydroxide (560 mg, 10 mmol) were added. The mixture was heated to 50°C for 4 h, passed through a short silica gel column, washed with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 64C (0.7 g, 65%).

[0828] LC-MS (ESI): m / z = 327.2 [M+H] + .

[0829] Step 4: Compound 64C (0.7 g, 2.1 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.8 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 64D (0.4 g, 90%), which was used directly in the next step.

[0830] Step 5: Compound 64D (0.4 mg, 1.7 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (0.5 g, 1.8 mmol) and N,N-diisopropylethylamine (1.8 g, 14.5 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 64 (0.4 g, 49%).

[0831] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0832] 1 H NMR(400MHz, CDCl3)δ8.77(s,2H),7.36(s,1H),7.29(s,1H),4.84(t,1H),4.46(s,2H),3.97(t,2H),3.75(d,2H),3.47–3.39(m,1H),3.26–3 .18(m,1H),2.98–2.92(m,1H),2.89–2.84(m,1H),2.66(s,2H),2.43– 2.30(m,2H),2.23–2.18(m,2H),1.84–1.75(m,4H),1.71–1.67(m,2H).

[0833] Example 60

[0834] Step 1: To a 3 L three-necked flask, add methyl thiocyanate (131.45 g, 1.80 mol) and dissolve it in 1,2-dichloroethane (1.2 L). Add trifluoromethanesulfonic anhydride (265.7 g, 0.94 mol) and slowly add cyclobutanone (60.0 g, 0.86 mol) dropwise at room temperature. Stir overnight at room temperature. The reaction mixture is washed with saturated sodium bicarbonate solution and adjusted to pH 8-9. The organic phase is allowed to stand and decompose. The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:EA = 100:1-20:1). Recrystallization (EA:PE = 1:2) affords the title compound 65C (15.0 g, 9% yield).

[0835] LCMS m / z=199.1[M+1] + .

[0836] Step 2: In a 500 mL single-necked flask, 65C (15.0 g, 75.6 mmol) was added and dissolved in dichloromethane (300 mL). m-Chloroperbenzoic acid (78.3 g, 453.8 mmol) was added and stirred at room temperature overnight. The reaction mixture was washed with 10% sodium hydroxide (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1-EA) to obtain the target compound 65D (3.8 g, 19% yield).

[0837] LCMS m / z=263.1[M+1] + .

[0838] Step 3: 65D (3.8 g, 14.5 mmol) was added to a 100 mL single-necked flask and dissolved in dichloromethane (40 mL). Ammonia (20 mL) was added and stirred at room temperature for 4 h. The reaction mixture was separated, and the aqueous phase was extracted once with dichloromethane (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:EA = 2:1-EA) to afford the target compound 65E (2.2 g, 76% yield).

[0839] LCMS m / z=200.1[M+1] + .

[0840] Step 4: To a 100 mL single-necked flask, 65E (2.2 g, 11.04 mmol) was added and dissolved in acetonitrile (40 mL). Isoamyl nitrite (3.9 g, 33.12 mmol) and copper bromide (4.9 g, 22.07 mmol) were added, and the mixture was stirred at 75°C under nitrogen for 6 h. The reaction mixture was concentrated, water (100 mL) was added, and the mixture was extracted with dichloromethane (2 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 3:1 to 1:1) to obtain the target compound 65G (2.0 g, 69% yield).

[0841] LCMS m / z=263.0[M+1] + .

[0842] Step 5: In a 100 mL single-necked flask, 65G (2.0 g, 7.6 mmol) was added and dissolved in ethyl acetate (40 mL). Palladium on carbon (10%, 6.0 g) was added and stirred at 60°C for 72 h. The reaction mixture was filtered through Celite, the filtrate was concentrated, and purified by column chromatography (DCM:EA = 2:1-EA) to afford the title compound 65H (0.48 g, 34% yield).

[0843] LCMS m / z=185.1[M+1] + .

[0844] Step 6: In a 50 mL single-necked vial, 65H (0.18 g, 0.98 mmol) was added and dissolved in dioxane (8 mL). 31A (0.42 g, 1.96 mmol) and N,N-diisopropylethylamine (0.38 g, 2.94 mmol) were then added and stirred at 95°C overnight. The reaction mixture was concentrated and purified by column chromatography (DCM:EA = 5:1 to 1:1) to afford the target compound 65I (60 mg, 19% yield).

[0845] LCMS m / z=317.2[M+1] + .

[0846] Step 7: In a 50 mL single-necked flask, add 65I (60 mg, 0.19 mmol) and dissolve in dioxane (3 mL). Add 4 M hydrogen chloride in dioxane (3 mL) and stir at room temperature for 4 h. The reaction mixture was concentrated to afford the target compound 65J (48 mg, 100% yield), which was used directly in the next step.

[0847] LCMS m / z=217.2[M+1] + .

[0848] Step 8: 1E (42 mg, 0.15 mmol) was added to a 50 mL single-necked vial and dissolved in dioxane (6 mL). 65J (48 mg, 0.18 mmol) and N,N-diisopropylethylamine (59 mg, 0.45 mmol) were then added sequentially. Stir at 95°C overnight. The reaction mixture was concentrated and purified by HPLC to afford the title compound 65 (30 mg, 43% yield).

[0849] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@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 chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonium acetate); b. Gradient elution, mobile phase A content ranging from 20% to 70%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 9.5 min.

[0850] LCMS m / z=468.1[M+1] + .

[0851] 1 H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.23(s,1H),4.81(s,1H),3.83-3.66(m,6H),3.43-3.35(m,6H),3.23- 3.18(m,2H),3.07-3.00(m,4H),2.94-2.76(m,2H),2.42-2.26(m,2H),2.17-2.12(m,2H),1.84-1.68(m,2H).

[0852] Example 61

[0853] Step 1: Under nitrogen, compound 66A (10.00 g, 31.96 mmol) was added to a mixture of 1,4-dioxane (100 mL) and water (10 mL). [1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (7.98 g, 35.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.30 g, 3.20 mmol), and potassium carbonate (11.04 g, 79.89 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the reaction mixture was heated to 85°C and stirred for 16 h. The starting material disappeared by TLC, and the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to a small volume, diluted with water (150 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 a crude product, which was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain the target compound 66B (8.00 g, yield: 67.98%).

[0854] LC-MS(ESI):m / z=312.20&314.20[M+H-56] + .

[0855] 1H NMR (400MHz, CDCl3) δ7.51-7.46(m,2H),7.15-7.12(m,1H),6.04(s,1H),4. 73(s,2H),4.05-4.03(m,2H),3.62-3.60(m,2H),2.49(s,2H),1.48(s,3H).

[0856] Step 2: Under nitrogen, compound 66B (2.00 g, 5.43 mmol) was dissolved in dichloromethane (40 mL). Triethylamine (1.37 g, 13.58 mmol) was added with stirring on an ice bath, followed by the slow dropwise addition of acetyl chloride (0.49 g, 6.25 mmol). After the addition was complete, the reaction mixture was stirred at 0°C for 1 h. The starting material disappeared by TLC, and the reaction was quenched with saturated aqueous ammonium chloride (100 mL). The mixture was then extracted three times with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (eluent: PE:EA = 100:1 to 4:1) to obtain the target compound 66C (2.00 g, yield: 95.96%).

[0857] 1 H NMR (400MHz, CDCl3) δ7.54-7.52(m,1H),7.40-7.39(m,1H),7.20-7.17(m,1H),6.05(s,1H) ,5.19(s,2H),4.07-4.06(m,2H),3.65-3.62(m,2H),2.50(s,2H),2.14(s,3H),1.49(s,9H).

[0858] Step 3: Under nitrogen, compound 66C (2.00 g, 4.87 mmol) was dissolved in 1,4-dioxane (80 mL). Diboron (1.49 g, 5.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (178 mg, 0.24 mmol), and potassium acetate (1.44 g, 14.62 mmol) were added sequentially with stirring at room temperature. After the additions were complete, the reaction mixture was heated to 80°C and stirred for 5 h. The starting material disappeared by TLC, and the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to a small volume, diluted 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 crude product 66D (2.5 g), which was used directly in the next step.

[0859] Step 4: Dissolve crude compound 66D (2.5 g, 5.47 mmol) in methanol (60 mL), then add 1M sodium hydroxide solution (655 mg, 16.40 mmol). Stir under nitrogen for 16 hours at room temperature. The reaction mixture is concentrated to a small volume under reduced pressure, diluted with water (50 mL), and extracted twice with ethyl acetate (100 mL). The aqueous phase is further concentrated and purified on a reverse-phase column (eluent: water:acetonitrile = 100:1 to 1:9) to yield compound 66E (1.20 g, 69.66%).

[0860] LCMS m / z=260.30[M-56+H] + .

[0861] 1 H NMR(400MHz,D2O)δ7.34-7.32(m,1H),7.18-7.16(m,1H),7.11(s,1H),5.9 6(s,1H),4.63(s,2H),3.93(s,2H),3.50(s,2H),2.41(s,2H),1.34(s,9H).

[0862] Step 5: Dissolve compound 66E (380 mg, 1.21 mmol) in dichloromethane (6 mL). Add 4M dioxane hydrochloride (176 mg, 4.82 mmol) under ice-cooling. Stir under nitrogen for 1.5 h. The reaction mixture was concentrated under reduced pressure to afford crude compound 66F (310 mg), which was used directly in the next reaction.

[0863] LCMS m / z=216.30[M+H] + .

