Benzopyrone compound as well as preparation method and application thereof

Abstract

The invention provides a benzopyrone compound as shown in a formula (I) or pharmaceutically acceptable salt, a preparation method and application thereof. The compound has a good inhibition effect on POLRMT, and can be used for treating and / or preventing diseases such as cancers mediated by POLRMT. # imgabs0 #

Description

Benzopyrone compounds, preparation methods and applications thereof

[0001] This application claims two priority applications of application No. 202211527029.6 filed in China on December 1, 2022 and application No. 202310065010.2 filed in China on February 6, 2023, and all of their contents are introduced into this application again. Technical Field

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

[0003] Cancer refers to a disease caused by abnormal cell proliferation. In addition to uncontrolled division, cancer cells can also locally invade surrounding normal tissues and even metastasize to other parts of the body through the circulatory or lymphatic systems, causing damage or even death. Cancer is characterized by high mortality, poor prognosis, and expensive treatment costs. Cancer patients often endure tremendous physical pain, making it one of the most pressing healthcare issues in the world. Despite decades of extensive research, technological innovation, and drug development, existing cancer treatments, including chemotherapy, radiotherapy, and immunotherapy, still cannot meet current cancer treatment needs and are often associated with severe side effects and drug resistance. There is an urgent need for additional and improved treatment options to combat cancer.

[0004] Interfering with cancer metabolism is another principle in cancer treatment. Energy metabolic reprogramming, which promotes rapid cell growth and proliferation by regulating energy metabolism, is considered a hallmark of malignancy. Targeting metabolic reprogramming has become a key area of ​​research for cancer drug development (Luengo et al., 2017, Cell Chem Biol 24, 1161-1180). Since the discovery of the Warburg effect, which states that cancer cells grow much faster than normal cells due to a differential energy source, favoring glycolysis over mitochondrial oxidative phosphorylation, this has led to the hypothesis that oxidative phosphorylation (OXPHOS) is universally downregulated in cancer. Research has also focused on pharmacological inhibition of glycolysis. However, many glycolysis inhibitors (such as 2-deoxyglucose) do not appear to have the expected significant effect on tumor growth. This is true for many cancers, but in some, this hypothesis is increasingly being challenged. Accumulating evidence indicates that mitochondrial metabolism is not impaired in a variety of cancers, including leukemia, lymphoma, pancreatic ductal adenocarcinoma, OXPHOS-high melanoma, and endometrial cancer (Luengo et al., 2017, Cell Chem Biol 24, 1161–1180; Moreno-Sanchez et al., 2007, FEBS J 274, 1393–1418). Recent studies have provided strong evidence that tumor metabolism is heterogeneous, with some tumors relying on oxidative phosphorylation (OXPHOS) for energy (Hu et al., 2013, Nat Biotechnol 31, 522–529; Roesch et al., 2013, Cancer Cell 23, 811–825; Sriskanthadevan et al., 2015, Blood 125, 2120-2130), elevated OXPHOS levels, increased mitochondrial contribution to total cellular energy, greater entry of fatty acid and glucose-derived carbons into the tricarboxylic acid (TCA) cycle, and increased lipogenesis are critical for enhanced tumor growth (Birsoy et al., 2015, Cell 162, 540-551; Martinez-Reyes et al., 2020, Nature 585, 288-292; Sullivan et al., 2015, Cell 162, 552-563), suggesting an opportunity to target OXPHOS for effective cancer treatments.

[0005] Studies have shown that acquired resistance to therapy can cause tumor cells to shift from glycolysis to a preference for OXPHOS. This metabolic heterogeneity allows tumors to adapt to environmental changes and survive. For example, inhibition of OXPHOS can overcome resistance to chemotherapy (Cannavino et al., 2014, J Physiol 592, 4575-4589; Farge et al., 2017, Cancer Discov 7, 716-735; Lee et al., 2017, Cell Metab 26, 633-647 e637) and tyrosine kinase inhibitors (Zhang et al., 2019, Sci Transl Med 11). OXPHOS is upregulated in some gene mutation subtypes, including those with RB1 deficiency, SMARCA4 mutations, and PTEN mutations (Ashton et al., 2018, Clin Cancer Res 24, 2482-2490). and tumor subtypes with high OXPHOS classification, such as OXPHOS-high diffuse large B-cell lymphoma (Caro et al., 2012, Cancer Cell 22, 547-560). Currently, tumor types with confirmed elevated oxidative phosphorylation include acute lymphoblastic leukemia (ALL), colorectal cancer (CRC), glioma, diffuse large B-cell lymphoma, endometrial cancer, esophageal squamous cell carcinoma (ESCC), head and neck cancer, non-Hodgkin's lymphoma, ovarian cancer, papillary thyroid carcinoma, prostate cancer, and salivary gland oncocytoma (Ashton et al., 2018, Clin Cancer Res 24, 2482-2490; Xu et al., 2020, J Med Chem 63, 14276-14307).

[0006] These findings suggest new uses for OXPHOS inhibitors, namely treating cancers in which OXPHOS is upregulated or alleviating tumor hypoxia to improve therapeutic efficacy. Alleviating tumor hypoxia can be achieved in cancers in which OXPHOS is not upregulated, making such inhibitors broadly applicable. Cancer-related studies have reported on inhibitors targeting respiratory chain complex IV and the mitochondrial ribosome machinery, inhibitors that control translation of respiratory chain subunits, and inhibitors of related enzymes (Ashton et al., 2018; Clin Cancer Res 24, 2482-2490; Xu et al., 2020, J Med Chem 63, 14276-14307).

[0007] Recently, mitochondrial RNA polymerase (POLRMT, also known as mtRNAP) has come into the spotlight as a regulatory gene that controls the OXPHOS process and has become a new target for targeting tumor metabolism. For example, inhibition of POLRMT can inhibit AML tumor growth. This conclusion has been verified in the mouse CDX model, and upregulation of the POLRMT gene is positively correlated with poor prognosis in AML (Bralha et al., 2015, Oncotarget 6, 37216-37228). POLRMT is responsible for mitochondrial gene expression and provides RNA primers to initiate mitochondrial genome replication, as well as the transcription of 13 subunits of the OXPHOS complexes (complexes I, III, and IV), serving as the RNA primer enzyme for mitochondrial DNA replication. Inhibition of POLRMT affects mtDNA transcription, resulting in decreased mtDNA expression and decreased OXPHOS levels.

[0008] Therefore, the development of drugs that specifically inhibit POLRMT is of great significance for cancer research.

[0009] Summary of the Invention

[0010] The technical problem to be solved by the present invention is how to develop drugs that specifically inhibit POLRMT to effectively treat and intervene in cancer.

[0011] Specifically, in order to solve the above technical problems, the present invention provides the following technical solutions.

[0012] A benzopyrone compound represented by formula (I), or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof,

[0013] wherein X1 and X2 are each independently selected from an O or NH group; Y is selected from a CR group or N, wherein R is H or a C1-C3 alkyl group; R1 and R1' may be the same or different and are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group;

[0014] L1 and L3 are each independently selected from -O-, -S-, -NR3-, -CR2R3-, -CR2(R3), -CO-, -SO- or -SO2- groups; L2 is directly linked, -CR2R3-, -CR2(R3)- or -C(R2R3)-, wherein R2 is selected from H or a C1-C4 chain alkyl group; R3 is selected from H or a C1-C4 chain alkyl group; or R2 and R3 in a group of -CR2(R3) together form an oxygen subunit;

[0015] R4, R5 and R6 are each independently selected from H, halogen, -C-OR8(R9), -CR8(R9), -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SO2R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, olefin, alkynyl, aryl or heteroaryl or aromatic heterocyclic group, wherein R8, R9, R 10 are independently selected from H, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be independently replaced by one or more R 11 Replacement, R 11 R4 and R5 are selected from the group consisting of halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, acyloxy, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic heterocyclic group, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic heterocyclic group can be substituted with one or more halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl, or haloalkyl; or R4 and R5 together form an oxysubyl group;

[0016] Alternatively, any two or three of R4, R5 and R6 together with the carbon atom connected to L3 form a cyclic group A connected to L3: Wherein, the ring group A is selected from any one of the following ring groups: aromatic ring group, saturated cycloalkyl group or unsaturated cycloalkyl group, single heterocyclic group, condensed heterocyclic group, benzoheterocyclic group, spirocyclic group, bridged ring group and the like. 11 substituted ring groups;

[0017] W is selected from hydrogen, H, alkyl, -CR 8a R 9a R 10a 、-NR 8a R 9a 、-OR 10a , or a ring group B1 containing a carbon atom which may be substituted by one or more R7 and is connected to the benzopyrone ring through the carbon atom: or a ring group B2 containing a nitrogen atom and connected to a benzopyrone ring through the nitrogen atom: Here, R8a 、R 9a and R 10a Each is independently selected from H, halogen, alkyl, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, acyloxy, amide, sulfonate, sulfonamide, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group; the ring group B1 and the ring group B2 are each independently selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0018] wherein R7 is selected from H, halogen, -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SO2R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group, preferably selected from halogen, alkyl, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, acyloxy, sulfonate, sulfonamide, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group is independently composed of one or more R 11 Replacement, R8, R9 and R 10 The meaning of R8, R9 and R appears in R4, R5 and R6 10 The meaning is exactly the same;

[0019] In addition, formula (I) does not contain the following compounds:

[0020] In one embodiment, the compound of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, wherein X1 is an -O- group, X2 is an -O- group, Y is a -CR- group, and R1 and R1' are both hydrogen;

[0021] Alternatively, X1 is a -NH- group, X2 is a -O- group, Y is a -CR- group, and R1 and R1' are both hydrogen;

[0022] Alternatively, X1 is an -O- group, X2 is an -NH- group, Y is a -CR- group, and R1 and R1' are both hydrogen;

[0023] Alternatively, X1 is an -O- group, X2 is an -O- group, Y is an -N- group, and R1 and R1' are both hydrogen;.

[0024] In one embodiment, the compound of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, wherein -L1-L2-L3- as a whole is any one group selected from the following groups: -O-CR2(R3)-CO-, -O-CR2R3-CO-, -CR2(R3)-CR2(R3)-CO-, -NR3-CR2(R3)-CO-, -S-CR2(R3)-CO-, -SO2-CR2(R3)-CO-, -O-CR2(R3)-CR2R3-, -O-CR2(R3)-SO2- and -CR2(R3)-NR3-CO-;

[0025] Wherein, R2 is preferably one of H, methyl and ethyl, more preferably methyl; R3 is preferably methyl or H, more preferably H.

[0026] In one embodiment, the compound of any of the foregoing embodiments of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, wherein -L1-L2-L3- as a whole is any one group selected from the following groups: -O-CH(CH3)-CO-, -O-CR2(R3)-CO-, -CR2R3-CH(CH3)-CO-, -NR3-CH(CH3)-CO-, -S-CH(CH3)-CO-, -SO2-CH(CH3)-CO-, -O-CR2(R3)-CR2(R3)-, and -O-CH(CH3)-SO2- or -CR2(R3)-NR3-CO-.

[0027] In one embodiment, the compound of any one of the foregoing embodiments of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated product, or its hydrate, or its solvate, wherein the ring group A is selected from any one of the following ring groups: C3-C 12 Cycloalkyl, C3-C 12 Heterocycloalkyl, C5-C 12 Aryl and C5-C 12 Heteroaryl, preferably selected from C3-C 12 cycloalkyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, anthraquinonyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, indolyl, benzimidazolyl, carbazolyl, thiolinyl, quinoline, isoquinolinyl, purinyl, acridinyl, phenazinyl, and phenothiazinyl;

[0028] More preferably, the ring group A is selected from any one of the following ring groups: Wherein these ring groups A can be substituted by one or more groups selected from halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0029] In one embodiment, in the compound of any of the foregoing items of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, R4, R5, and R6 are each independently selected from -CR8(R9), R8 is H, a chain alkyl group, a cyano group, or a cycloalkyl group, and R9 is a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group substituted with halogen, cyano group, hydroxyl group, thiol group, ether group, nitro group, alkoxy group, amino group, amine group, carboxyl group, sulfonic acid group, ester group, acyl group, amide group, sulfonate group, or sulfonamide group, R9 is connected to the carbon atom connected to L3 through an oxygen atom, a nitrogen atom, or a carbon atom on the substituent.