[0864] Step 6: Compound 1E (300 mg, 1.04 mmol) and compound 66F (310 mg, 1.23 mmol) were dissolved in 1,4-dioxane (8 mL), followed by the addition of DIPEA (405 mg, 3.13 mmol). After the addition was complete, the mixture was heated to 85°C and stirred for 16 hours under nitrogen. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 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 obtain the target compound 66 (150 mg, 30.85%).

[0865] LCMS m / z=467.20[M+H] + .

[0866] 1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.70-7.68(m,1H),7.46-7.44(m,2H),7. 38(s,1H),6.34(s,1H),4.98(s,2H),4.87-4.84(m,1H),4.37(s,2H),4.00-3.9 7(m,2H),3.76-3.75(m,2H),3.47-3.39(m,1H),3.26-3.18(m,1H),2.98-2.84 (m,2H),2.56(s,2H),2.43-2.30(m,2H),2.22-2.18(m,2H),1.82-1.76(m,2H).

[0867] Example 62

[0868] Step 1: To a 250 mL single-necked flask were added 67A (5.0 g, 31.3 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (6.8 g, 31.3 mmol), potassium hydroxide (5.3 g, 93.9 mmol), and N,N-dimethylformamide (100 mL). The mixture was allowed to react at room temperature for 6 hours. The temperature was then raised to 80°C and the reaction was continued for 24 hours. The filtrate was filtered and added with ethyl acetate (500 mL). The mixture was washed with water (100 mL x 3) and saturated brine (100 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 67B (10.0 g, 95.2% yield).

[0869] LC-MS(ESI):m / z=281.1[M-56+H] + .

[0870] Step 2: To a 1000 mL single-necked flask were added 67B (10.0 g, 29.8 mmol), ethyl acetate (300 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 67C (8.0 g, 87.9% yield).

[0871] LC-MS (ESI): m / z = 307.1 [M+H] + .

[0872] Step 3: Acetonitrile (30 mL), tert-butyl nitrite (3.5 g, 33.83 mmol), and cuprous iodide (5.1 g, 27.06 mmol) were added sequentially to a 100 mL single-necked flask and heated to 65°C. A solution of 67C (6.9 g, 22.55 mmol) in acetonitrile (40 mL) was added dropwise. After the addition was complete, the mixture was reacted at 65°C for 4 hours. After turning off the heating, the reaction was continued for 12 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to give 67D (1.5 g, 15.6% yield).

[0873] LC-MS (ESI): m / z = 418.4 [M+H] + .

[0874] Step 4: To a 100 mL single-necked flask were added 67D (1.4 g, 3.36 mmol), tetrahydrofuran (30 mL), cuprous iodide (127 mg, 0.67 mmol), triethylamine (1.0 g, 10.08 mmol), bistriphenylphosphine palladium dichloride (238 mg, 0.34 mmol), and trimethylsilylacetylene (1.01 g, 5.05 mmol) in sequence under nitrogen protection. The reaction was carried out at room temperature for 6 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 67E (1.2 g, 92.3% yield).

[0875] LC-MS (ESI): m / z = 388.2 [M+H] + .

[0876] Step 5: To a 50 mL single-necked flask were added 67E (1.2 g, 3.1 mmol), methanol (30 mL), and potassium carbonate (1.3 g, 9.3 mmol) in sequence. The mixture was reacted at room temperature for 2 h. The reaction was filtered and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to give 67F (0.8 g, 81.9% yield).

[0877] LC-MS (ESI): m / z = 316.1 [M+H] + .

[0878] Step 6: 67F (0.3 g, 0.95 mmol), triethylamine (1.9 g, 19 mmol), and iodotrimethylsilane (1.9 g, 9.5 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was reacted at room temperature for 2 h. After concentration under reduced pressure, the crude product 67G was obtained, which was directly used for the next step.

[0879] LC-MS (ESI): m / z = 216.1 [M+H] + .

[0880] Step 7: To a 50 mL single-necked flask were added 1E (273 mg, 0.95 mmol), 67G (crude product 0.8 g, 0.95 mmol), dioxane (5 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.

[0881] The title compound 67-1 (80 mg, 18.06%, retention time: 1.855 min) and the title compound 67-2 (50 mg, 11.31%, retention time: 2.423 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% ammonia); Isocratic elution: 30% mobile phase B; Flow rate: 150 mL / min; Back pressure: 100 bar; Column temperature: 38°C; Wavelength: 220 nm; Elution time: 3.9 min.

[0882] (Compound 67-1)

[0883] 1 H NMR (400MHz, DMSO-d6) δ7.90-7.83(m,1H),7.46(s,1H),7.09-7.04(m,1H),4.87-4.79(m,1H),4.81-4.60(m,2H),4.52-4.35(m,2H),4.08(s ,1H),4.04-3.95(m,1H),3.78-3.65(m,2H),3.51-3.37(m,2H),3.28- 3.15(m,1H),3.07-2.74(m,5H),2.43-2.16(m,4H),1.86-1.70(m,2H).

[0884] LC-MS (ESI): m / z = 467.1 [M+H] + .

[0885] (Compound 67-2)

[0886] 1H NMR (400MHz, DMSO-d6) δ7.96-7.71(m,1H),7.47(s,1H),7.25-6.78(m,1H),4.88-4.64(m,3H),4.53-4.36(m,2H),4.08(s,1H), 4.04-3.90(m,1H),3.72(s,2H),3.48-3.39(m,2H),3.27-3.21(m,1H),3.06-2.75(m,5H),2.40-2.17(m,4H),1.87-1.72(m,2H).

[0887] LC-MS (ESI): m / z = 467.1 [M+H] + .

[0888] Example 63

[0889] Step 1: To a 100 mL single-necked flask were added acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), and cuprous chloride (1.2 g, 11.8 mmol) in sequence. The mixture was heated to 65°C, and a solution of 67C (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 heat, 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 68A (0.5 g, 13.7% yield).

[0890] LC-MS(ESI):m / z=270.1[M-56+H] + .

[0891] Step 2: 68A (0.5 g, 1.5 mmol) and hydrogen chloride-dioxane solution (4N, 10 mL) were added sequentially to a 50 mL single-necked bottle. The mixture was reacted at room temperature for 1 hour and concentrated under reduced pressure to obtain 68B (0.5 g, 100.0% yield).

[0892] LC-MS (ESI): m / z = 226.1 [M+H] + .

[0893] Step 3: To a 50 mL single-necked flask were added 1E (430 mg, 1.5 mmol), 68B (500 mg, 1.5 mmol), dioxane (5 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 500 mg of the mixture.

[0894] The title compound 68-1 (50 mg, 7.0%, retention time: 1.704 min) and the title compound 68-2 (110 mg, 15.4%, retention time: 2.183 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; 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: 4 min.

[0895] (Compound 68-1)

[0896] 1 H NMR(400MHz,DMSO-d6)δ7.77-7.73(m,1H),7.48(s,1H),7.21-7.15(m,1H),4.88-4.81(m,1H),4.80-4.59(m,2H),4.48-4.33(m,2H),4.09-3.9 5(m,1H),3.79-3.68(m,2H),3.47-3.34(m,2H),3.28-3.17(m,1H),3.07 -2.84(m,3H),2.80-2.67(m,2H),2.42-2.15(m,4H),1.87-1.67(m,2H).

[0897] LC-MS (ESI): m / z = 477.1 [M+H] + .

[0898] (Compound 68-2)

[0899] 1 H NMR (400MHz, DMSO-d6) δ7.77-7.73(m,1H),7.48(s,1H),7.19-7.15(m,1H),4.90-4.82(m,1H),4.82-4.63(m,2H),4.47-4.31(m,2H),4.10-3.9 4(m,1H),3.76-3.67(m,2H),3.48-3.33(m,2H),3.27-3.17(m,1H),3.06 -2.84(m,3H),2.80-2.69(m,2H),2.38-2.15(m,4H),1.87-1.68(m,2H).

[0900] LC-MS (ESI): m / z = 477.1 [M+H] + .

[0901] Example 64

[0902] Step 1: Compound 69A (10 g, 84.6 mmol) and paraformaldehyde (25.4 g, 0.85 mol) were dissolved in acetic acid (30 mL). 40% hydrobromic acid solution (49.2 mL, 0.85 mol) was slowly added at 0°C and stirred for 30 min. The mixture was heated to 80°C for 12 h, concentrated, and purified by column chromatography (pure petroleum ether) to give compound 69B (2 g, 8%).

[0903] Step 2: Compound 69B (1.0 g, 3.3 mmol) was dissolved in ethanol (30 mL) and benzylamine (0.35 g, 3.3 mmol). The mixture was heated under reflux for 4 h, passed through a short silica gel column, washed with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 69C (0.6 g, 73%).

[0904] LC-MS (ESI): m / z = 250.4 [M+H] + .

[0905] Step 3: Compound 69C (0.5 g, 2.0 mmol) was dissolved in methanol (30 mL), and palladium on carbon (50 mg) was added. The mixture was ventilated with a hydrogen balloon three times, reacted at room temperature for 12 h, filtered, concentrated, and purified by column chromatography (methanol / triethylamine = 100 / 1) to give compound 69D (0.2 g, 62%).

[0906] LC-MS (ESI): m / z = 160.2 [M+H] + .

[0907] Step 4: Compound 69D (0.2 mg, 1.3 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (0.36 g, 1.3 mmol) and N,N-diisopropylethylamine (0.32 g, 2.6 mmol) were added. The mixture was heated to 90°C for 4 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 69 (0.1 g, 19%).