[0030] In one embodiment, the compound of any one of the foregoing embodiments of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, the substituted ring group B1 and the substituted ring group B2 are each independently selected from: a halogenated cycloalkyl group, a halogenated heterocycloalkyl group, a halogenated aryl group, and a halogenated heteroaryl group;

[0031] Further preferably, the substituted ring group B1 and the substituted ring group B2 are each independently 2-chloro-4-fluorophenyl, chlorophenyl, methyl-substituted phenyl, amide-substituted phenyl, amino-substituted phenyl or phenylalkyl.

[0032] In one embodiment, the compound of any one of the foregoing embodiments of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated product, or its hydrate, or its solvate, wherein the ring group B1 is C5-C 10 Aryl, C5-C 10 Heteroaryl, C3-C 10 Cycloalkyl or C3-C 10 Heterocycloalkyl.

[0033] In one embodiment, the compound of any of the foregoing embodiments of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, wherein the compound of formula (I) is selected from the compounds represented by any of the following structural formulas:

[0034] Wherein, the R7 is preferably F, Cl, Br, I, OH, OR2, C 1-3Any one or more of alkyl, sulfonic acid, nitro, amino, and amine; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy; wherein R2 is the same as defined in claim 1; n is an integer of 0-5;

[0035] Wherein R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-3 Any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, or an amine group; R 11 Preferably, F, Cl, Br, I, C 1-4 Alkoxy, acyl, or C 1-3 Alkyl, sulfonic acid, nitro, amino, cyano, amino, -C0-4 alkyl-COOH, ester, acyloxy, ether, amide, aminoacyl, cycloalkyl-substituted aminoacyl, or arylalkyl-substituted aminoacyl, carboxyl-substituted C 1-3 Alkoxy, carboxyl substituted amino, cycloalkyl substituted C 1-3 Alkoxy, acyloxy-containing C 3-5 Cycloalkyl, or Any one or more groups in 11 The benzene ring connected thereto may form a benzene ring and nitrogen heterocyclic or oxygen heterocyclic structure; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkyloxy; R 2a is selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy-substituted C1-C4 alkyl, C1-C4 alkyl-substituted formyl; n is an integer of 0-5;

[0036] Among them, R 11 Preferably -C0-4 alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0037] in, Preferably C 1-4 Alkyl, C 1-4 Alkylphenyl, more preferably methyl, isobutyl or benzyl; R 11 Preferably -C0-4 alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0038] Among them, R 10 Preferably C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or hydroxy substituted C 1-4 Alkoxy, R 11 Preferably -C0-C4 alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0039] wherein R8 and R9 are independently selected from hydrogen or C 1-4 Alkyl; R 11 Preferably -C0-C4 alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0040] The cyclic group, ie, the cyclic group B1, is preferably selected from: 3-12 cycloalkyl, four to ten-membered heterocyclic group, or five to ten-membered aryl group; R 11 Preferably, it is -C0-C4 alkyl-COOH; the heterocyclic group is further preferably any one of furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, indolyl, benzimidazolyl, carbazolyl, thiolinyl, quinoline, isoquinolyl, purinyl, acridinyl, phenazinyl and phenothiazinyl; R1 and R1' are preferably hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; the ring group B1 is optionally substituted by 1 or 2 or more hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-substituted hydroxy, amino, amine, or unsubstituted;

[0041] The cyclic group B2 is preferably selected from: 3-12 cycloalkyl, four to ten-membered heterocyclic group, or five to ten-membered aryl group; R 11Preferably, -C0-4 alkylcarboxyl; the heterocyclic group is further preferably any one of furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, indolyl, benzimidazolyl, carbazolyl, thiolinyl, quinolyl, isoquinolyl, purinyl, acridinyl, phenazinyl and phenothiazinyl; R1 and R1' are preferably hydrogen; the ring group B2 is optionally replaced by one or more hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-substituted hydroxyl, amino, amine, or unsubstituted;

[0042] Wherein R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 The benzene ring in the structural formula is substituted by any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-3 any one or more of alkoxy or alkyl, cycloalkyl, sulfonic acid, nitro, amino, cyano, amine, -C0-4 alkyl-carboxyl, ester, acyloxy, and ether groups; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl;

[0043] The R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 The benzene ring in the structural formula is substituted by any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group or an amine group, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 any one or more of alkyl, cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C0-4 alkyl-carboxyl; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl;

[0044] Wherein, the R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 The benzene ring in the structural formula is substituted by any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group or an amine group, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, hydroxyl, hydroxyl substituted C 1-6 Any one or more of alkyl, nitro, amino, cyano, amine or -C0-4 alkylcarboxyl; n is an integer of 0-5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl;

[0045] Wherein, the R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 Alkyl, C 3-10 The benzene ring in the structural formula is substituted by any one or more of cycloalkyl, sulfonic acid, nitro, amino or amine, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-3 any one or more of alkoxy, alkyl, cycloalkyl, sulfonic acid, hydroxy, nitro, amino, cyano, amine, and -C0-4 alkylcarboxyl; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl;

[0046] Among them, wherein, the R7 is preferably F, Cl, Br, I, OH, OR 2a or any one or more of C1-3 alkyl, sulfonic acid, nitro, amino, and amine, more preferably chlorine and fluorine together replace the benzene ring in the structural formula; R 11 It can be hydrogen or replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 any one or more of cycloalkyl, sulfonic acid, hydroxyl, nitro, amino, cyano, amine, and -C0-4 alkylcarboxyl; n is an integer from 0 to 5; R 2aSelected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl;

[0047] The ring group A is an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group which may be substituted or unsubstituted by one or more groups selected from halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, -C0-4 alkyl-carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, and heterocycloalkyl; wherein the cycloalkyl group is preferably C 3-6 The heterocycloalkyl group is preferably any one of oxirane, oxetane, aziridine, azetidine and thietane; heteroaryl includes a five-membered heteroaryl group such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyrazolyl, or an oxygen-containing imidazolyl or pyrazolyl, a six-membered heteroaryl group such as pyridyl, pyrimidinyl, pyranyl, pyridazinyl, pyrazinyl, a group formed by pyrone or pyranyl, a benzoheterocyclic group such as benzofuranyl, benzothienyl, benzopyrrolyl, indolyl, quinolyl, isoquinolyl, benzopyranyl, a group formed by benzo-γ-pyrone, a heterocyclic and heterocyclic group such as purinyl; W is preferably 2-chloro-4-fluoro substituted phenyl, or 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0048] Wherein, the ring group A is preferably a condensed ring or an aromatic heterocyclic group, more preferably a benzoheterocyclic group is a benzofuranyl, benzothienyl, benzopyrrolyl, a benzoheterocyclic group such as an indolyl, quinolyl, isoquinolyl, benzopyranyl, or a group formed by benzo-γ-pyrone, W is preferably a 2-chloro-4-fluoro substituted phenyl or a 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0049] Wherein, the ring group A is preferably selected from a spiro ring or a bridged ring group; W is preferably 2-chloro-4-fluoro substituted benzene or 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0050] Wherein, the ring group A is preferably phenyl, halogenated phenyl, -C0-4 alkylcarboxyl substituted phenyl, more preferably phenyl or carboxyl substituted phenyl; W is preferably 2-chloro-4-fluoro substituted benzene or 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0051] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C0-4 alkyl-carboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0052] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C0-4 alkyl-carboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0053] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C0-4 alkyl-carboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0054] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C0-4 alkylcarboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0055] wherein R7 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy; n is an integer of 0-5; R2, R3 are independently selected from hydrogen, C 1-4 Alkyl; R4 and R5 together form an oxygen subunit;

[0056] Wherein, R2 and R3 are each independently preferably hydrogen, C 1-6 or one group of R2, R3 together to form an oxygen subunit, the other group of R2, R3 are independently preferably hydrogen, C 1-6 Alkyl; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0057] Among them, the ring group A is preferably substituted by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 A phenyl group which is substituted or unsubstituted with any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or carboxyl groups; further, the ring group A is preferably replaced by R as a carboxyl group. 11 substituted phenyl; W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are preferably hydrogen;

[0058] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C0-4 alkylcarboxyl groups as R 11 Substituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0059] The ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 A phenyl group which is substituted or unsubstituted by any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C0-4 alkylcarboxyl groups; further, the ring group A is preferably replaced by R as a carboxyl group. 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0060] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 A phenyl group substituted with any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C0-4 alkylcarboxyl groups; further, the ring group A is preferably R as a carboxyl group. 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl;

[0061] as well as

[0062] Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10A phenyl group substituted with any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C0-4 alkylcarboxyl groups; further, the ring group A is preferably R as a carboxyl group. 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl.

[0063] The present invention also provides a pharmaceutical composition comprising the compound according to any of the foregoing items, or its stereoisomer, or its salt, or its prodrug, or its deuterated substance, or its hydrate, or its solvate; or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0064] The present invention also provides the use of the compound described in any of the above items, or its stereoisomer, or its salt, or its prodrug, or its deuterated product, or its hydrate, or its solvate; or its pharmaceutically acceptable salt, or the pharmaceutical composition described above in the preparation of a POLRMT inhibitor drug.

[0065] The present invention also provides the use of the compound described in any of the above items, or its stereoisomer, or its salt, or its prodrug, or its deuterated product, or its hydrate, or its solvate; or its pharmaceutically acceptable salt, or the pharmaceutical composition described above in the preparation of a drug for a disease associated with abnormally high expression of POLRMT oxidative phosphorylation.

[0066] In a more specific embodiment, the use of the present invention is characterized in that the disease is cancer; preferably, the cancer is melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, multiple myeloma, breast cancer, glioma, glioblastoma, cervical cancer, kidney cancer, colorectal cancer or ovarian cancer.

[0067] The beneficial technical effects achieved by the present invention are:

[0068] 1) The compounds of the present invention have better inhibitory activity against ovarian cancer cells than the compounds disclosed in the prior art.

[0069] 2) The compounds of the present invention have good pharmacokinetic properties, such as good Cmax, AUC and other parameters. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] FIG1 is a diagram showing the BLI imaging results of the MOLM-13-luc orthotopic mouse tumor model in Experimental Example 4;

[0071] FIG2 is a survival curve of the MOLM-13-luc orthotopic mouse tumor model in Experimental Example 4. DETAILED DESCRIPTION

[0072] In order to develop drugs that specifically inhibit POLRMT to effectively treat, prevent or block cancer, the present invention provides the following technical solutions.

[0073] The first set of technical solutions

[0074] One of the objects of the present invention is to provide a benzopyrone compound, such as the general formula α-(I), the general formula α-(II), the general formula α-(III), etc., and pharmaceutically acceptable salts thereof;

[0075] Another object of the present invention is to provide a pharmaceutical composition comprising any one of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

[0076] Another object of the present invention is to provide a compound of the above general formula or a pharmaceutically acceptable salt thereof as a POLRMT inhibitor or in the preparation of a drug for a disease associated with abnormally high expression of POLRMT oxidative phosphorylation;

[0077] Another object of the present invention is to provide the use of the compound of the above general formula or a pharmaceutically acceptable salt thereof in a medicament for treating and / or preventing cancer, such as melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer;

[0078] Another object of the present invention is to provide a method for preparing the compound of the above general formula.

[0079] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0080] In some embodiments of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0081] Wherein, R1, R2, and R3 are independently selected from: a hydrogen atom, a C1-C6 alkyl group, and R1, R2, and R3 are not hydrogen atoms at the same time;

[0082] Alternatively, R1 and R2 are linked to each other to form a ring as shown below, and R3 is a hydrogen atom or is absent:

[0083] Optionally, the ring formed by the R1 and R2 connected to each other is substituted by m R';

[0084] m is selected from: 0, 1, 2, 3, 4 or 5;

[0085] R' is selected from: hydrogen atom, amino group, carboxyl group, C 1-6 Alkyl carboxyl;

[0086] R4 and R5 are independently selected from: hydrogen atom, halogen, C 1-6 alkyl.

[0087] In some embodiments of the present invention, a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof is provided:

[0088] wherein R1, R2, and R3 are independently selected from a hydrogen atom and a C1-C6 alkyl group, and R1, R2, and R3 are not hydrogen atoms at the same time; or, R1 and R2 are connected to form a ring as shown below, and R3 is a hydrogen atom or does not exist:

[0089] Optionally, the ring formed by R1 and R2 is substituted by m R', m is selected from: 0 or 1, and the R' is selected from: hydrogen atom, amino group, carboxyl group or C1-C6 alkylcarboxyl group.

[0090] In some embodiments of the present invention, a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof is provided:

[0091] Wherein, R1 and R2 are connected to form a ring as shown below, and R3 is a hydrogen atom or does not exist:

[0092] Optionally, the ring formed by R1 and R2 is substituted by m R', m is selected from: 0 or 1, and the R' is selected from: hydrogen atom, amino group, carboxyl group or C1-C6 alkylcarboxyl group.

[0093] In some embodiments of the present invention, the compounds shown below are provided, but are not limited to the following specific compounds:

[0094] In some embodiments of the present invention, a pharmaceutical composition is provided, comprising at least one compound of the present invention described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, additive, or excipient.

[0095] In some embodiments of the present invention, provided are uses of the compounds of the present invention described herein or pharmaceutically acceptable salts thereof, as well as the aforementioned pharmaceutical compositions, in the preparation of POLRMT inhibitors or drugs for diseases associated with abnormally high expression of POLRMT oxidative phosphorylation.

[0096] In some embodiments of the present invention, there is provided use of the compounds of the present invention described herein, or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates thereof, and the aforementioned pharmaceutical compositions, in the preparation of medicaments for treating and / or preventing cancer; preferably, use in the preparation of medicaments for treating and / or preventing melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, myeloma, breast cancer, glioma, glioblastoma, cervical cancer, kidney cancer, colorectal cancer or ovarian cancer.

[0097] The second technical solution

[0098] The present invention provides a benzopyrone compound, such as general formula (I'), and pharmaceutically acceptable salts thereof;

[0099] Another object of the present invention is to provide a pharmaceutical composition comprising any one of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

[0100] Another object of the present invention is to provide a compound of the above general formula or a pharmaceutically acceptable salt thereof as a POLRMT inhibitor or in the preparation of a drug for a disease associated with abnormally high expression of POLRMT oxidative phosphorylation;

[0101] Another object of the present invention is to provide the use of the compound of the above general formula or a pharmaceutically acceptable salt thereof in a medicament for treating and / or preventing cancer, such as melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer;

[0102] Another object of the present invention is to provide a method for preparing the compound of the above general formula.

[0103] In some embodiments of the present invention, a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof is provided:

[0104] Wherein, ring A is optionally selected from

[0105] *The configuration of carbon is R or S;

[0106] Ring A is optionally substituted by any one or more of R'1, R'2, R'3, R'4 and R'5;

[0107] Said R'1, R'2, R'3, R'4 and R'5 are independently selected from any one of: a hydrogen atom, a halogen, a carboxyl group and a C1-6 alkylcarboxyl group;

[0108] R4 and R5 are independently selected from any one of hydrogen atom, halogen and C1-6 alkyl.

[0109] In some embodiments of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

[0110] The salt is optionally a sodium salt, a potassium salt or an ammonium salt.

[0111] Table β-1: A1-1 series compounds

[0112] Table β-2: A2-1 series compounds

[0113] Table β-3: A1-2 series compounds

[0114] Table β-4: A2-2 series compounds

[0115] Table β-5: A1-3 series compounds

[0116] Table β-6: A2-3 series compounds

[0117] Table β-7: A1-4 series compounds

[0118] Table β-8: A2-4 series compounds

[0119] The third technical solution

[0120] The present invention provides a benzopyrone compound, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof.

[0121] wherein X1 and X2 are each independently selected from an O or NH group; Y is selected from a CR group or N, wherein R is H or a C1-C3 alkyl group; R1 and R1' may be the same or different and are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group;

[0122] L1 and L3 are each independently selected from -O-, -S-, -NR3-, -CR2R3-, -CR2(R3), -CO-, -SO- or -SO2- groups; L2 is directly linked, -CR2R3-, -CR2(R3)- or -C(R2R3)-, wherein R2 is selected from H or a C1-C4 chain alkyl group; R3 is selected from H or a C1-C4 chain alkyl group; or R2 and R3 in a group of -CR2(R3) together form an oxygen subunit;

[0123] R4, R5 and R6 are each independently selected from H, halogen, -C-OR8(R9), -CR8(R9), -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SO2R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, olefin, alkynyl, aryl or heteroaryl or aromatic heterocyclic group, wherein R8, R9, R 10 are independently selected from H, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be independently replaced by one or more R 11 Replacement, R 11 R4 and R5 are selected from the group consisting of halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, acyloxy, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic heterocyclic group, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic heterocyclic group can be substituted with one or more halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl, or haloalkyl; or R4 and R5 together form an oxysubyl group;

[0124] Alternatively, any two or three of R4, R5 and R6 together with the carbon atom connected to L3 form a cyclic group A connected to L3: Wherein, the ring group A is selected from any one of the following ring groups: aromatic ring group, saturated cycloalkyl group or unsaturated cycloalkyl group, single heterocyclic group, condensed heterocyclic group, benzoheterocyclic group, spirocyclic group, bridged ring group and the like. 11 substituted ring groups;

[0125] W is selected from hydrogen, H, alkyl, -CR8a R 9a R 10a 、-NR 8a R 9a 、-OR 10a , or a ring group B1 containing a carbon atom which may be substituted by one or more R7 and is connected to the benzopyrone ring through the carbon atom: or a ring group B2 containing a nitrogen atom and connected to a benzopyrone ring through the nitrogen atom: Here, R 8a 、R 9a and R 10a Each is independently selected from H, halogen, alkyl, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, acyloxy, amide, sulfonate, sulfonamide, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group; the ring group B1 and the ring group B2 are each independently selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0126] wherein R7 is selected from H, halogen, -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SO2R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group, preferably selected from halogen, alkyl, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, acyloxy, sulfonate, sulfonamide, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group is independently composed of one or more R 11 Replacement, R8, R9 and R 10 The meaning of R8, R9 and R appears in R4, R5 and R6 10 The meaning is exactly the same;

[0127] In addition, formula (I) does not contain the following compounds:

[0128] In one embodiment of the present invention, various types of benzopyrone compounds as shown in Table γ-1 below, as well as preparation methods and uses thereof in the preparation of POLRMT inhibitor drugs are specifically provided:

[0129] Table γ-1 Various types of benzopyrone compounds

[0130] Terms used in this invention

[0131] The following terms and the like are used to describe the present invention. It should be understood that terms not specifically defined are given a meaning consistent with the use of the terms in the context of the present invention as understood by those of ordinary skill in the art.

[0132] The term "alkyl" as used herein refers to a saturated aliphatic hydrocarbon group, which includes straight-chain and branched hydrocarbon groups. For example, "C m-n "Alkyl" refers to an alkyl group having m to n carbon atoms (m and n are integers), for example, C 1-6 Alkyl. "C1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms, for example, an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, including but not limited to methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl), and the like.

[0133] In the present invention, X n , L n , R n , R na The subscript numbers and / or letters "n" or "na" in the formula are only used to distinguish different groups (or substituents or atoms) and do not indicate the number of these groups, such as X1, X2, R2, R 2a , L1, L2, L3, R3, R3, R4, R5, R6, R7, R8, R9, R 10 , R 8a , R 9a , R 10a , R 11 The subscript numbers and / or letters in the substituents, such as 1, 2, 2a, etc., are merely numbers given to distinguish different substituents, groups, or atoms; specifically, examples of the connection modes of these R substituents, which are not limiting, are as follows:

[0134] For example, "-C(R2R3)-" may refer to a form in which R2 is directly connected to the C atom, while R3 is connected to R2, but R3 is not directly connected to the C atom. The structural formula is

[0135] For example, "-CR2R3-" can mean -CR 2- R3-structure;

[0136] For example, "-CR8(R9)" may refer to a structure in which R9 is only connected to a C atom, such as:

[0137] For example, "-C-OR8(R9)" may refer to a structure in which R9 is directly connected to a carbon atom and is not connected to R8;

[0138] For example, "-NR3-" can refer to

[0139] For example, "-NR8R9" can refer to

[0140] The term "oxo" as used herein refers to "O=".

[0141] The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0142] The term "carboxyl" as used herein refers to -COOH.

[0143] The term "alkylcarboxyl" as used herein refers to an alkyl group having a carboxyl substituent.

[0144] The "heterocyclic group" used in the present invention refers to any group formed by saturated or unsaturated oxygen heterocyclic, nitrogen heterocyclic and sulfur heterocyclic compounds, for example, including heterocycloalkyl and heteroaryl, including but not limited to the following groups: heterocycloalkyl such as oxirane, oxetane, aziridine, azetidine, thietane and hydrogenated aromatic heterocyclic groups (such as tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, dioxane, piperazinyl, hexahydropyrazinyl, morpholinyl, dithianyl, etc.); "heteroaryl" includes but is not limited to five-membered heteroaryl, six-membered heteroaryl, benzoheteroaryl, etc., such as furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, oxygen-containing imidazolyl or pyrazolyl any of the following groups or partially hydrogenated aromatic heterocyclic groups: benzofuranyl, benzothiophenyl, benzopyrrolyl, indolyl, quinolyl, isoquinolyl, benzopyranyl, benzo-γ-pyrone, and fused-ring heterocyclic groups, as well as heterocyclic heterocyclic groups such as purinyl; the “aryl” refers to any of phenyl, naphthyl, anthracenyl, and phenanthryl; “heteroaryl” is also referred to herein as “aromatic heterocyclic group” or “heteroaromatic ring group” or “aromatic heterocyclic group”, and refers to any of the above aromatic groups in which the carbon atoms are substituted by oxygen atoms or nitrogen atoms, such as anthraquinone;

[0145] "Benzopyrone compounds" refer to compounds containing a benzopyrone ring, a structure in which a carbon atom on the benzene ring of a benzopyrone ring is replaced with a nitrogen atom, a derivative structure in which either of the two oxygen atoms on the pyrone ring of a benzopyrone ring is replaced with a nitrogen atom, and any of the various structures formed after substitution of the above structures. "Coumarin ring" refers to the benzopyrone ring in the "benzopyrone compounds" described above, including structures in which a carbon atom on the benzene ring is replaced with a nitrogen atom or structures in which either of the two oxygen atoms on the pyrone ring is replaced with a nitrogen atom.

[0146] The term "pharmaceutically acceptable salt" used in the present invention refers to a salt of the compound of the present invention, which is prepared by reacting the compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0147] The term "pharmaceutically acceptable carrier" as used herein refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc.

[0148] Preparation Example

[0149] In order to further illustrate in detail the preparation of the benzopyrone compounds of the present invention and the technical effects of the compounds as drugs that specifically inhibit POLRMT, the following is a detailed description by way of examples.

[0150] The first group of preparation examples (including embodiments of the first set of technical solutions)

[0151] Preparation Example (I) 1 Compound α-1

[0152] first step

[0153] To a 100 mL three-necked flask protected by N2, α-1a (2.03 g, 20.3 mmol) and dry tetrahydrofuran (20 mL) were added sequentially. After complete dissolution, the mixture was cooled to 0°C, followed by the dropwise addition of lithium hexamethyldisilazide (0.5 mL, 2.0 M / THF). After completion of the addition, the mixture was allowed to react for 10 minutes, then cooled to -78°C, and liquid bromine (1 mL, 20 mmol) was slowly added dropwise. The reaction temperature was maintained for 3 hours. TLC monitoring indicated that the reaction was complete. The reaction solution was added dropwise to saturated aqueous sodium bicarbonate solution, followed by extraction with diethyl ether (20 mL x 3). The organic phases were combined and washed sequentially with sodium thiosulfate solution and saturated brine. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude α-1b (3.58 g, 19.99 mmol, 98% yield).