[0908] LC-MS (ESI): m / z = 411.2 [M+H] + .

[0909] 1H NMR (400MHz, CDCl3) δ7.38–7.32(m,1H),7.23–7.12(m,2H),4.91–4.85(m,1H),4.78–4.71(m,3H),3.79(d,2H),3.49–3.41(m,1H),3 .27–3.15(m,1H),3.00–2.94(m,1H),2.94–2.83(m,5H),2.44–2.33(m,2H),2.25–2.20(m,2H),2.08–1.99(m,2H),1.87–1.74(m,2H).

[0910] Example 65

[0911] Step 1: Compound 70A (1.2 g, 5.0 mmol) was dissolved in tetrahydrofuran (50 mL), and bis(triphenylphosphine)palladium dichloride (350.0 mg, 0.5 mmol), triethylamine (1.1 g, 10.0 mmol), trimethylsilyl acetylene (650.0 mg, 6.5 mmol) and cuprous iodide (40.0 mg, 0.25 mmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 50°C for 14 h. The mixture was passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 70B (800 mg, 76%).

[0912] Step 2: Compound 70B (420.0 mg, 2.0 mmol) was dissolved in 1,4-dioxane (30 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (144.0 mg, 0.2 mmol), potassium carbonate (560.0 mg, 4.0 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (720.0 mg, 2.4 mmol) and water (6.0 mL) were added. The nitrogen atmosphere was replaced three times, and the mixture was heated to 45 ° C. and reacted 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 70C (400 mg, 56%).

[0913] LC-MS (ESI): m / z = 357.2 [M+H] + .

[0914] Step 3: Compound 70C (356.0 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.2 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 70D (150.0 mg, 78%), which was used directly in the next step.

[0915] LC-MS (ESI): m / z = 257.1 [M+H] + .

[0916] Step 4: Compound 70D (128.1 mg, 0.5 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (172.0 mg, 0.6 mmol) was added. The mixture was heated to 90°C for 4 h, cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 70E (200 mg, 79%).

[0917] LC-MS (ESI): m / z = 508.2 [M+H] + .

[0918] Step 5: Compound 70E (200.0 mg, 0.4 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 70 (110.0 mg, 62%).

[0919] LC-MS (ESI): m / z = 436.2 [M+H] + .

[0920] 1 H NMR(400MHz, CDCl3)δ8.66(d,1H),7.74–7.72(m,1H),7.35(d,1H),6.75(t,1H),6.57(s,1H),4.47(s,2H),4.06(s,2H),3.87–3.79(m,2H),3 .65–3.57(m,1H),3.40–3.32(m,1H),3.23(s,1H),3.08–2.98(m,2H), 2.71(s,2H),2.43–2.35(m,2H),2.26–2.18(m,2H),1.96–1.78(m,2H).

[0921] Example 66

[0922] Step 1: Compound 71A (5.00 g, 22.60 mmol) and dimethylphosphine oxide (2.65 g, 33.90 mmol) were weighed into a 250 mL single-necked flask and dissolved in 1,4-dioxane (50 mL). Potassium phosphate (14.39 g, 67.80 mmol), tris(dibenzylideneacetone)dipalladium (1.03 g, 1.13 mmol), and 5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.31 g, 2.26 mmol) were added. After the addition was complete, the mixture was stirred at 90°C for 16 h. The reaction was complete as determined by TLC (petroleum ether:ethyl acetate = 5:1). Water (50 mL) was added, stirred for 5 min, and extracted with ethyl acetate (50 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 = 1:1) to obtain the target compound 71B (2.2 g, yield: 57%).

[0923] LCMS m / z=172.1[M+1] + .

[0924] Step 2: Compound 71B (2.2 g, 12.85 mmol) was weighed into a 100 mL single-necked flask and dissolved in acetonitrile (30 mL). Isoamyl nitrite (3.01 g, 25.70 mmol) and cuprous bromide (4.37 g, 19.22 mmol) were added and stirred at 70°C for 12 h. TLC (petroleum ether:ethyl acetate = 5:1) confirmed the reaction was complete. Water (50 mL) was added, stirred for 5 min, and extracted with ethyl acetate (50 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 = 3:1) to obtain the target compound 71C (0.43 g, 14% yield).

[0925] LCMS m / z=235.0[M+1] + .

[0926] Step 3: Compound 71C (0.20 g, 0.85 mmol) and compound 1B (0.32 g, 1.02 mmol) were weighed into a 100 mL single-necked flask, 1,4-dioxane (8 mL) was dissolved, 2N sodium carbonate solution (2 mL) and tetrakistriphenylphosphine palladium (0.1 g, 0.09 mmol) were added, and the mixture was stirred at 90°C for 16 h. The reaction was complete as determined by TLC (petroleum ether:ethyl acetate = 5:1). Water (20 mL) was added, stirred for 5 min, and extracted with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 71E (1.0 g, yield: 58%).

[0927] LCMS m / z=338.1[M+1] + .

[0928] Step 4: Compound 71E (0.20 g, 0.59 mmol) was weighed into a 100 mL single-necked flask and dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added and stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid remained, yielding the target compound 71F (0.20 g, crude product).

[0929] LCMS m / z=238.1[M+1] + .

[0930] Step 5: To a 100 mL single-necked flask, add compound 1E (150 mg, 0.52 mmol), compound 71F (150 mg, 0.62 mmol), and dissolve in 1,4-dioxane (10 mL). Then, add N,N-diisopropylethylamine (0.16 g, 1.56 mmol). After the addition is complete, stir the system at 90°C under nitrogen for 16 h. The reaction mixture is concentrated under reduced pressure to obtain the crude product, which is then separated by preparative HPLC to afford the title compound 71 (110 mg, 43%).

[0931] 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 70%; c. Flow rate: 15 mL / min; d. Elution time: 20 min; Retention time: 11.20 min.

[0932] LCMS m / z=489.2[M+1] + .

[0933] 1 H NMR(400MHZ,DMSO-d6)δ8.99(t,1H),7.79(t,1H),7.38(s,2H),4.84(t,1H),4.48(s,2H),3.99(t,2H),3.75(d,2H),3.48-3.39(m,1H), 3.26-3.18(m,1H),2.98-2.84(m,2H),2.70(s,2H),2.42-2.30(m,2H),2.24-2.18(m,2H),1.86-1.76(m,2H),1.73(s,3H),1.70(s,3H).

[0934] Example 67

[0935] Step 1: To a 50 mL single-necked flask, 65H (90 mg, 0.49 mmol) was added and dissolved in dioxane (6 mL). Piperazine (84 mg, 0.98 mmol) was added and stirred at 90°C for 3 h. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the target compound 72A (60 mg, crude product), which was used directly in the next step.

[0936] LCMS m / z=191.2[M+1] + .

[0937] Step 2: 1E (60 mg, 0.21 mmol) was added to a 50 mL single-necked vial and dissolved in dioxane (6 mL). 72A (60 mg, 0.32 mmol) and N,N-diisopropylethylamine (68 mg, 0.53 mmol) were then added sequentially. The mixture was stirred at 95°C overnight. The reaction mixture was concentrated and purified by SFC to afford the title compound 72 (9 mg, 10% yield).

[0938] Preparation method: Instrument: SFC Prep 150; Chromatographic column: SunFire silica (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: methanol / acetonitrile (7:3); b. Isocratic elution, mobile phase B content: 35%; c. Flow rate: 40 mL / min; d. Elution time: 15 min.

[0939] LCMS m / z=442.31[M+1] + .

[0940] 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.36(s,1H),4.81(s,1H),3.84-3.69(m,10H),3.26-3.20(m,4 H),3.04-3.02(m,2H),2.98-2.83(m,2H),2.40-2.26(m,2H),2.22-2.16(m,2H),1.83-1.71(m,2H).

[0941] Example 68

[0942] Step 1: Methanol (10 mL), 67D (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 73A (0.31 g, 88.9% yield).

[0943] LC-MS (ESI): m / z = 292.1 [M+H] + .

[0944] Step 2: To a 50 mL single-necked flask were added 73A (0.31 g, 1.07 mmol) and hydrogen chloride-dioxane solution (4N, 15 mL) in sequence. The mixture was reacted at room temperature for 1 hour and concentrated under reduced pressure to afford 73B (0.25 g, 100.0% yield).

[0945] LC-MS (ESI): m / z = 192.1 [M+H] + .

[0946] Step 3: To a 50 mL single-necked flask were added 1E (287 mg, 1.0 mmol), 73B (250 mg, 1.07 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 350 mg of the mixture.

[0947] Chiral preparation yielded the title compound 73-1 (91 mg, 20.6%, retention time: 1.472 min) and the title compound 73-2 (63 mg, 14.3%, retention time: 1.770 min). Chiral preparation method: Instrument: Waters 150 MGM; 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: 4.2 min.

[0948] (Compound 73-1)

[0949] 1H NMR(400MHz,DMSO-d6)δ7.79-7.67(m,1H),7.44(s,1H),7.06-6.94(m,1H),6.68-6.5 5(m,1H),4.89-4.80(m,1H),4.79-4.62(m,2H),4.50-4.34(m,2H),4.06-3.92(m,1H), 3.79-3.65(m,2H),3.50-3.37(m,1H),3.36-3.32(m,1H),3.28-3.16(m,1H),3.06-2.8 1(m,3H),2.79-2.63(m,2H),2.41-2.25(m,2H),2.25-2.14(m,2H),1.89-1.71(m,2H).