[0154] Step 2

[0155] In a 200 mL single-necked flask, α-1c (20.62 g, 100 mmol) and methanesulfonic acid (65 mL) were added in sequence. After sufficient dissolution, resorcinol (10.392 g, 94 mmol) was added. The temperature was raised to 45°C and the reaction was carried out for 4 h. TLC monitoring indicated that the raw materials had reacted completely. The reaction solution was diluted with ethanol and stirred with water. Solid precipitated and was filtered to obtain the intermediate α-1d (18.0 g, 71.35 mmol, yield 72%).

[0156] Step 3

[0157] In a 100 mL single-necked flask, α-1d (0.73 g, 2.89 mmol) and N,N-dimethylformamide (10 mL) were added sequentially. After complete dissolution, cesium carbonate (2.36 g, 7.23 mmol) was added at room temperature. After the addition was complete, the mixture was reacted for 10 minutes. α-1b (0.52 g, 2.89 mmol) was added and the reaction was continued for 4 hours. TLC monitoring indicated that the reaction of the raw materials was complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product α-1 (0.32 g, 0.91 mmol, 32% yield) was obtained by column chromatography. MS-ESI calculated value [M+H] + 351.1, measured value 351.4.

[0158] Preparation Example (I) 2 Compound α-2

[0159] first step

[0160] In a 100 mL single-necked flask, α-2a (1 g, 7.14 mmol) and carbon tetrachloride (10 mL) were added in sequence. After sufficient dissolution, the mixture was stirred for 5 min, and liquid bromine (0.3 mL, 5.71 mmol) was added dropwise and reacted for 4 h. After TLC monitoring, the reaction was complete. The reaction solution was added dropwise to a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate solution and saturated brine in sequence, and the organic phase was dried over anhydrous sodium sulfate. After concentration on a rotary evaporator, the mixture was separated and purified using a rapid separation column to obtain α-2b (1.33 g, 6.07 mmol, yield 85%).

[0161] Step 2

[0162] In a 100 mL single-necked flask, α-1d (1.10 g, 4.36 mmol) and N,N-dimethylformamide (10 mL) were added sequentially and fully dissolved. Cesium carbonate (4.11 g, 12.6 mmol) was added at room temperature and allowed to react for 10 min. α-2b (1.33 g, 6.07 mmol) was then added and allowed to react for 4 h. TLC monitoring indicated that the reaction was complete. The reaction solution was concentrated using a rotary evaporator. Water was added to precipitate a solid, which was filtered and purified by column chromatography to give the product α-2 (1.00 g, 2.56 mmol, 59% yield). MS-ESI calculated value [M+H] + 391.1, measured value 391.4. 1H NMR (400MHz, DMSO-d6) δ7.48-7.37(m,2H),7.34(t,J=7.3Hz,1H),7.23(d,J=7.4Hz,1H),6.98(t,J=2.5Hz,1H ),6.92-6.78(m,2H),6.18(s,1H),5.34(qd,J=6.8,2.3Hz,1H),2.77(ddd,J=11.2,7.8,3.3Hz,1H),2.11(d,J= 2.1Hz, 3H), 1.78-1.58 (m, 4H), 1.47 (d, J = 6.8Hz, 3H), 1.37-1.10 (m, 6H).

[0163] Preparation Example (I) 3 Compound α-3

[0164] first step

[0165] In a 250 mL single-necked flask, α-3a (3 g, 34.83 mmol) and diethyl ether (87 mL) were added sequentially. After full dissolution, liquid bromine (1.8 mL, 34.83 mmol) was added dropwise at room temperature and reacted for 4 h. After TLC monitoring, the reaction of the raw materials was complete. The reaction solution was added dropwise to a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed sequentially with sodium thiosulfate solution and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The crude product α-3b (4.6 g, 27.87 mmol, yield 80%) was obtained after concentration on a rotary evaporator. It can be used directly in the next experiment without purification.

[0166] Step 2

[0167] In a 200 mL single-necked flask, α-1d (1.21 g, 4.8 mmol) and N,N-dimethylformamide (20 mL) were added sequentially. After complete dissolution, cesium carbonate (4.07 g, 12.5 mmol) was added at room temperature and allowed to react for 10 min. α-3b (1.32 g, 8 mmol) was then added and allowed to react for 8 h. TLC monitoring indicated that the reaction was complete. The reaction solution was filtered, the filtrate diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and then separated and purified using a flash column to obtain the desired product (0.70 g, 2.08 mmol, 43% yield). MS-ESI calculated value [M+H] + 337.1, measured value 337.4. 1H NMR(400MHz,DMSO-d6)δ7.38(dt,J=29.0,8.3Hz,3H),7.24(d,J=7.7Hz,1H),7.01(s,1H),6.86(s,2H),6.19 (s, 1H), 5.17 (q, J = 7.0Hz, 1H), 2.84-2.52 (m, 2H), 2.11 (s, 3H), 1.47 (d, J = 6.0Hz, 3H), 0.94 (t, J = 6.2Hz, 3H).

[0168] Preparation Example (I) 4 Compound α-4

[0169] first step

[0170] In a dry 100 mL three-necked flask, α-4a (7.00 g, 33.90 mmol) was dissolved in perchloric acid (20 mL). Resorcinol (4.50 g, 40.7 mmol) was then added and allowed to react at room temperature for 16 h until completion. After completion, the reaction was quenched by adding water (40 mL) in an ice-water bath. The product was extracted with ethyl acetate, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield α-4b (6.94 g, 27.51 mmol, 81.1% yield).

[0171] MS-ESI calculated value [M+H]+ 253.1, found 253.0.

[0172] 1 H NMR(600MHz,DMSO-d6)δ10.64(s,1H),7.44–7.37(m,2H),7.34(t,J=7.4,1H),7.23(d, J=7.5,1H),6.84–6.79(m,2H),6.73(dd,J=8.7,2.3Hz,1H),6.09(s,1H),2.11(s,3H).

[0173] Step 2

[0174] In a dry 50 mL three-necked flask, compound α-4c (1.00 g, 7.40 mmol) was dissolved in acetic acid: carbon tetrachloride = 1:1 (10 mL), and then bromine (3.55 g, 22.21 mmol) was added. The reaction was allowed to proceed at room temperature for 16 h until completion. After completion, saturated sodium sulfite solution (10 mL) and saturated sodium bicarbonate solution (20 mL) were added in an ice-water bath to quench the reaction. The mixture was extracted with ethyl acetate, dried, and concentrated to give the crude product α-4d (1.10 g, 5.14 mmol, yield: 63.39%).

[0175] MS-ESI calculated value [M+H]+ 214.1, found 214.0.

[0176] Step 3

[0177] In a dry 50 mL three-necked flask, compound α-4d (407.0 mg, 1.9 mmol), α-4b (400.0 mg, 1.59 mmol), and potassium carbonate (438.0 mg, 3.17 mmol) were dissolved in acetonitrile (10 mL). The reaction was allowed to proceed at room temperature for 16 hours, after which the reaction was complete. After completion, the reaction was quenched by the addition of water (20 mL), extracted with ethyl acetate, and then dried and concentrated. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to afford α-4 (69.0 mg, 0.18 mmol, 11% yield) as a white solid.

[0178] MS-ESI calculated value [M+H]+ 386.4, found 386.0.

[0179] 1 H NMR (600MHz, DMSO-d6) δ8.83(d,J=4.7,1H),8.09(t,J=7.7,1H),8.01(d,J=7.8,1H),7.81–7.75(m,1H),7.43–7.37(m,2H),7.33(q, J=7.3,1H),7.25–7.20(m,1H),6.91–6.79(m,3H),6.43(q,J=6.8Hz,1H),6.17(s,1H),2.10(d,J=5.1Hz,3H),1.63(d,J=6.8Hz,3H).

[0180] Preparation Example (I) 5 Compound α-5

[0181] first step

[0182] Compound α-5a (500.0 mg, 3.70 mmol) was dissolved in diethyl ether (5 mL) in a dry 50 mL three-necked flask, and bromine (1.18 mg, 7.4 mmol) was added. The reaction was carried out at 50°C for 20 h until completion. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product α-5b (500 mg, 2.34 mmol, yield: 63.1%).

[0183] MS-ESI calculated value [M+H] + 214.1, measured value 214.0.

[0184] Step 2

[0185] In a dry 50 mL three-necked flask, compound α-5b (500 mg, 2.34 mmol), α-4b (250 mg, 0.99 mmol), and N,N-diisopropylethylamine (645.0 mg, 5.0 mmol) were dissolved in acetone (10 mL). The reaction was allowed to proceed at room temperature for 16 h, leading to completion. After completion, the reaction was quenched with water (20 mL), extracted with ethyl acetate, and then dried and concentrated. The residue was purified by silica gel column chromatography and then by preparative high-pressure chromatography to yield product α-5 (70 mg, 0.18 mmol, 18% yield) as a white solid.

[0186] MS-ESI calculated value [M+H] + 386.4, measured value 386.0.

[0187] 1 H NMR(600MHz, DMSO-d6)δ9.24(s,1H),8.87(d,J=4.2Hz,1H),8.41(dq,J=8.0,2.2Hz,1H),7.64(dd,J=8.0,4.8Hz,1H),7.45–7.37(m,2H),7.36–7.31 (m,1H),7.25–7.22(m,1H),7.11(s,1H),6.93–6.87(m,2H),6.23(p,J=6. 7Hz, 1H), 6.20 (s, 1H), 2.11 (d, J = 3.4Hz, 3H), 1.59 (dd, J = 6.8, 1.3Hz, 3H).

[0188] Preparation Example (I) 6 Compound α-6

[0189] first step:

[0190] Compound α-6a (500 mg, 3.70 mmol) was dissolved in diethyl ether (5 mL) in a dry 50 mL three-necked flask, and then liquid bromine (1.18 mg, 7.40 mmol) was added. The reaction was carried out at 50°C for 20 h until the reaction was complete. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product α-6b (500.0.0 mg, 2.34 mmol, yield: 63%).

[0191] MS-ESI calculated value [M+H] + 214.06, measured value 214.0.

[0192] Step 2:

[0193] In a dry 50 mL three-necked flask, compound α-6b (500 mg, 2.34 mmol), α-4b (250.0 mg, 0.99 mmol), and N,N-diisopropylethylamine (645.0 mg, 5.0 mmol) were dissolved in acetone (10 mL). The reaction was allowed to proceed at room temperature for 16 h, after which the reaction was complete. After completion, the reaction was quenched with water (20 mL), extracted with ethyl acetate, and then dried and concentrated. The residue was purified by silica gel column chromatography and then by preparative high-pressure chromatography to yield product α-6 (60.0 mg, 0.16 mmol, 16% yield) as a white solid.

[0194] MS-ESI calculated value [M+H]+ 386.4, found 386.0.

[0195] 1 H NMR(600MHz, DMSO-d6)δ8.86(d,J=17.4,4.7,2H),7.95–7.84(m,2H),7.45–7.37(m,2H),7.37–7.30(m,1H),7.26–7.21( m,1H),7.11(d,J=2.0Hz,1H),6.92–6.86(m,2H),6.26–6.19(m,2H),2.11(d,J=3.7Hz,3H),1.57(dd,J=6.7,1.2Hz,3H).

[0196] Preparation Example (I) 7 Compound α-7

[0197] first step:

[0198] In a dry 100 mL three-necked flask, compound α-7a (4.00 g, 17.45 mmol) was dissolved in N,N-dimethylformamide (40 mL). Dimethylhydroxylamine hydrochloride (2.00 g, 20.90 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.96 g, 20.90 mmol), and N,N-diisopropylethylamine (6.75 g, 52.35 mmol) were then added. The reaction was allowed to proceed to completion at room temperature for 3 h. After completion, water (40 mL) was added to quench the reaction, which was then extracted with ethyl acetate and dried and concentrated. The residue was concentrated under reduced pressure and purified by medium-pressure reverse phase chromatography to afford product α-7b (4.75 g, 17.44 mmol, yield: 99%).

[0199] MS-ESI calculated value [M+H]+ 273.2, found 273.0.

[0200] Step 2:

[0201] In a dry 100 mL three-necked flask, compound α-7b (4.50 g, 16.52 mmol) was dissolved in tetrahydrofuran (40 mL), followed by the addition of ethylmagnesium bromide (1 M in tetrahydrofuran) (24.80 mmol). The reaction was allowed to proceed at room temperature for 18 h until completion. After completion, the reaction was quenched by the addition of water (40 mL), extracted with ethyl acetate, and then dried and concentrated. The residue was concentrated under reduced pressure and purified by medium-pressure reverse phase chromatography to afford product α-7c (3.50 g, 14.50 mmol, yield: 87%).

[0202] MS-ESI calculated value [M+H]+ 242.3, found 242.0.

[0203] Step 3:

[0204] In a dry 50 mL three-necked flask, compound α-7c (2.00 g, 8.29 mmol) was dissolved in diethyl ether (10 mL), followed by the addition of bromine (1.45 g, 9.1 mmol). The reaction was allowed to proceed at 40°C for 4 h until completion. After completion, the mixture was concentrated under reduced pressure to afford the crude product α-7d (1.50 g, 6.84 mmol, 82% yield).

[0205] MS-ESI calculated value [M+H]+ 220.1, found 220.0.

[0206] Step 4:

[0207] In a dry 50 mL three-necked flask, crude compound α-7d (650 mg, 2.95 mmol) was dissolved in acetone (20 mL), followed by the addition of α-4b (500.0 mg, 1.98 mmol) and potassium carbonate (821 mg, 5.94 mmol). The reaction was allowed to proceed to completion at room temperature for 16 h. After completion, water (20 mL) was added to quench the reaction, which was then extracted with ethyl acetate and dried and concentrated. The residue was purified by silica gel column chromatography and then by preparative high-pressure chromatography to yield α-7 (50.0 mg, 0.13 mmol, 4% yield, as a white solid). The resulting product was dissolved in acetonitrile and diluted hydrochloric acid was added until the pH reached approximately 2. The product was then lyophilized to obtain the hydrochloride salt.

[0208] MS-ESI calculated value [M+H]+ 392.4, found 392.1.

[0209] 1H NMR (600MHz, DMSO-d6) δ9.11(d,J=11.2Hz,1H),8.79(q,J=11.0Hz,1H),7.46–7.39(m,2H),7.35(t,J=7.5Hz,1H),7.24(d,J=7 .5Hz,1H),7.06–7.01(m,1H),6.91–6.83(m,2H),6.21(s,1H),5.49–5.33(m,1H),3.27(dd,J=31.6,12.7Hz,2H),3.18–3.12(m, 1H),2.97–2.87(m,2H),2.17–2.08(d,J=3.2Hz,4H),1.85–1.77(m,1H),1.74–1.61(m,2H),1.49(d,J=6.8Hz,3H).

[0210] Preparation Example (I) 8 Compound α-8

[0211] first step

[0212] In a dry 100 mL three-necked flask, α-8a (5.00 g, 20.55 mmol), methoxymethylamine hydrochloride (2.203 g, 22.61 mmol), 1-propylphosphonic anhydride (13.07 g, 41.1 mmol), and triethylamine (6.23 g, 61.65 mmol) were dissolved in N,N-dimethylformamide (35 mL) and reacted at room temperature for 1-2 h. The reaction was monitored by LCMS. Once the starting materials were consumed, the mixture was diluted with water and extracted with ethyl acetate to afford α-8b as a white flocculent compound (5.32 g, 18.6 mmol, yield: 75.96%, purity: 95%).

[0213] MS-ESI:[M+H] + =287.2

[0214] Step 2

[0215] In a dry 100mL three-necked flask, α-8b (3.60g, 12.59mmol) was dissolved in anhydrous tetrahydrofuran (25mL). Ethylmagnesium bromide (2M, 18.89mL, 37.76mmol) was added dropwise under an ice-salt bath. After completion of the addition, the mixture was allowed to react at room temperature for 14h. 10% hydrochloric acid was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1, R f =0.67, iodine fumigation) to give a colorless oil α-8c (2.74 g, 10.72 mmol, yield: 51.82%, purity: 93%).

[0216] MS-ESI:[M+H] + =256.2

[0217] Step 3

[0218] In a dry 100 mL three-necked flask, α-8c (2.00 g, 7.8 mmol) was dissolved in chloroform (30 mL). Bromine (1.88 g, 11.76 mmol) was added dropwise under an ice-salt bath. The mixture was allowed to react at room temperature for 14 h. LCMS and TLC monitoring indicated no residual starting material (the starting material was colorless). The reaction mixture was poured into saturated sodium bicarbonate solution to quench the reaction, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to afford crude compound 4 and α-8d (1.85 g, 5.52 mmol, yield: 44.87%, purity: 80.34%) as a pale yellow oil.

[0219] MS-ESI:[M+H] + =234.2

[0220] Step 4

[0221] Compound A1-1-1c (300.0 mg, 1.03 mmol) was dissolved in acetonitrile (10 mL), and α-8d (483.0 mg, 2.06 mmol) and potassium carbonate (427.3 mg, 3.09 mmol) were added. The reaction was allowed to react at room temperature for 2 h, monitored by LCMS and TLC. After 16 h, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by medium-pressure and preparative HPLC to afford compound α-8 (42.0 mg, 87.40 μmol μmol, yield: 8.5%).

[0222] MS-ESI:[M+H] + =444.3

[0223] Preparation Example (I) 9 Compound α-9

[0224] first step

[0225] In a dry 500 mL three-necked flask, α-9a (10.00 g, 46.93 mmol) was dissolved in 35 mL of N,N-dimethylformamide and cuprous cyanide (5.50 g, 61.40 mmol) was added. The mixture was refluxed and stirred for 6 hours. After cooling to room temperature, ferric chloride (4.70 g, 28.97 mmol) dissolved in water and 37% aqueous hydrochloric acid (10 mL) were added. The reaction was heated to 80°C and stirred for 0.5 hours, then returned to room temperature and stirred overnight. LCMS and TLC monitoring indicated the near disappearance of the starting material, indicating the reaction was complete. The reaction mixture was diluted with water and extracted with methyl tert-butyl ether. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and filtered through a normal phase column chromatography (PE:EA = 10:1) to afford α-9b (6.00 g, 37.69 mmol, yield: 80%) as a yellow solid.

[0226] 1 H NMR (400MHz, DMSO-d6) δ8.39(td,J=1.7,0.6Hz,1H),8.24(ddd,J=7.9,1.8,1.2Hz,1H),8.10(d t,J=7.8,1.3Hz,1H),7.74(td,J=7.8,0.6Hz,1H),3.11(q,J=7.1Hz,2H),1.09(t,J=7.1Hz,3H).

[0227] Step 2

[0228] Add 30 mL of methanol to a dry 250 mL three-necked flask and cool to -78°C. Add acetyl chloride (30 mL) dropwise and add α-9b (6.00 g, 37.69 mmol) to the reaction flask. Slowly increase the temperature, paying attention to safety and being careful of the rapid release of HCl gas from the reaction solution at around -40°C. Continue to warm to room temperature and stir for 2 hours. LCMS monitors the reaction until complete, and then concentrate the reaction solution by rotary evaporation to obtain the imine intermediate. Add 0.5% aqueous TFA to the flask, stir at room temperature overnight, and concentrate by rotary evaporation. Pass the solution through a normal phase column with (PE:EA=10:1). The spot above the raw material is the product, yielding α-9c (1.00 g, 5.2 mmol, 13.8% yield) as a white solid.

[0229] MS-ESI:[M+H] + =193.0

[0230] 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.12–7.99(m,2H),7.61(t,J=7.8Hz,1H), 3.82(s,3H),3.10(q,J=7.1Hz,2H),1.10(t,J=7.2Hz,3H).

[0231] Step 3

[0232] In a dry 50 mL three-necked flask, dissolve α-9c (800 mg, 4.16 mmol) in 10 mL of ultra-dry dichloromethane under nitrogen. Add bromine (3.33 g, 20.83 mmol, 1.06 mL) and hydrogen bromide (244 μL, 4.16 mmol) at 0°C. Return to room temperature and stir for 2 h. LCMS confirms complete reaction, confirming complete disappearance of starting material. Add saturated sodium bicarbonate, extract, and dry over anhydrous sodium sulfate. Concentrate the organic phase to obtain α-9d (800 mg, 2.95 mmol, 70% yield) as a yellow oil. Drain the water from the pump and use directly in the next step.

[0233] MS-ESI:[M+H] + =271.2

[0234] 1 H NMR(400MHz,DMSO-d6)δ8.54(td,J=1.8,0.5Hz,1H),8.35–8.28(m,1H),8.26–8.17(m,1H ),7.73(td,J=7.8,0.6Hz,1H),5.87(p,J=6.2Hz,1H),3.91(s,3H),1.80(d,J=6.5Hz,3H).

[0235] Step 4

[0236] In a dry 50 mL three-necked flask, compound α-9d (300.0 mg, 1.11 mmol) was dissolved in 6 mL of N,N-dimethylformamide and added to the three-necked flask. A1-1-1c (450 mg, 1.55 mmol) and cesium carbonate (840 mg, 2.58 mmol) were then stirred at room temperature for 2 h under nitrogen. LCMS monitored the reaction completion. Water and ethyl acetate were added, and the mixture was washed with saturated brine. The organic phase was concentrated to obtain the crude product. The product was dissolved in N,N-dimethylformamide and purified by MPLC to obtain α-9e (310 mg, 0.64 mmol, 41.5% yield) as a yellow solid.

[0237] MS-ESI:[M+H] + =481.2

[0238] 1H NMR (400MHz, DMSO-d6) δ8.55(t,J=1.8Hz,1H),8.36(dq,J=7.8,1.6Hz,1H),8.26(d t,J=7.8,1.4Hz,1H),7.76(t,J=7.8Hz,1H),7.69(dt,J=8.9,2.3Hz,1H),7.55(ddd, J=8.6,6.1,1.7Hz,1H),7.42(tdd,J=8.5,4.4,2.5Hz,1H),7.10(dd,J=6.4,2.4Hz,1 H),6.98–6.84(m,2H),6.35–6.23(m,2H),3.90(s,3H),1.59(dd,J=6.8,1.1Hz,3H).

[0239] Step 5

[0240] In a dry 100 mL three-necked flask, α-9e (200.0 mg, 442 μmol) was added and dissolved in 1 mL of tetrahydrofuran. 2 mL of aqueous hydrochloric acid (6 M) was added and stirred at 100 degrees for 16 h. The reaction was complete when detected by LCMS. The reaction solution was directly concentrated and dried to obtain the crude product, which was dissolved in N,N-dimethylformamide and purified by MPLC to obtain a white solid α-9 (55.0 mg, 112.5 μmol, 26% yield).

[0241] MS-ESI:[M+H] + =467.1

[0242] 1 H NMR(400MHz, DMSO-d6)δ8.50(t,J=1.7Hz,1H),8.15(dt,J=7.6,1.4Hz,1H),8.01(dq,J=7.8, 1.7Hz,1H),7.68(dt,J=8.9,2.7Hz,1H),7.55(ddd,J=8.8,6.1,2.9Hz,1H),7.47(t,J=7.6Hz, 1H),7.45–7.38(m,1H),7.01(dd,J=4.6,2.4Hz,1H),6.94(dd,J=8.9,1.5Hz,1H),6.87(ddd,J =8.9,6.4,2.4Hz,1H),6.29(d,J=1.4Hz,1H),6.27–6.16(m,1H),1.58(dd,J=6.7,1.2Hz,3H).

[0243] Preparation Example (I) 10 Compound α-10

[0244] first step

[0245] In a dry 100 mL three-necked flask, compound α-10a (5.00 g, 26.85 mmol) was dissolved in tert-butanol (70 mL). 4-Dimethylaminopyridine (1.31 g, 10.74 mmol) and di-tert-butyl dicarbonate (15.24 g, 69.82 mmol) were added and allowed to react at room temperature for 2 h. TLC confirmed the reaction was complete (PE:EA = 4:1, Rf = 0.77, iodine fumigation). The reaction mixture was dried by spin drying, dissolved in ethyl acetate, and washed with 1 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate and then spin dried to afford crude α-10b as a white solid (6.4 g, 26.41 mmol, 98% yield, 80% purity).