[0950] LC-MS (ESI): m / z = 443.2 [M+H] + .

[0951] (Compound 73-2)

[0952] 1 H NMR(400MHz,DMSO-d6)δ7.84-7.64(m,1H),7.44(s,1H),7.15-6.83(m,1H),6.80-6.46(m,1H), 4.87-4.81(m,1H),4.80-4.62(m,2H),4.50-4.31(m,2H),4.04-3.94(m,1H),3.76-3.68(m,2H), 3.50-3.38(m,1H),3.36-3.31(m,1H),3.28-3.16(m,1H),3.05-2.82(m,3H), 2.81-2.64(m,2H),2.43-2.25(m,2H),2.25-2.14(m,2H),1.85-1.71(m,2H).

[0953] LC-MS (ESI): m / z = 443.2 [M+H] + .

[0954] Example 69

[0955] Step 1: In a 250 mL single-necked flask, N,N-dimethylformamide (50 mL), 74A (5.0 g, 35.97 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (7.77 g, 35.97 mmol), and potassium hydroxide (6.05 g, 107.85 mmol) were added in sequence. The reaction was carried out at 100°C for 16 hours. After filtration, ethyl acetate (100 mL) was added to the filtrate, and the mixture was washed with water (50 mL × 3) and saturated brine (100 mL × 1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 74B (0.5 g, yield 4.4%).

[0956] LC-MS (ESI): m / z = 316.2 [M+H] + .

[0957] Step 2: Into a 50 mL single-necked flask were added 74B (0.5 g, 1.59 mmol), dichloromethane (15 mL), and triethylamine (3.21 g, 31.8 mmol) in sequence. Iodotrimethylsilane (3.18 g, 15.9 mmol) was added dropwise at 0°C. The mixture was reacted at room temperature for 1 hour. After concentration under reduced pressure, the crude product 74C (4.5 g, 100.0% yield) was obtained.

[0958] LC-MS (ESI): m / z = 216.2 [M+H] + .

[0959] Step 3: To a 50 mL single-necked flask were added 1E (456 mg, 1.59 mmol), crude 74C (4.5 g, 1.59 mmol), dioxane (10 mL), and DIPEA (1.03 g, 8.0 mmol) in this order. 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 / 10) to yield 450 mg of the mixture.

[0960] The title compound 74-1 (112 mg, 15.1%, retention time: 0.925 min) and the title compound 74-2 (86 mg, 11.6%, retention time: 1.896 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: isopropanol (0.1% ammonia); Isocratic elution: 70% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 5.1 min.

[0961] (Compound 74-1)

[0962] 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H),7.35-7.31(m,1H),7.14-7.09(m,1H),6.89-6.84(m, 1H),4.88-4.79(m,1H),4.78-4.60(m,2H),4.51-4.39(m,1H),4.10-4.00(m,1H),3.97-3.8 8(m,1H),3.77-3.66(m,2H),3.52-3.36(m,1H),3.29-3.16(m,1H),3.16-3.02(m,2H),3.00 -2.81(m,2H),2.79-2.62(m,2H),2.44-2.25(m,2H),2.25-2.14(m,2H),1.88-1.69(m,2H).

[0963] LC-MS (ESI): m / z = 467.1 [M+H] + .

[0964] (Compound 74-2)

[0965] 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H),7.40-7.30(m,1H),7.14-7.10(m,1H),6.88-6.84(m, 1H),4.88-4.79(m,1H),4.79-4.60(m,2H),4.51-4.38(m,1H),4.12-3.98(m,1H),3.95-3.8 7(m,1H),3.79-3.65(m,2H),3.52-3.38(m,1H),3.28-3.17(m,1H),3.15-3.02(m,2H),3.01 -2.83(m,2H),2.79-2.61(m,2H),2.45-2.25(m,2H),2.24-2.13(m,2H),1.87-1.67(m,2H).

[0966] LC-MS (ESI): m / z = 467.1 [M+H] + .

[0967] Example 70

[0968] Step 1: To a 250 mL single-necked flask were added 47B (10.0 g, 29.8 mmol) and hydrogen chloride-1,4-dioxane (100 mL) in sequence. The mixture was reacted at room temperature for 1 hour. After concentration, the pH was adjusted to >7 by adding saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 75A (7.0 g, 99.8%).

[0969] LC-MS (ESI): m / z = 236.1 [M+H] + .

[0970] Step 2: To a 50 mL single-necked flask were added 75A (3.5 g, 14.9 mmol), anhydrous ethanol (40 mL), paraformaldehyde (3.5 g), and sodium cyanoborohydride (1.88 g, 29.8 mmol) in sequence. The mixture was reacted at room temperature for 12 h. After concentration under reduced pressure, the mixture was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 90 / 10) to obtain 75B (2.5 g, 67.6%).

[0971] LC-MS (ESI): m / z = 250.2 [M+H] + .

[0972] Step 3: 75B (2.5 g, 10.0 mmol), ethyl acetate (50 mL), and palladium on carbon (10%, 0.5 g) were added sequentially to a 100 mL single-necked flask. The mixture was subjected to hydrogenation reduction reaction at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain 75C (2.2 g, 100%).

[0973] LC-MS (ESI): m / z = 220.2 [M+H] + .

[0974] Step 4: To a 100 mL single-necked flask were added 75C (2.2 g, 10.0 mmol), methanol (20 mL), and aqueous hydrochloric acid (3 M, 10 mL). Sodium nitrite (693 mg, 10.0 mmol) was added at -5°C, and immediately added with diboronic acid pinacol ester (5.1 g, 20.1 mmol). The mixture was reacted at room temperature for 1 hour. Saturated sodium bicarbonate was added to adjust the pH to >7, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 90 / 10) to give 75D (2.0 g, 63.1%).

[0975] LC-MS (ESI): m / z = 317.2 [M+H] + .

[0976] Step 5: Under nitrogen, to a 100 mL single-necked flask were added 1E (907 mg, 3.16 mmol), 75D (1.0 g, 3.16 mmol), water (4 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (224 mg, 0.32 mmol), and potassium carbonate (1.3 g, 9.48 mmol). 1,4-Dioxane (20 mL) was added to dissolve the mixture. The temperature was raised to 100°C and the reaction was allowed to react for 5 hours. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 90 / 10) to obtain a mixture of compounds 75-1 and 75-2 (200 mg, 13.8%).

[0977] The title compound 75-1 (81 mg, 5.6%, retention time: 0.885 min) and the title compound 75-2 (74 mg, 5.1%, retention time: 1.795 min) were obtained by chiral preparation.

[0978] Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phase: A: carbon dioxide and B: isopropanol (0.1% ammonia); Isocratic elution: 70% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 5.1 min.

[0979] (Compound 75-1)

[0980] 1 H NMR(400MHz,DMSO-d6)δ7.84-7.79(m,1H),7.75(s,1H),7.64-7.61(m,1H),6.98-6.89(m,1H) ,4.93-4.83(m,1H),4.31-4.23(m,1H),3.96-3.89(m,1H),3.84-3.73(m,3H),3.66-3.51(m,1H ),3.40-3.31(m,1H),3.22-3.09(m,2H),3.02-2.94(m,1H),2.91-2.71(m,3H),2.47-2.32(m, 2H),2.31-2.24(m,2H),2.23(s,3H),2.11-2.02(m,1H),1.90-1.77(m,2H),1.75-1.66(m,1H).

[0981] LC-MS (ESI): m / z = 456.2 [M+H] + .

[0982] (Compound 75-2)

[0983] 1 H NMR(400MHz,DMSO-d6)δ7.83-7.80(m,1H),7.75(s,1H),7.64-7.61(m,1H),6.98-6.91(m,1H) ,4.93-4.86(m,1H),4.30-4.23(m,1H),3.99-3.87(m,1H),3.85-3.73(m,3H),3.63-3.52(m,1H ),3.38-3.31(m,1H),3.21-3.11(m,2H),3.02-2.93(m,1H),2.91-2.71(m,3H),2.46-2.32(m, 2H),2.31-2.24(m,2H),2.23(s,3H),2.14-1.99(m,1H),1.89-1.78(m,2H),1.75-1.66(m,1H).

[0984] LC-MS (ESI): m / z = 456.2 [M+H] + .

[0985] Example 71

[0986] Step 1: Under nitrogen, compound 76A (2.00 g, 7.02 mmol), [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (2.28 g, 7.37 mmol), potassium carbonate (1.94 g, 14.04 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (770 mg, 1.05 mmol) were added to a reaction flask. Tetrahydrofuran (40 mL) and water (8 mL) were added. After replacing the nitrogen atmosphere, the temperature was raised to 75°C and the reaction was allowed to react for 16 h. The starting material disappeared by TLC. The mixture was diluted with water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 95 / 5) to give the target compound 76B (1.00 g, 41.9%).

[0987] LC-MS(ESI):m / z=254.60[M-56+H] + .

[0988] 1H NMR (400MHz, CDCl3) δ8.71(s,2H),7.21-7.20(m,1H),4.16-4.15(m,2H),3.64-3.61(m,2H),2.69-2.68(m,2H),1.49(s,9H).