[0246] 1 H NMR (400MHz, DMSO-d6) δ3.58(s,3H),2.33–2.20(m,1H),2.20–2.08(m,1H),1.96–1.81(m,4H),1.38(s,9H),1.36–1.26(m,4H).

[0247] Step 2

[0248] In a dry 250 mL three-necked flask, compound α-10b (6.40 g, 26.41 mmol) was dissolved in a mixture of methanol (128 mL) and water (77 mL). Sodium hydroxide (5.28 g, 132.06 mmol) was added and allowed to react at room temperature for 1 h. Most of the methanol was removed by rotary evaporation under reduced pressure, and the mixture was washed twice with ethyl acetate. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to afford α-10c as a white solid (5.46 g, 23.92 mmol, 90% yield, 100% purity).

[0249] 1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),2.23–.04(m,2H),1.97–1.79(m,4H),1.38(s,8H),1.34–1.26(m,4H).

[0250] Step 3

[0251] In a dry 100 mL three-necked flask, compound α-10c (5.43 g, 23.79 mmol) and methoxymethylamine hydrochloride (2.55 g, 26.16 mmol) were dissolved in N,N-dimethylformamide (55 mL). Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.92 g, 26.16 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol), and N,N-diisopropylethylamine (15.37 g, 118.93 mmol) were added under ice-cooling and allowed to react at room temperature for 2 h. The reaction was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and saturated brine, respectively, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=4:1, Rf=0.46, iodine fumigation) to give a colorless oil α-10d (5.96 g, 21.96 mmol, yield 92%, purity 95%).

[0252] Step 4

[0253] In a dry 100 mL three-necked flask, compound α-10d (5.46 g, 20.12 mmol) was dissolved in anhydrous tetrahydrofuran (23 mL) and added dropwise to ethylmagnesium bromide (2M, 25.15 mL, 50.30 mmol) under an ice-salt bath. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched by the addition of 10% hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1, Rf = 0.67, iodine fumigation) to afford α-10e (4.21 g, 17.52 mmol, 87% yield, 95% purity) as a colorless oil.

[0254] Step 5

[0255] In a dry 50 mL three-necked flask, compound α-10e (500 mg, 2.08 mmol) was dissolved in methanol (7 mL). 48% hydrobromic acid (15 μL) was added, followed by the dropwise addition of bromine (339 mg, 2.12 mmol, 108.7 μL). The mixture was allowed to react at room temperature for 16 h. TLC indicated no residual starting material (the product was colorless). The reaction mixture was poured into saturated sodium bicarbonate solution to quench the reaction, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to afford the crude compound α-10f (596.0 mg, 1.87 mmol, 89% yield, 50% purity) as a pale yellow oil.

[0256] 1H NMR (400MHz, Chloroform-d) δ4.52 (qd, J=6.8, 1.4Hz, 1H), 2.89–2.76 (m, 1H), 2. 37–2.13(m,1H),2.12–1.90(m,4H),1.73(d,J=6.8,Hz,3H),1.66–1.24(m,13H).

[0257] Step 6

[0258] In a dry 50 mL three-necked flask, compound α-10f (494.0 mg, 1.55 mmol) and A1-1-1c (300 mg, 1.03 mmol) were dissolved in N,N-dimethylformamide (7.5 mL). Cesium carbonate (873 mg, 2.68 mmol) was added and allowed to react at room temperature for 2 h. The reaction was complete by LCMS. The mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by medium-pressure reverse phase chromatography to afford α-10g (211.0 mg, 379 μmol, 38% yield, 95% purity) as a white solid.

[0259] MS-ESI:[M+Na] + =551.1

[0260] Step 7

[0261] In a dry 50 mL three-necked flask, compound α-10g (180 mg, 340 μmol) was dissolved in dichloromethane (2.7 mL). Trifluoroacetic acid (0.9 mL) was added and the mixture was allowed to react at room temperature for 1 h. LCMS confirmed the reaction was complete. The reaction solution was spin-dried to dryness, and the residue was dissolved in acetonitrile (1 mL). Saturated sodium bicarbonate was added to adjust the pH to 8-9, and the mixture was purified by medium-pressure reverse phase chromatography to afford α-10 as a white solid (45 mg, 91 μmol, 26% yield, 98.31% purity).

[0262] MS-ESI:[M-Na] - =471.2

[0263] 1H NMR (400MHz, DMSO-d6) δ7.70 (dd, J=8.6, 2.2Hz, 1H), 7.57 (ddd, J=8.6, 6.1, 1.4Hz, 1H), 7.43 (tdd ,J=8.5,2.6,1.0Hz,1H),6.99(dd,J=4.1,2.5Hz,1H),6.95(dd,J=8.9,2.3Hz,1H),6.88–6.81(m,1 H),6.31(s,1H),5.36(qd,J=6.9,4.1Hz,1H),2.71-2.64(m,1H),1.94(dd,J=26.4,11.0Hz,2H),1 .85-1.83(m,1H),1.77-1.71(m,1H),1.65-1.63(m,1H),1.47(d,J=6.8Hz,3H),1.35–1.09(m,4H).

[0264] Preparation Example (I) 11 Compound α-11

[0265] first step

[0266] To a dry 100 mL three-necked flask, α-11a (2.0 g, 8.29 mmol) and tetrahydrofuran (30 mL) were added sequentially. Once fully dissolved, pyridinium tribromide (2.92 g, 2.07 mmol) was added. After addition, the mixture was allowed to react overnight at room temperature, monitored by TLC until complete reaction. After completion of the reaction, the reaction system was filtered, and the filtrate was collected, concentrated on a rotary evaporator, and purified using a flash column to afford α-11b (2.08 g, 6.50 mmol, yield: 78%).

[0267] Step 2

[0268] To a dry 100 mL three-necked flask, α-11b (1.00 g, 3.12 mmol), A1-1-1c (760.0 mg, 2.61 mmol), and dry acetone (30 mL) were added sequentially. After complete dissolution, potassium carbonate (0.72 g, 5.21 mmol) and tetrabutylammonium iodide (0.96 g, 2.60 mmol) were added sequentially. After addition, the temperature was slowly raised to 25°C and maintained for 6 h. TLC was used to monitor the reaction until the starting materials were completely reacted. After completion of the reaction, the reaction solution was washed with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a flash column to obtain α-11c (1.28 g, 2.42 mmol, yield: 92%).

[0269] Step 3

[0270] To a dry, clean eggplant-shaped flask, add α-11c (1.36 g, 2.56 mmol). Then, slowly add a 3.0 M solution of hydrogen chloride in ethyl acetate (20 mL) dropwise. Stir at room temperature and monitor the reaction progress by TLC. Upon completion, a white suspension is obtained. The solid is filtered and dried to yield the desired product, α-11 (1.10 g, 2.36 mmol, yield: 92%, purity: 97%).

[0271] MS-ESI:[M+H] + =430.0

[0272] 1 H NMR: (400MHz, Methanol-d4)δ7.50–7.42(m,2H),7.29(td,J=8.3,2.5Hz,1H),7 .04(d,J=8.6Hz,1H),6.99(s,1H),6.92(d,J=8.6Hz,1H),6.23(s,1H),5.24(d,J =6.7Hz,1H),3.51–3.37(m,2H),3.31–3.23(m,2H),3.11(m,2H),2.24(d,J=14. 4Hz, 1H), 1.95 (d, J = 14.3Hz, 1H), 1.85 (t, J = 12.1Hz, 2H), 1.56 (d, J = 6.4Hz, 3H).

[0273] Preparation Example (I) 12 Compound α-12

[0274] first step

[0275] In a dry 100 mL three-necked flask, compound α-12a (5.00 g, 18.99 mmol) and methoxymethylamine hydrochloride (2.04 g, 20.89 mmol) were dissolved in N,N-dimethylformamide (50 mL). Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.92 g, 20.89 mmol), 1-hydroxybenzotriazole (2.82 g, 20.89 mmol), and N,N-diisopropylethylamine (12.27 g, 94.95 mmol) were added under ice-cooling. The mixture was reacted at room temperature for 16 h. LCMS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with 1 M hydrochloric acid, 1 M sodium hydroxide and saturated brine, respectively, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. Medium-pressure reverse phase was used to obtain a colorless oil α-12b (5.24 g, 17.10 mmol, yield 90%, purity 90%).

[0276] MS-ESI:[M+H] +=307.1

[0277] Step 2

[0278] Compound α-12b (5.30 g, 17.30 mmol) was dissolved in anhydrous tetrahydrofuran (21 mL) in a dry 100 mL three-necked flask and added dropwise to ethylmagnesium bromide (2M tetrahydrofuran, 21.63 mL, 43.25 mmol) under an ice-salt bath. The mixture was allowed to react at room temperature for 1 h. TLC confirmed the reaction was complete (PE:EA = 4:1, Rf = 0.41). The reaction was quenched with 10% hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography to afford α-12c (3.79 g, 13.76 mmol, 79% yield, 90% purity) as a colorless oil.

[0279] MS-ESI:[M+H] + =276.0

[0280] Step 3

[0281] In a dry 50 mL three-necked flask, compound α-12c (500.0 mg, 1.82 mmol) was dissolved in methanol (7.5 mL). 48% hydrobromic acid (15 μL) was added dropwise, followed by the addition of bromine (296.0.0 mg, 1.85 mmol, 95 μL). The mixture was allowed to react at room temperature for 16 hours, and the reaction was complete by LCMS. The reaction mixture was quenched by pouring into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, α-12d (542.0 mg, 1.53 mmol, 84% yield, 70% purity), as a pale yellow oil.

[0282] MS-ESI:[M+H] + =354.0

[0283] Step 4

[0284] In a dry 50 mL three-necked flask, compound α-12d (418 mg, 1.18 mmol, 70% purity) and compound A1-1-1c (160 mg, 550 μmol) were dissolved in N,N-dimethylformamide (4 mL). Cesium carbonate (466 mg, 1.43 mmol) was added and allowed to react at room temperature for 3 h. The reaction was complete by LCMS. The mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by medium-pressure reverse phase chromatography to afford α-12e (251.0 mg, 455 μmol, 82% yield, 95% purity) as a white solid.

[0285] MS-ESI:[M+H]+ =564.1

[0286] Step 5

[0287] In a dry 50 mL three-necked flask, compound α-12e (256 mg, 453.90 μmol) was dissolved in methanol (6 mL). Palladium hydroxide on carbon (78 mg, 20%) was added. After three replacements with hydrogen, the mixture was reacted at room temperature under normal pressure for 1 h. LCMS confirmed the reaction was complete. Filter, wash the filter cake with methanol, and combine the filtrates, spin-drying, to obtain the crude product. Purification with medium-pressure reverse phase chromatography afforded α-12f (132 mg, 307 μmol, 67% yield, 95% purity) as a white solid.

[0288] MS-ESI:[M+H] + =430.0

[0289] Step 6

[0290] In a dry 50 mL three-necked flask, compound α-12f (110 mg, 255.89 μmol) was dissolved in N,N-dimethylformamide (2.2 mL). Tert-butyl bromoacetate (54.9.0 mg, 281.48 μmol) and triethylamine (28 mg, 281 μmol) were added. The mixture was allowed to react at room temperature for 2 h. LCMS confirmed the reaction was complete. The reaction mixture was purified by medium-pressure reverse phase chromatography to afford α-12g (135 mg, 248 μmol, 96% yield, 99% purity) as a white solid.

[0291] MS-ESI:[M+H] + =544.3,[M- t Bu] + =488.3

[0292] Step 7

[0293] In a dry 50 mL three-necked flask, compound α-12g (110 mg, 202.2 μmol) was dissolved in dichloromethane (1.8 mL). Trifluoroacetic acid (0.6 mL) was added and the mixture was allowed to react at room temperature for 4 h. LCMS confirmed the reaction was complete. The reaction solution was spin-dried to dryness, and the residue was dissolved in acetonitrile (1 mL). Saturated sodium bicarbonate was added to adjust the pH to 8-9. The mixture was purified by medium-pressure reverse phase chromatography to afford α-12 as a white solid (42 mg, 82 μmol, 40% yield, 95.37% purity).