[0989] Step 2: Compound 76B (1.00 g, 2.94 mmol), 1-(trimethylsilyl)propyne (660 mg, 5.88 mmol), potassium carbonate (1.02 g, 7.35 mmol), cuprous iodide (112 mg, 0.59 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (160 mg, 0.44 mmol) were added to a reaction flask. 1,4-dioxane (20 mL) was added, and the atmosphere was replaced with nitrogen. The temperature was raised to 85°C and the reaction was allowed to react for 16 h. TLC indicated the disappearance of the starting material. The mixture was diluted with water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified three times by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 95 / 5) to afford the target compound 76C (200 mg, 22.7%).

[0990] LC-MS(ESI):m / z=244.10[M-56+H] + .

[0991] Step 3: Dissolve compound 76C (200 mg, 0.67 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir at 0°C for 30 min. After TLC analysis, the reaction mixture was concentrated at room temperature to obtain crude product 76D (230 mg), which was used directly in the next reaction.

[0992] LC-MS (ESI): m / z = 200.20 [M+H] + .

[0993] Step 4: Dissolve compound 1E (130 mg, 0.45 mmol) and compound 76D (230 mg, 0.63 mmol) in 1,4-dioxane (6 mL), then add N,N-diisopropylethylamine (350 mg, 2.71 mmol). After the addition is complete, heat to 85°C and stir under nitrogen for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 90 / 10) and further purified by prep.HPLC (preparative method: instrument: Waters 2767 preparative liquid phase; 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 30% to 95%; c. flow rate: 15 mL / min; d. elution time: 15 min; retention time: 6.0 min) to obtain the target compound 76 (48 mg, 23.6%).

[0994] 1 H NMR(400MHz,DMSO-d6)δ8.80(s,2H),7.34(s,1H),7.29(s,1H),4.85-4.8 2(m,1H),4.46(s,2H),3.98-3.95(m,2H),3.75-3.74(m,2H),3.47-3.39(m ,1H),3.26-3.19(m,1H),2.98-2.92(m,1H),2.89-2.84(m,1H),2.65(s,2 H),2.43-2.30(m,2H),2.22-2.18(m,2H),2.12(s,3H),1.83-1.73(m,2H).

[0995] LCMS m / z=451.2[M+H] + .

[0996] Example 72

[0997] Step 1: Compound 65H (0.5 g, 2.72 mmol) was dissolved in glacial acetic acid (20 mL), and dithionyl chloride (10 mL) was added. The mixture was stirred at 60°C overnight. After the reaction was completed, the mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The pH of the reaction system was adjusted to neutral with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was quickly separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to obtain compound 77A (100 mg, 26%).

[0998] LCMS (ESI): m / z = 141.1 [M+H] + .

[0999] Step 2: Under nitrogen, compound 42C (238 mg, 0.71 mmol), 77A (100 mg, 0.71 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (51 mg, 0.07 mmol), and sodium carbonate (226 mg, 2.13 mmol) were dissolved in a mixture of 1,4-dioxane and water (10 mL / 2 mL). The mixture was heated to 90°C and reacted 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 the resulting residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 90 / 10) to afford the target compound 77B (102 mg, 45%).

[1000] LCMS (ESI): m / z = 258.1 [M+H-56] + .

[1001] Step 3: Compound 77B (102 mg, 0.33 mmol) was dissolved in a mixed solvent of dichloromethane / trifluoroacetic acid (6 mL / 2 mL), stirred at room temperature for 1 h, and directly dried to obtain the trifluoroacetate salt of compound 77C, which was directly used in the next reaction (111 mg).

[1002] LCMS (ESI): m / z = 214.1 [M+H] + .

[1003] Step 4: Dissolve the trifluoroacetate salt of compound 77C (111 mg) in 1,4-dioxane (5 ml), add 1E (95 mg, 0.33 mmol) and diisopropylethylamine (128 mg, 0.99 mmol), and place the reaction system 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 reaction mixture was directly spin-dried to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 80 / 20) to obtain a mixture of compounds 77-1 and 77-2 (50 mg, 33%). Chiral separation was then performed to afford compound 77-1 (26 mg, retention time: 1.891 s) and compound 77-2 (21.6 mg, retention time: 2.901 s).

[1004] Chiral preparation method: Instrument: Waters 150 Prep-SFC E; Chromatographic column: Chiralcel Cellulose-2 column; Mobile phase: A: carbon dioxide and B: methanol (0.1% ammonia); Gradient elution: B 40%; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 7.0 min.

[1005] (Compound 77-1)

[1006] 1 H NMR(400MHz, CDCl3)δ8.23(s,1H),6.78(s,1H),5.67(s,1H),5.09(d,1H), 4.07-3.92(m,1H),3.89-3.73(m,4H),3.67(s,1H),3.61-3.53(m,1H),3.49 -3.44(m,2H),3.40(d,1H),3.31(d,1H),3.23(t,2H),3.16(s,1H),3.11-2. 92(m,3H),2.85(d,1H),2.36(d,2H),2.23-2.15(m,2H),1.97-1.89(m,2H).

[1007] LCMS (ESI): m / z = 465.2 [M+H] + .

[1008] (Compound 77-2)

[1009] 1H NMR(400MHz, CDCl3)δ8.23(s,1H),6.78(s,1H),5.83(s,1H),5.09(d,1H),4.06-3.90(m,1H),3.89-3.73(m,4H),3.67(s,1H),3.57(d,1H) ),3.46(s,2H),3.43-3.28(m,2H),3.23(s,2H),3.18-2.96(m,4H),2.87(d,1H),2.41-2.31(m,1H),2.28-2.15(m,3H),1.99-1.83(m,2H).

[1010] LCMS (ESI): m / z = 465.2 [M+H] + .

[1011] Example 73

[1012] Step 1: 75A (3.5 g, 14.89 mmol) was dissolved in dichloromethane (35 mL), and triethylamine (4.5 g, 44.67 mmol) and acetic anhydride (1.5 g, 14.89 mmol) were added. After reacting at room temperature for 1 hour, water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91 / 9) to obtain 78A (3.2 g, 77.6%).

[1013] LC-MS (ESI): m / z = 278.1 [M+H] + .

[1014] Step 2: Compound 78A (3.2 g, 11.55 mmol) was dissolved in ethyl acetate (50 mL), and palladium on carbon (10%, 0.5 g) was added. The reaction was heated to 50°C under a hydrogen atmosphere for 12 hours. After the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to yield 78B (2.8 g, 98.2%).

[1015] LC-MS (ESI): m / z = 248.2 [M+H] + .

[1016] Step 3: To a 100 mL single-necked flask were added 78B (2.5 g, 10.12 mmol), methanol (20 mL), and aqueous hydrochloric acid (3 M, 10 mL). Sodium nitrite (698 mg, 10.12 mmol) was added at -5°C, followed immediately by the addition of pinacol diboron (5.1 g, 20.24 mmol). The reaction was allowed to react at room temperature for 1 hour. After completion of the reaction, saturated sodium bicarbonate was added to adjust the pH to >7, as monitored by TLC. The mixture was extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91 / 9) to afford 78C (2.5 g, 71.8%).

[1017] LC-MS (ESI): m / z = 345.2 [M+H] + .

[1018] Step 4: To a 100 mL single-necked flask, 1E (907 mg, 3.16 mmol), 78C (1.1 g, 3.16 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (224 mg, 0.32 mmol), and potassium carbonate (1.3 g, 9.48 mmol) were added in sequence. A mixed solvent of 1,4-dioxane (20 mL) and water (4 mL) was added to dissolve the mixture. The mixture was heated to 100°C under nitrogen and reacted for 5 hours. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91 / 9) to obtain a mixture of 78-1 and 78-2 (250 mg).

[1019] The title compound 78-1 (78 mg, 5.1%, retention time: 0.960 min) and the title compound 78-2 (69 mg, 4.5%, retention time: 1.256 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: ethanol (0.1% ammonia); Isocratic elution: 70% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 4.0 min.

[1020] (Compound 78-1)

[1021] 1H NMR(400MHz,DMSO-d6)δ7.92-7.75(m,2H),7.69-7.55(m,1H),7.05-6.93 (m,1H),4.97-4.82(m,1H),4.50-4.31(m,2H),4.06-3.85(m,3H),3.85-3 .73(m,2H),3.64-3.52(m,1H),3.38-3.31(m,1H),3.30-2.60(m,6H),2.4 6-2.34(m,2H),2.32-2.21(m,2H),2.12-1.98(m,3H),1.94-1.71(m,2H).

[1022] LC-MS (ESI): m / z = 484.4 [M+H] + .

[1023] (Compound 78-2)

[1024] 1 H NMR(400MHz,DMSO-d6)δ7.94-7.74(m,2H),7.70-7.56(m,1H),7.05-6.82 (m,1H),5.00-4.84(m,1H),4.51-4.29(m,2H),4.02-3.87(m,3H),3.84-3 .75(m,2H),3.64-3.52(m,1H),3.39-3.32(m,1H),3.29-2.62(m,6H),2.4 6-2.35(m,2H),2.32-2.20(m,2H),2.09-2.02(m,3H),1.91-1.77(m,2H).

[1025] LC-MS (ESI): m / z = 484.4 [M+H] + .

[1026] Example 74

[1027] Step 1: Under nitrogen, compound 79A (20.00 g, 70.20 mmol) was dissolved in methanol (200 mL). Trifluoroacetic acid (8.17 g, 71.61 mmol) and benzoyl peroxide (19.05 g, 78.63 mmol) were added sequentially with stirring at room temperature. After the additions were complete, the reaction mixture was heated to 65°C and stirred for 16 h. The starting material disappeared after TLC analysis, and the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to a small volume, diluted with saturated aqueous sodium carbonate (400 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. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to afford the target compound 79B (2.00 g, 9.05%).

[1028] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),5.58-5.55(m,1H),4.56-4.54(m,2H).

[1029] LC-MS (ESI): m / z = 314.9 [M+H] + .

[1030] Step 2: Under nitrogen, compound 79B (2.00 g, 6.35 mmol) was added to a mixture of 1,4-dioxane (20 mL) and water (4 mL). [1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (2.00 g, 6.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.68 g, 0.93 mmol), and potassium carbonate (1.76 g, 12.70 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the reaction mixture was heated to 85°C and stirred for 16 h. The starting material disappeared by TLC, and the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to a small volume, diluted with water (100 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to give the target compound 79C (950 mg, 40.40%).

[1031] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),7.27-7.26(m,1H),4.74(s,2H),4.19-4.18(m,2H),3.66-3.63(m,2H),2.73(s,2H),1.49(s,9H).

[1032] LC-MS(ESI):m / z=314.9[M+H-56] + .

[1033] Step 3: Under nitrogen, compound 79C (950 mg, 2.57 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (650 mg, 6.41 mmol) was added with stirring on an ice bath, followed by the slow dropwise addition of acetyl chloride (300 mg, 3.85 mmol). After the addition was complete, the reaction mixture was stirred at 0°C for 1 h. After TLC analysis of the disappearance of the starting material, the reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted three times with dichloromethane (40 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to yield the target compound 79D (750 mg, 70.90%).

[1034] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),7.19(br s,1H),5.25(s,2H),4.16-4.15(m,2H),3.63-3.60(m,2H),2.66(s,2H),2.22(s,3H),1.49(s,9H).

[1035] LC-MS(ESI):m / z=356.3[M+H-56] + .

[1036] Step 4: Under nitrogen, compound 79D (750 mg, 1.82 mmol) was dissolved in 1,4-dioxane (20 mL). Bis(pinacolato)diboron (530 mg, 2.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg, 0.20 mmol), and potassium acetate (540 mg, 5.48 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the reaction mixture was heated to 80°C and stirred for 5 h. After TLC analysis indicated the disappearance of the starting material, the mixture was cooled to room temperature, concentrated under reduced pressure to a small volume, diluted with water (50 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to afford crude product 79E (1.2 g), which was used directly in the next step.

[1037] Step 5: Dissolve crude compound 79E (1.2 g) in methanol (20 mL) and add 1 M sodium hydroxide solution (240 mg, 6.01 mmol). After complete addition, stir at room temperature under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure to a small volume, diluted with water (20 mL), and extracted twice with ethyl acetate (50 mL). The aqueous phase was further concentrated and purified on a reverse-phase column (water / acetonitrile (v / v) = 100 / 0 to 10 / 90) to yield compound 79F (270 mg, 42.51%).

[1038] LCMS m / z=262.2[M-56+H] + .

[1039] Step 6: Dissolve compound 79F (270 mg, 0.85 mmol) in dichloromethane (4 mL). Add 4M dioxane hydrochloride (310 mg, 8.51 mmol) under ice-cooling. Stir under nitrogen for 1.5 h. The reaction mixture was concentrated under reduced pressure to yield crude compound 79G (200 mg), which was used directly in the next reaction.

[1040] LCMS m / z=218.2[M+H] + .

[1041] Step 7: Compound 1E (100 mg, 0.35 mmol) and crude compound 79G (200 mg) were dissolved in 1,4-dioxane (6 mL), followed by the addition of N,N-diisopropylethylamine (135 mg, 1.04 mmol). After the addition was complete, the mixture was heated to 85°C and stirred for 16 hours under nitrogen. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 91 / 9) and further purified by reverse-phase column chromatography (water / acetonitrile (v / v) = 100 / 1 to 1 / 85) to afford the target compound 79 (21 mg, 12.90%).

[1042] 1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.33-7.27(m,1H),4.84(s,1H),4.67-4.55(m,1H),4.43(br s,1H),3.97(s,1H),3.76-3.75(m,2H),3.51-3.40(m,1H),3.24-3.19(m,3H),2.99-2.83(m,2H),2.67(s,2H),2. 42-2.34(m,2H),2.22-2.21(m,2H),1.81-1.76(m,2H),1.53-1.47(m,1H),1.27-1.21(m,1H),1.10-0.95(m,1H).

[1043] LCMS m / z=469.40[M+H] + .

[1044] Example 75

[1045] Step 1: To a 100 mL single-necked flask were added 67D (0.8 g, 1.92 mmol), tetrahydrofuran (15 mL), cuprous iodide (72 mg, 0.38 mmol), triethylamine (582 mg, 5.76 mmol), bistriphenylphosphine palladium dichloride (139 mg, 0.19 mmol), and propyne-tetrahydrofuran solution (1 M, 19.2 mL, 19.2 mmol) in sequence. The mixture was reacted at room temperature under nitrogen for 6 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 80A (500 mg, 79.2%).

[1046] LC-MS (ESI): m / z = 330.2 [M+H] + .

[1047] Step 2: 80A (0.5 g, 1.5 mmol), triethylamine (3.0 g, 30 mmol), and iodotrimethylsilane (3.0 g, 15 mmol) were added to a 50 mL single-necked flask in sequence. The mixture was reacted at room temperature for 2 h. After concentration under reduced pressure, the crude product 80B was obtained, which was directly used for the next step.

[1048] LC-MS (ESI): m / z = 230.1 [M+H] + .

[1049] Step 3: To a 50 mL single-necked flask were added 1E (431 mg, 1.5 mmol), 80B (crude product 0.8 g, 1.5 mmol), dioxane (5 mL), and N,N-diisopropylethylamine (1.16 g, 9.0 mmol) in sequence. The mixture was reacted at 100°C for 6 hours. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 8) to yield 450 mg of the mixture.

[1050] The title compound 80-1 (110 mg, 15.3%, retention time: 0.983 min) and the title compound 80-2 (106 mg, 14.7%, retention time: 1.247 min) were obtained by chiral preparation. Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: ethanol (0.1% ammonia); Isocratic elution: 70% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 4.0 min.

[1051] (Compound 80-1)

[1052] 1 H NMR(400MHz,DMSO-d6)δ7.80-7.75(m,1H),7.43(s,1H),7.03-6.94(m,1H),4.8 9-4.79(m,1H),4.79-4.60(m,2H),4.52-4.31(m,2H),4.01-3.92(m,1H),3.78-3 .65(m,2H),3.49-3.35(m,2H),3.27-3.16(m,1H),3.05-2.83(m,3H),2.81-2.6 9(m,2H),2.42-2.26(m,2H),2.24-2.14(m,2H),2.00(s,3H),1.87-1.71(m,2H).

[1053] LC-MS (ESI): m / z = 481.2 [M+H] + .

[1054] (Compound 80-2)

[1055] 1H NMR(400MHz,DMSO-d6)δ7.85-7.70(m,1H),7.43(s,1H),7.12-6.77(m,1H),4.9 3-4.80(m,1H),4.79-4.59(m,2H),4.50-4.32(m,2H),4.10-3.89(m,1H),3.78-3 .62(m,2H),3.49-3.34(m,2H),3.28-3.16(m,1H),3.06-2.83(m,3H),2.81-2.7 1(m,2H),2.40-2.25(m,2H),2.24-2.14(m,2H),2.00(s,3H),1.86-1.72(m,2H).

[1056] LC-MS (ESI): m / z = 481.2 [M+H] + .

[1057] Example 76

[1058] Step 1: Compound 48A (1.0 g, 3.27 mmol), 1,3-dibromo-2-methylpropane (0.78 g, 3.60 mmol), and N,N-dimethylformamide (15 mL) were added to a 50 mL round-bottom flask at room temperature. Cesium carbonate (3.20 g, 9.82 mmol) was then added and heated to 70°C for 14 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent EA / PE = 0-35%) afforded the target compound 81A (0.3 g, 25%).

[1059] LC-MS (ESI): m / z = 360.5 [M+H] + .

[1060] Step 2: 81A (0.30 g, 0.83 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added to a 25 mL round-bottom flask at room temperature and stirred for 2 h. After the reaction, the reaction mixture was concentrated under reduced pressure to yield the crude trifluoroacetate salt of target compound 81B (0.20 g, 92%).

[1061] LC-MS (ESI): m / z = 260.3 [M+H] + .

[1062] Step 3: The crude trifluoroacetate salt of compound 81B (0.20 g, 0.77 mmol), compound 1E (0.27 g, 0.92 mmol), and 1,4-dioxane (5 mL) were added to a 25 mL round-bottom flask at room temperature. N,N-diisopropylethylamine (0.30 g, 2.31 mmol) was added at room temperature, and the mixture was heated to 100°C for 12 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. It was then purified by silica gel column chromatography (eluent: MeOH / DCM = 0-10%) to obtain 0.26 g of a racemate. The racemate was separated by SFC to obtain two isomers, compound 81-1 (50 mg, retention time 1.94 min, 13%) and compound 81-2 (50 mg, retention time 2.18 min, 13%).

[1063] Preparative chromatography conditions: 1. Instrument: SHIMADZU LC-20AP; 2. Chromatographic column: C18; 3. Mobile phase system: A for 0.1% TFA in H2O; B for ACN; 4. Gradient: B 3-33%; 5. Flow rate: 75 mL / min.