[0294] MS-ESI:[M-Na] - =486.2.

[0295] 1H NMR (400MHz, DMSO-d6) δ7.70 (ddd, J=8.9, 2.6, 1.0Hz, 1H), 7.57 (ddd, J=8.6, 6.1, 1.6Hz, 1H) ,7.43(tdd,J=8.5,2.6,1.2Hz,1H),7.04–7.00(m,1H),7.00–6.89(m,1H),6.85(ddd,J=9.1, 6.9, 2.5Hz, 1H), 6.32 (s, 1H), 5.38 (qd, J=6.8, 3.5Hz, 1H), 2.93 (dd, J=24.8, 11.2Hz, 2H), 2. 73(s,2H),2.71-2.64(m,1H),2.15–1.99(m,2H),1.88(d,J=12.5Hz,1H),1.61–1.43(m,6H).

[0296] 19 F NMR (376MHz, DMSO-d6DMSO-D6) δ109.97 (s, 1F).

[0297] Preparation Example (I) 13 Compound α-13

[0298] first step

[0299] In a dry 50mL three-necked flask, compound α-13a (500.0mg, 3.70mmol) was placed in a dry three-necked flask, hydrobromic acid (4mL) was added, and bromine (621.0mg, 3.88mmol, 200μL) was added dropwise to the flask at 15-20°C. After the addition was completed, the reaction was stirred at 40°C for 1h, and the temperature was raised to 80°C and continued to stir for 1h. After the reaction was completed by LCMS detection, the mixture was cooled to 25-30°C. Methyl tert-butyl ether (12mL) was added to the reaction solution. Stir at 25-30°C for 5 minutes and filter the mixture under vacuum. Wash the filter cake with methyl tert-butyl ether (10mL) and dry the filter cake to obtain the product. The crude product was used in the next step without purification. α-13b (900.0mg, 3.05mmol, yield: 82%, purity: 91.5%, HBr)

[0300] MS-ESI:[M+H] + =214.0

[0301] Step 2

[0302] Acetone (2.40 mL), α-13b (183.0 mg, 620 μmol, HBr), and A1-1-1c (120.0 mg, 413 μmol) were placed in a dry 50 mL three-necked flask. Diisopropylethylamine (53.3 mg, 413 μmol, 71.9 μL, 1.00 eq) was added dropwise at 20°C. The mixture was stirred at 20°C for 16 h. LCMS analysis confirmed the completion of the reaction. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product. The crude product was purified by Pre-HPLC (column: Waters*bridge 150*25 mm 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile; B%: 43%-73%; 14 min). The mixture was freeze-dried to obtain product α-13 (60.0 mg, 142 μmol, yield: 34%, purity: 95.3%)

[0303] MS-ESI:[M+H] + =424.1

[0304] The second group of preparation examples (including embodiments of the second set of technical solutions)

[0305] Preparation Example (II) 1 Compound A1-1-1

[0306] first step

[0307] Dissolve diethyl carbonate (136.90 g, 1.16 mol) in tetrahydrofuran (500 mL), replace the nitrogen atmosphere, and add sodium hydride (23.18 g, 579.44 mmol) at 0°C. Continue the reaction for 1 hour. Then, add compound A1-1-1a (50 g, 289.72 mmol), transfer the reaction mixture to 55°C, and react for 8 hours. Pour the reaction mixture into 2M hydrochloric acid (400 mL) and extract with ethyl acetate. Wash the extracted organic phase twice with saturated brine (400 mL). After preliminary column chromatography, obtain the crude product A1-1-1b, which is used directly in the next reaction.

[0308] Step 2

[0309] Dissolve the crude product A1-1-1b in methanesulfonic acid (400 mL), add resorcinol (45.01 g, 408.75 mmol), and react at 45°C for 3 h to obtain a black, viscous reaction solution. TLC indicates complete consumption of the starting material. The reaction solution is slowly poured into ethanol (200 mL), and the resulting solution is then poured into water (500 mL). Extract with ethyl acetate (300 mL x 3). The combined organic phases are washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and purified by column chromatography to obtain A1-1-1c (40.00 g, 137.61 mmol, total yield for two steps: 47.5%).

[0310] 1 HNMR(400MHz,Chloroform-d)7.35-7.29(m,1H),7.26-7.21(m,1H),7.20-7.10(m,1H ),7.02-7.08(m,1H),6.76-6.82(m,1H),6.40-6.52(m,1H),6.21(s,1H),5.51(s,1H).

[0311] Step 3

[0312] In a 250 mL three-necked flask under nitrogen, Al-1-1d (13.32 g, 89.93 mmol), cuprous bromide (0.91 g, 6.36 mmol), and anhydrous tetrahydrofuran (120 mL) were added in sequence. After sufficient dissolution, the mixture was cooled to -20°C, and then ethylmagnesium bromide tetrahydrofuran solution (50 mL, 2.0 M) was slowly added dropwise. After the addition was complete, the mixture was reacted at this temperature for 1 h, then the temperature was slowly raised to 30°C and the reaction was continued for 2 h. TLC monitoring was performed. After the reaction of the raw materials was complete, saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL 3). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a rapid separation column to obtain Al-1-1e (13.0 g, 72.96 mmol, yield: 81%).

[0313] MS-ESI:[MH] - =177.1

[0314] Step 4

[0315] To a 100 mL three-necked flask, A1-1-1e (13.0 g, 72.96 mmol), anhydrous potassium carbonate (20.17 g, 145.92 mmol), and N,N-dimethylformamide (50 mL) were added sequentially. The reaction solution was heated to 60°C, and iodomethane (20.71 g, 145.92 mmol) was slowly added dropwise. After the addition was complete, the reaction was incubated at this temperature for 6 h, monitored by TLC. After the reaction of the starting materials was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a flash column to obtain A1-1-1f (5.9 g, 30.70 mmol, yield: 42%).

[0316] 1 H NMR (400MHz, Chloroform-d) δ7.93 (dd, J=7.7, 1.4Hz, 1H), 7.59 (td, J=7.5, 1.3Hz, 1H), 7.51 (td, J=7. 6,1.4Hz,1H),7.36(dd,J=7.5,1.4Hz,1H),3.91(s,3H),2.83(q,J=7.3Hz,2H),1.25(t,J=7.3Hz,3H).

[0317] Step 5

[0318] In a 100 mL three-necked flask, A1-1-1f (5.9 g, 30.70 mmol) and dichloromethane (15 mL) were added at room temperature, and hydrogen bromide (1.86 mL, 34.24 mmol) and liquid bromine (4.38 mL, 85.60 mmol) were slowly added dropwise in sequence. The reaction was carried out at room temperature for 4 h and monitored by TLC. After the reaction of the raw materials was complete, the reaction solution was quenched with saturated aqueous sodium thiosulfate solution (100 mL), extracted with dichloromethane (30 mL×3), and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a rapid separation column to obtain A1-1-1g (1.7 g, 6.27 mmol, yield: 20%).

[0319] 1 H NMR (400MHz, Chloroform-d) δ8.02 (dd, J=8.1, 1.3Hz, 1H), 7.65 (td, J=7.5, 1.4Hz, 1H), 7. 55(ddt,J=8.7,3.8,1.5Hz,2H),4.85(q,J=6.6Hz,1H),3.93(s,3H),2.00(d,J=6.6Hz,3H).

[0320] Step 6

[0321] In a 100 mL three-necked flask, A1-1-1g (1.7 g, 6.27 mmol) and acetone (5 mL) were added at room temperature, followed by A1-1-1c (1.92 g, 6.61 mmol), tetrabutylammonium iodide (2.44 g, 6.61 mmol), and anhydrous potassium carbonate (1.83 g, 13.22 mmol). The mixture was stirred at room temperature overnight and monitored by TLC. After the reaction of the raw materials was complete, the reaction solution was diluted with water (25 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a rapid separation column to obtain A1-1-1h (1.17 g, 2.43 mmol, yield: 39%). MS-ESI: [M+H] + =481.2

[0322] Step 7

[0323] In a 100 mL three-necked flask, A1-1-1h (1.17 g, 2.43 mmol) and methanol (20 mL) were added, followed by aqueous sodium hydroxide solution (20 mL, 0.5 M). The mixture was allowed to react at this temperature for 3 h. After TLC monitoring of the complete reaction of the starting material, the pH of the reaction solution was adjusted to 2-3 with dilute aqueous hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed sequentially with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a flash column to obtain compound A1-1-1i (290.0 mg, 0.62 mmol, yield: 25%).

[0324] Step 8

[0325] Compound A1-1-1i was separated by SFC to obtain A1-1-1. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30*250mm 5μm) (Daicel); Separation conditions: ethanol (0.2% TFA), 75% °C2; Flow rate: 45 mL:min. ESI-LCMS: m:z 467.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6DMSO-D6)δ8.40(d,J=31.2Hz,1H),7.88–7.66(m,4H),7.63–7.51(m,1H),7.43(d,J=8.6Hz,1H) ,7.10(s,1H),6.94–6.63(m,2H),6.29(d,J=6.4Hz,1H),5.12(dd,J=86.7,6.7Hz,1H),1.39(dd,J=40.3,6.2Hz,3H).

[0326] Preparation Example (II) 2 Compound A2-1-1

[0327] Compound A1-1-1i was separated by SFC to afford A2-1-1. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30×250 mm 5 μm) (Daicel); Separation conditions: ethanol (0.2% TFA), 75% °C; Flow rate: 45 mL / min.

[0328] Preparation Example (II) 3 Compound A1-1-5

[0329] first step

[0330] Palladium acetate (0.63 g, 2.82 mmol) and XantPhos (1.63 g, 2.82 mmol) were added to a dry three-necked flask. A1-1-5a (20 g, 93.87 mmol), N,N-dimethylformamide (250 mL), and DCC (3.87 g, 18.77 mmol) were added under nitrogen protection, and nitrogen protection was repeated. Formic acid (30.25 g, 657.09 mmol) and triethylamine (19.00 g, 26.02 mmol) were added, and the reaction was carried out at 110°C for 12 h. TLC showed that the starting materials were almost completely reacted. Water (500 mL) and methyl tert-butyl ether (500 mL) were added, stirred, and filtered through celite to separate the layers. The aqueous phase was extracted three times with methyl tert-butyl ether (300 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product A1-1-5b, which was used directly in the next reaction.

[0331] Step 2

[0332] Dissolve the crude product of A1-1-5b in methanol (200 mL), add DMAP (5.14 g, 42.09 mmol), N,N-diisopropylethylamine (21.76 g, 168.36 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.21 g, 126.27 mmol), and react at room temperature for 12 h. TLC shows that the starting materials are essentially reacted. After concentration, ethyl acetate (200 mL) and saturated aqueous sodium chloride (200 mL) were added, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate (100 mL x 2). The combined organic phases were washed sequentially with 1 M aqueous hydrogen chloride (100 mL), saturated aqueous sodium chloride (200 mL), saturated aqueous sodium bicarbonate (200 mL), and saturated aqueous sodium chloride (200 mL). The obtained organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain A1-1-5c (8.00 g, 41.62 mmol, total yield for two steps: 44%).

[0333] Step 3

[0334] A1-1-5c (8.00 g, 41.62 mmol) was dissolved in tetrahydrofuran (100 mL), and pyridinium tribromide (26.62 g, 83.24 mmol) was added. The reaction was allowed to proceed at 45°C for 3 h. TLC indicated that the starting material had essentially reacted. After filtration and concentration, ethyl acetate (100 mL) and saturated aqueous sodium chloride (100 mL) were added and the layers separated. The aqueous phase was extracted twice with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford A1-1-5d (6.50 g, 23.98 mmol, 57% yield).