[1064] Compound 81-1:

[1065] 1 H NMR(400MHz,Chloroform-d)δ6.76-6.66(m,1H),6.09-5.95(m,3H),4.83-4.57(m,2H ),4.27-4.21(m,1H),4.07-4.01(m,1H),3.98-3.90(m,2H),3.85(s,2H),3.70-3.62(m ,1H),3.62-3.54(m,1H),3.44-3.32(m,3H),3.25-3.17(m,1H),3.08-2.96(m,3H),2.8 4-2.74(m,2H),2.70-2.61(m,1H),2.36-2.20(m,4H),1.98-1.84(m,2H),1.24(d,3H).

[1066] LC-MS (ESI): m / z = 511.3 [M+H] + .

[1067] Compound 81-2: 1H NMR(400MHz,Chloroform-d)δ6.76-6.68(m,1H),6.19-6.08(m,2H),6.04(s,1H) ,4.80-4.58(m,2H),4.31-4.22(m,1H),4.09-3.98(m,3H),3.92-3.81(m,2H),3.7 0-3.54(m,2H),3.47-3.36(m,3H),3.26-3.16(m,1H),3.09-2.95(m,3H),2.89-2. 75(m,2H),2.72-2.60(m,1H),2.32-2.26(m,4H),1.97-1.84(m,2H),1.25(d,3H).

[1068] LC-MS (ESI): m / z = 511.3 [M+H] + .

[1069] Example 77

[1070] Step 1: Compound 82A (2.0 g, 8.4 mmol) was dissolved in toluene (50 mL). Tributylstannane (3.1 g, 9.2 mmol) and tetrakis(triphenylphosphine)palladium (0.1 g, 0.8 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and heated to 100°C for 14 h. The reaction was monitored for completion by TLC. The mixture was cooled to room temperature, concentrated, and purified on a silica gel column (PE / EA = 10 / 1) to afford product 82B (1.2 g, 94.4%).

[1071] 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),7.62(d,1H),7.25(d,1H),2.07(s,3H).

[1072] Step 2: Compound 82B (1.2 g, 7.9 mmol) was dissolved in 1,4-dioxane (20 mL), and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (0.6 g, 0.8 mmol), cesium carbonate (5.2 g, 15.8 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.9 g, 9.5 mmol) and water (4 mL) were added. The nitrogen atmosphere was replaced three times, and the mixture was heated to 90°C for 4 h. After reaction, the mixture was passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 82C (2.0 g, 84.6%).

[1073] LC-MS (ESI): m / z = 299.4 [M+H] + .

[1074] Step 3: Compound 82C (1.5 g, 5.0 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3.8 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain trifluoroacetate salt of compound 82D (0.9 g, 90.3%), which was used directly in the next step.

[1075] LC-MS (ESI): m / z = 199.4 [M+H] + .

[1076] Step 4: Compound 1E (1.68 g, 5.8 mmol) was dissolved in 1,4-dioxane (20.0 mL), and trifluoroacetate of compound 82D (1.4 g, 7.0 mmol) and diisopropylethylamine (3.0 g, 23.3 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 the target product 82 (2.5 g, 95%).

[1077] 1 H NMR(400MHz,DMSO-d6)δ8.54(d,1H),7.78 7.76(m,1H),7.57(d,1H),7.42(s,1H),6.84(s,1H),4.87(s,1H),4.41(s,2H),3.96(t,2H),3.75(s,2H),3.51-3.38(m,1H) ,3.25-2.17(m,1H),2.98-2.84(m,2H),2.61(s,2H),2.39-2.28(m,2H),2.22-2.18(m,2H),2.08(s,3H),1.87-1.72(m,2H).

[1078] LC-MS (ESI): m / z = 450.1 [M+H] + .

[1079] Example 78

[1080] Step 1: Under nitrogen, tetrahydrofuran (50 mL) was added to a reaction flask containing compound 83A (5.00 g, 17.01 mmol). The mixture was stirred at 0°C for 15 min, and 1 M borane tetrahydrofuran complex (4.39 g, 51.03 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 80°C and stirred for 16 h. The reaction mixture was cooled to room temperature after the disappearance of the starting material by TLC. The reaction mixture was quenched by the addition of water (20 mL). The reaction mixture was concentrated under reduced pressure to a small volume, diluted 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 afford crude product 83B (4.50 g, 94.50%), which was used directly in the next step.

[1081] 1 H NMR (400MHz, DMSO-d6) δ7.65-7.62(m,2H),7.11-7.07(m,1H),3.57-3.53(m,2H),3.16-3.12(m,2H).

[1082] Step 2: Under nitrogen, compound 83B (4.50 g, 16.07 mmol) was dissolved in dichloromethane (45 mL). N-bromosuccinimide (3.43 g, 19.29 mmol) and triphenylphosphine (5.86 g, 22.34 mmol) were added with stirring on an ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 16 hours. After the disappearance of the starting material by TLC, tert-butyl hydroperoxide (2 mL) was added and stirred for 10 minutes. The reaction was quenched by the addition of saturated aqueous sodium bisulfite (100 mL) and extracted three times with dichloromethane (50 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) to yield the target compound 83C (3.20 g, 58.07%).

[1083] 1 H NMR (400MHz, CDCl3) δ7.53-7.51(m,2H), 6.98-6.94(m,1H), 3.58-3.47(m,4H).

[1084] Step 3: Under nitrogen, compound 83C (3.20 g, 9.33 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). n-Butyl lithium (3.6 mL, 2.5 M) was slowly added dropwise with stirring at -70°C. After the addition, the reaction mixture was stirred at -70°C for 5 h. Water (20 mL) was slowly added dropwise to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield 83D (2.10 g, 86.04%).

[1085] 1H NMR (400MHz, CDCl3) δ7.29-7.25(m,1H),7.08-7.04(m,1H),6.99-6.98(m,1H),3.13(s, 4H).

[1086] Step 4: Compound 83D (1.00 g, 5.46 mmol) was dissolved in 1,4-dioxane (20 mL). T-butyl carbamate (960 mg, 8.19 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (260 mg, 0.55 mmol), cesium carbonate (3.56 g, 10.93 mmol), and palladium acetate (62 mg, 0.27 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 100°C under nitrogen for 4 h. After the disappearance of the starting material by TLC monitoring, the reaction solution was cooled to room temperature, quenched by the addition of saturated sodium bicarbonate solution (30 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 50:1) to obtain the target compound 83E (1.00 g, 93.27%).

[1087] 1 H NMR (400MHz, CDCl3) δ7.28-7.26(m,1H),7.15-7.11(m,1H),6.77-6.75(m,1H),6.30(s,1H),3.20-3.18(m,2H),3.12-3.10(m,2H),1.52(s,9H).

[1088] LCMS m / z=164.1[M-56+H] + .

[1089] Step 5: Dissolve compound 83E (880 mg, 3.65 mmol) in acetic acid (6 mL), then add N-bromosuccinimide (715 mg, 4.01 mmol). Stir under nitrogen for 16 h at room temperature. Dilute the reaction mixture with water (30 mL) and extract three times with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product. The crude product is purified by column chromatography (eluent: PE:EA = 100:1 to 50:1) to yield the target compound 83F (700 mg, 64.35%).

[1090] 1H NMR (400MHz, CDCl3) δ7.48-7.47(m,1H),7.27-7.26(m,1H),6.77(s,1H),3.36-3.33(m,2H),2.98-2.96(m,2H),1.51(s,9H).

[1091] Step 6: Compound 83F (700 mg, 2.35 mmol) was dissolved in 6 mL of dichloromethane. Dioxane hydrochloride (6 mL) was added and stirred at 0°C for 30 min. After TLC detection of the disappearance of the starting material, the reaction solution was concentrated at room temperature to obtain crude product 83G (750 mg), which was used directly in the next reaction.

[1092] Step 7: Dissolve crude compound 83G (750 mg, 2.34 mmol) in 15% wt aqueous hydrochloric acid (5 mL) under ice. Add sodium nitrite (265 mg, 3.84 mmol). Stir for 20 minutes and slowly add the resulting mixture dropwise to a reaction flask containing cuprous chloride (1.14 g, 11.51 mmol) and concentrated hydrochloric acid (10 mL). After addition, stir the mixture at room temperature for 16 hours. Dilute with water (20 mL) and extract three times with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude product, which is then purified by column chromatography (eluent: PE) to yield the target compound 83H (300 mg, 43.13%).

[1093] 1 H NMR (400MHz, CDCl3) δ7.60-7.59(m,1H),7.48-7.47(m,1H),3.16-3.15(m,2H),3.04-3.02(m,2H).

[1094] Step 8: Under nitrogen, compound 83H (300 mg, 1.38 mmol) was dissolved in tetrahydrofuran (12 mL) and water (2 mL). [1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (435 mg, 1.41 mmol), potassium carbonate (480 mg, 3.45 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.21 mmol) were added sequentially. After the additions were complete, the reaction mixture was incubated at 75°C under nitrogen for 16 h. After the disappearance of the starting material, the mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 10:1) to yield the target compound 83I (140 mg, 31.37%).

[1095] 1H NMR (400MHz, CDCl3) δ7.43-7.42(m,2H),6.07-6.05(m,1H),4.08-4.07(m, 2H),3.62-3.59(m,2H),3.20-3.16(m,4H),2.48-2.42(m,2H),1.49(s,9H).

[1096] LC-MS(ESI):m / z=282.0[M-56+H+18] + .

[1097] Step 9: Dissolve compound 83I (130 mg, 0.41 mmol) in 2 mL of dichloromethane, add dioxane hydrochloride (2 mL), and stir at 0°C for 30 min. After TLC monitoring, the reaction solution was concentrated at room temperature to obtain crude product 83J (110 mg), which was used directly in the next reaction.

[1098] Step 10: Dissolve 1E (80 mg, 0.28 mmol) in 1,4-dioxane (4 mL). Add 83J (110 mg, 0.42 mmol) and N,N-diisopropylethylamine (110 mg, 0.84 mmol) sequentially. After addition, heat the reaction mixture to 85°C under nitrogen and stir for 16 h. 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 obtain a crude product. The crude product was purified twice by column chromatography (eluent: DCM:MeOH = 100:1 to 10:1) and further purified by prep.HPLC (preparative method: instrument: Waters 2767 preparative liquid phase; 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 35% to 90%; c. flow rate: 15 mL / min; d. elution time: 15 min; retention time: 6.0 min) to obtain the target compound 83 (2.5 mg, 1.91%).

[1099] 1H NMR (400MHz, CDCl3) δ7.16-7.15(m,1H),7.12-7.11(m,1H),6.98-6.97(m,1H),4.36(s,2H),4.02(s,2H),3.91-3.90(m,2H),3.65 -3.56(m,1H),3.45-3.38(m,1H),3.19-3.16(m,2H),3.15-3.13(m,2H),2.57-2.53(m,3H),2.34-2.27(m,6H),2.00-1.89(m,3H).

[1100] LCMS m / z=471.4[M+H] + .

[1101] Biological testing:

[1102] 1. Effects of compounds on PDE4B2 activity

[1103] The effects of compounds on PDE4B2 activity were determined using a Fluorescence Polarization Assay Kit (BPS Bioscience, Catalog #60343). According to the kit instructions, a final concentration of 0.1 μM FAM-Cyclic-3',5'-AMP and 1 ng / well PDE4B2 were added to each well (negative control wells were treated with PDE buffer). A serial dilution of compound was added (positive control wells were treated with PDE buffer containing 10% DMSO). The mixture was mixed thoroughly and incubated at room temperature for 1 hour. The binding agent was diluted 1:100 with binding agent diluent (cAMP). 50 μl / well of the binding agent diluent was added to the assay plate and incubated at room temperature with slow shaking for 20 minutes. After incubation, FP was detected using Envision (excitation 480 nm, emission 535 nm). FP is typically expressed as mP values.

[1104] I II (S535): Fluorescence intensity in the parallel direction

[1105] I ┴ (P535): Fluorescence intensity in the vertical direction

[1106] G:G factor = 1

[1107] Calculation of inhibition rate (%Inhibition): %Inhibition=[1-(mP (样品) -mP (阴性对照) ) / (mP (阳性对照) -mP(阴性对照) )]x100%

[1108] mP (样品)： mP of the test compound reaction well

[1109] mP (阴性对照)： Negative control well mP

[1110] mP (阳性对照)： Positive control well mP

[1111] According to the calculated inhibition rate at each concentration, the IC of each compound was calculated using GraphPad Prism 8 software. 50 value.

[1112] IC of the compounds of the present invention against PDE4B2 50 The value is less than 300nM, and the preferred compound IC 50 The IC values ​​of some specific compounds are less than 100 nM, more preferably less than 50 nM, and even more preferably less than 10 nM. 50 The values ​​are shown in Table 3 below, where A<10nM, 10nM≤B<50nM, and 50nM≤C<100nM.

[1113] Table 3 PDE4B2 activity

[1114] As can be seen from the above, the compounds of the present invention, such as the examples, have good inhibitory activity. For example, the IC values ​​of compound 1 and compound 5 are 50 The values ​​were 2.45 nM and 8.10 nM, respectively.

[1115] 2. Effects of Compounds on PDE4D3 Activity

[1116] The effects of compounds on PDE4D3 activity were determined using a Fluorescence Polarization Assay Kit (BPS Bioscience, Catalog #60346). According to the kit instructions, a final concentration of 0.1 μM FAM-Cyclic-3',5'-AMP and 0.05 ng / well PDE4D3 were added to each well (negative control wells w...

Claims

1. A compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, in, Cy is selected from Cy1, Cy2, a 5-membered monocyclic heteroaryl or an 8-10-membered bicyclic heteroaryl, wherein the monocyclic heteroaryl or bicyclic heteroaryl is optionally further substituted with 1-3 R; Cy2 is optionally substituted with 1-3 R; L is -(L1)n-(L2)m-; L1 is -NR1-, -CR2=N-, -CR2=CR2- or -CR2R2-; L2 is C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, CO, O, NR L2 、C 3-5 Cycloalkylene, 6-9 membered arylene, 5-6 membered heteroarylene containing 1-3 heteroatoms selected from N, S, O, 5 membered monoheterocycloalkylene containing 1-3 heteroatoms selected from N, S, O, 7-8 membered monoheterocycloalkylene containing 1-3 heteroatoms selected from N, S, O, 5-10 membered cycloheterocycloalkylene containing 1-3 heteroatoms selected from N, S, O, 6-10 membered bridged heterocycloalkylene containing 1-3 heteroatoms selected from N, S, O, 7-12 membered spirocycloheterocycloalkylene containing 1-3 heteroatoms selected from N, S, O, said alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, monoheterocycloalkylene, cycloheterocycloalkylene, bridged heterocycloalkylene and spirocycloheterocycloalkylene are 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; X1 and X2 are independently CR X1 or N; Each R X1 are independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -SO2NH2, or R X1 With R1, R X1 With R2, or R X1 Together with R3 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, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHCONH2, -NHCOC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, -SO2C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, -SCF3, -SF5 or -C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; Or two adjacent R, R and R X1 and its connected atoms together form C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; R1 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl; R2 is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl or C 3-6 Cycloalkyl; R3 is H, halogen, =O, CN, C 1-4 Alkyl or C 1-4 alkoxy; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, or 3; The condition is, The compound is not 2. The compound according to claim 1, 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; Each R X1 are independently H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-7 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(C 1-2 Alkyl)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; or two adjacent R, R and R X1 and its connected atoms together form C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, 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(O)C 1-4 Alkyl and NH2 group substitution; R1 is H, C 1-4 Alkyl or C 1-4 alkyl halide; R2 is H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 alkoxy; R3 is H, halogen, =O, CN or C 1-4 alkyl; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2.

3. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt, wherein The compound has the structure of the following formula II, Wherein, L is selected from one of the following structures: X1 and X2 are independently CR X1 or N; Each R X1 are independently H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl, or R X1 With R1, R X1 With R2, or R X1 Together with R3 and the atoms to which it is attached, it forms C 3-6 Cycloalkyl, 5-7 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 halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH and NH2 group substitution; Each R is independently H, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, P, -SO2NH2, -NHSO2C 1-4 Alkyl, -SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, -P(O)(CH3)2, SCF3, SF5 or C 1-4 The cycloalkyl and heterocycloalkyl groups are optionally substituted by 1-3 groups selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; or two adjacent R, R and R X1 and its connected atoms together form C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, P, B, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from halogen, =O, CN, C 1-4 Alkyl, C 1-4 alkyl Oxygen group, OH, -C(O)C 1-4 Alkyl and NH2 group substitution; R1 is H or C 1-4 Alkyl or C 1-4 alkyl halide; R2 is H, C 1-4 Alkyl or C 1-4 alkyl halide; R3 is H, halogen, =O, CN or C 1-4 alkyl.

4. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein Cy is selected from the following groups optionally further substituted with 1-3 R: 5-membered monocyclic heteroaryl, 5-membered heteroaryl acene ring, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 6-membered cycloalkyl, 5-membered heteroaryl and 4-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heterocycloalkyl, 6-membered heteroaryl acene ring, 6-membered heteroaryl and 5-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 6-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 6-membered heteroaryl and 6-membered heterocycloalkyl; Alternatively, Cy is selected from the following structures optionally further substituted with 1-3 R:

5. The compound according to claim 3, its stereoisomer or pharmaceutically acceptable salt, wherein L is selected from X1 and X2 are independently CR X1 or N; Each R X1 are independently H, F, Cl, methyl, ethyl, or R X1 Together with R3 and the atoms to which it is attached, it forms a C5 cycloalkyl group, a C6 cycloalkyl group, a 5-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a 6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O; R3 is H, F, Cl, =O, CN, C 1-3 alkyl; Each R is independently H, F, Cl, methyl, ethyl, acetylene, propyne, or two adjacent Rs and the atoms to which they are connected together form a cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group, and the cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group is optionally substituted with 1-3 groups selected from F, Cl, =O, CN, methyl, ethyl, methoxy, ethoxy, OH, and NH2.

6. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein Selected from the following structures:

7. The compound as described in Table 1 of the specification, its stereoisomers or pharmaceutically acceptable salts.

8. The compound according to claim 7, its stereoisomer or pharmaceutically acceptable salt, wherein The compound is selected from one of the structures in Table 2.

9. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 8, its stereoisomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

10. The pharmaceutical composition or pharmaceutical preparation according to claim 9, comprising 1-1500 mg of the compound according to any one of claims 1-8, its stereoisomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

11. Use of the compound according to any one of claims 1 to 8, its stereoisomers or pharmaceutically acceptable salts in the preparation of a medicament for treating / preventing a PDE4B-mediated disease.

12. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8, a stereoisomer 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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