[0335] Step 4

[0336] A1-1-5d (6.5 g, 23.98 mmol), A1-1-1c (6.97 g, 23.98 mmol), and potassium carbonate (8.29 g, 59.95 mmol) were added to acetone (100 mL) and allowed to react overnight at room temperature. TLC indicated that the starting materials had reacted almost completely. After concentration, ethyl acetate (100 mL) and water (100 mL) were added and the layers separated. The aqueous phase was extracted twice with ethyl acetate (100 mL x 2). The combined organic phases were washed with 1 M aqueous hydrogen chloride (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford A1-1-5e (7.01 g, 14.58 mmol, yield: 60%).

[0337] 1H NMR(400MHz,Chloroform-d)δ8.61(q,J=1.6Hz,1H),8.18(ddt,J=21.2,7.9,1.6Hz,2H),7.53(t,J=7.8Hz,1H),7.21–7.16(m,2H),7.11–7.00(m,1H ),6.87(dd,J=8.8,3.8Hz,1H),6.70(ddd,J=18.7,9.6,2.5Hz,2H),6.08(d ,J=1.1Hz,1H),5.58(q,J=6.9Hz,1H),3.88(s,3H),1.70(d,J=6.9Hz,3H).

[0338] Step 5

[0339] A1-1-5e (3 g, 6.24 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (100 mL). 2M aqueous sodium hydroxide solution (50 mL) was added under ice-cooling and the reaction continued for 25 min. TLC indicated completion of the reaction. 1M hydrochloric acid (120 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The aqueous phase was washed twice with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford A1-1-5f (1.34 g, 2.87 mmol, yield: 46%, purity: 96.45%).

[0340] Step 6

[0341] Compound A1-1-5f was separated by SFC to afford A1-1-5. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30*250 mm 5 μm) (Daicel); Separation conditions: ethanol (0.2% TFA), 75% °C2; Flow rate: 45 mL / min.

[0342] 1 HNMR: (400MHz, Chloroform-d), 8.81 (s, 1H), 8.35 (dd, J=26.9, 7.8Hz, 2H), 7.68 (t, J=7.8Hz, 1H), 7.33–7.28 (m, 2H), 7.17–7. 10(m,1H),6.97(dd,J=8.8,4.0Hz,1H),6.81(dd,J=11.2,5.2,2H),6.20(s,1H),5.65(q,J=6.8Hz,1H),1.82(d,J=6.8Hz,3H).

[0343] MS(ES), C 25H 16 ClFO6 theoretical value: 466.1; measured value: 465.0 (MH) - .

[0344] Preparation Example (II) 4 Compound A2-1-5

[0345] Compound A1-1-5f was separated by SFC to afford A2-1-5. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30×250 mm 5 μm) (Daicel); Separation conditions: ETOH (0.2% FATFA), 75% ethanol, °C2; Flow rate: 45 mL / min.

[0346] Preparation Example (II) 5 Compound A1-1-6

[0347] A1-1-5 (100.0 mg, 214 μM) was dissolved in N,N-dimethylformamide (0.5 mL), and then sodium carbonate aqueous solution was added to adjust the solution to alkalinity. The mixture was purified by reverse phase medium pressure (MeCN:H2O) to obtain a white solid A1-1-6 (63.0 mg, 129 μM, 60%). 1 H NMR (400MHz, DMSO-d6) δ8.50(t,J=1.7Hz,1H),8.15(dt,J=7.6,1.4Hz,1H),8.01(dq,J=7.8,1. 7Hz,1H),7.68(dt,J=8.9,2.7Hz,1H),7.55(ddd,J=8.8,6.1,2.9Hz,1H),7.47(t,J=7.6Hz,1H), 7.45–7.38(m,1H),7.01(dd,J=4.6,2.4Hz,1H),6.94(dd,J=8.9,1.5Hz,1H),6.87(ddd,J=8.9,6 .4,2.4Hz,1H),6.29(d,J=1.4Hz,1H),6.27–6.16(m,1H),1.58(dd,J=6.7,1.2Hz,3H).MS(ES),C 25 H 15 ClFO6Na free acid C 25 H 16 ClFO6 theoretical value: 466.1; found value: 467.0 (M+H) + .

[0348] Preparation Example (II) 6 Compound A1-1-9

[0349] first step

[0350] To a dry 100 mL three-necked flask, A1-1-9a (2.0 g, 11.22 mmol) and dry N,N-dimethylformamide (30 mL) were added sequentially. After complete dissolution, iodomethane (4.78 g, 33.66 mmol) and sodium bicarbonate (2.83 g, 33.66 mmol) were added sequentially. After the addition was completed, the temperature was slowly raised to 30°C and maintained for 6 hours. TLC was monitored until the reaction of the raw materials was complete. After the reaction was completed, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with water (50 mL × 2) and saturated brine. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. After concentration on a rotary evaporator, separation and purification using a rapid separation column were performed to obtain A1-1-9b (2.0 g, 10.41 mmol, yield: 92%).

[0351] Step 2

[0352] To a dry 100 mL three-necked flask, A1-1-9b (2.0 g, 10.41 mmol) and dry tetrahydrofuran (30 mL) were added sequentially. After complete dissolution, 2-pyrrolidone (1.06 g, 12.49 mmol) and pyrrolidone tribromide (5.09 g, 15.62 mmol) were added sequentially. After the addition was completed, the temperature was slowly raised to 50°C and maintained for 3 h. TLC was used to monitor the reaction until the starting materials were completely reacted. After the reaction was completed, the reaction solution was dropwise added with a saturated aqueous solution of sodium metabisulfite (20 mL) and stirred for 5 min. Water (50 mL) was then added and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL x 2), then dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a flash column to obtain A1-1-9c (2.10 g, 7.75 mmol, yield: 74%).

[0353] Step 3

[0354] In a dry 100 mL three-necked flask, A1-1-9c (2.00 g, 7.38 mmol), A1-1-1c (2.13 g, 7.38 mmol), and dry acetone (30 mL) were added sequentially. After complete dissolution, potassium carbonate (2.04 g, 14.76 mmol) and tetrabutylammonium iodide (2.73 g, 7.38 mmol) were added sequentially. After the addition was completed, the temperature was slowly raised to 25°C and maintained for 6 h. TLC was monitored until the reaction of the raw materials was complete. After the reaction was completed, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a rapid separation column to obtain A1-1-9d (2.14 g, 4.45 mmol, yield: 60%).

[0355] Step 4

[0356] To a dry 100 mL three-necked flask, A1-1-9d (1.0 g, 2.08 mmol) and tetrahydrofuran (30 mL) were added sequentially. After complete dissolution, a 2.0 M aqueous NaOH solution (15 mL) was slowly added dropwise. Methanol (10 mL) was then added to the reaction solution to aid dissolution. After the addition was completed, the reaction mixture was maintained at room temperature for 10 minutes. TLC was used to monitor the reaction until the starting material reacted completely. After the reaction, the reaction solution was adjusted to acidity (pH: 3-5) with dilute aqueous hydrochloric acid (1.0 M), then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a flash column to obtain compound A1-1-9e (380.0 mg, 0.81 mmol, yield: 39%).

[0357] Step 5

[0358] Compound A1-1-9e was separated by SFC to afford A1-1-9. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30*250 mm 5 μm) (Daicel); Separation conditions: ethanol (0.2% TFA), 75% °C; Flow rate: 45 mL / min.

[0359] MS-ESI:[M+H] + =467.2

[0360] 1 H NMR(400MHz,DMSO-d6)δ12.99(s,1H),7.94–7.86(m,2H),7.66–7.61(m,1H),7.57–7.33(m,4H),7.13 (dd,J=8.2,2.4Hz,1H),6.69(s,1H),6.33–6.28(m,1H),6.21(s,1H),4.61(m,1H),1.34–1.22(m,3H).

[0361] Preparation Example (II) 7 Compound A2-1-9

[0362] Compound A1-1-9e was separated by SFC to afford A2-1-9. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30×250 mm 5 μm) (Daicel); Separation conditions: ETOH (0.2% FATFA), 75% ethanol, °C2; Flow rate: 45 mL / min.

[0363] Preparation Example (II) 8 Compound A1-4-5

[0364] first step

[0365] In a dry 500 mL three-necked flask, A1-4-5a (13.0 g, 64.35 mmol) and dry dichloromethane (130 mL) were added in sequence. After sufficient dissolution, methoxymethylamine hydrochloride (6.28 g, 64.35 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29.36 g, 77.22 mmol) and triethylamine (16.28 g, 160.88 mmol) were added in sequence. After the addition was completed, the mixture was reacted at room temperature for 16 h and monitored by TLC until the reaction of the raw materials was complete. After the reaction was completed, water (150 mL) was added to the reaction solution, and then extracted with dichloromethane (200 mL×3). The organic phases were combined and washed again with purified water (300 mL). After washing, the organic phase was washed with saturated brine (300 mL) and then dried over anhydrous sodium sulfate. After concentration on a rotary evaporator, separation and purification were performed using a rapid separation column to obtain A1-4-5b (14.3 g, 58.36 mmol, yield: 90%).

[0366] Step 2

[0367] In a dry 500 mL three-necked flask, A1-4-5b (14.00 g, 57.13 mmol) and dry tetrahydrofuran (150 mL) were added sequentially. After complete dissolution, the mixture was replaced with N2 three times and the temperature was lowered to -15°C. Ethylmagnesium bromide (11.2 mL, 85.70 mmol, 2.0 M: tetrahydrofuran) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was allowed to proceed for 3 h. TLC was monitored until the reaction of the raw materials was complete. After the reaction was completed, the reaction solution was added dropwise to a saturated aqueous solution of ammonium chloride (50 mL) and stirred for 5 min. Water (50 mL) was then added and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a rapid separation column to obtain A1-4-5c (8.66 g, 40.46 mmol, yield: 70%).

[0368] Step 3

[0369] In a dry 250 mL three-necked flask, A1-4-5c (8.50 g, 39.71 mmol), Xantphos (4.60 g, 7.94 mmol), DCC (16.39 g, 79.42 mmol) and Pb(OAc)2 (1.78 g, 7.94 mmol) were added in sequence, and then dry N,N-dimethylformamide (150 mL) was added. The atmosphere was replaced with nitrogen three times, and triethylamine (16.5 mL, 119.13 mmol) and formic acid (3 mL, 79.42 mmol) were slowly added dropwise to the reaction solution. After the addition was completed, the temperature was slowly raised to 100 ° C. The temperature was maintained for 6 h and monitored by TLC until the reaction of the raw materials was complete. After the reaction, water (100 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate. After concentration on a rotary evaporator, the product was separated and purified using a rapid separation column to obtain A1-4-5d (5.13 g, 29.64 mmol, yield: 72%), which was directly used in the next step.

[0370] Step 4

[0371] To a dry 250 mL three-necked flask, A1-4-5d (5.00 g, 27.91 mmol) and dry N,N-dimethylformamide (80 mL) were added sequentially. Once fully dissolved, iodomethane (5.94 g, 41.87 mmol) and potassium carbonate (7.71 g, 55.82 mmol) were added sequentially. After addition, the temperature was slowly raised to 25°C and maintained for 6 h. TLC was used to monitor the reaction until the starting materials reacted completely. After the reaction, water (80 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined and washed again with purified water (100 mL x 2). After washing, the organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a flash column to obtain A1-4-5e (1.47 g, 7.61 mmol, yield: 27%).

[0372] Step 5

[0373] To a dry 100 mL three-necked flask, A1-4-5e (1.40 g, 7.25 mmol) and dry tetrahydrofuran (30 mL) were added sequentially. After complete dissolution, 2-pyrrolidone (0.74 g, 8.70 mmol) and pyrrolidone tribromide (3.54 g, 10.88 mmol) were added sequentially. After the addition was completed, the temperature was slowly raised to 50°C and maintained for 3 h. TLC was monitored until the reaction of the starting materials was complete. After the reaction was completed, the reaction solution was dropwise added with a saturated aqueous solution of sodium metabisulfite (20 mL) and stirred for 5 min. Water (50 mL) was then added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and separated and purified using a flash column to obtain A1-4-5f (1.49 g, 5.47 mmol, yield: 76%).

[0374] Step 6

[0375] In a dry 100 mL three-necked flask, A1-4-5f (1.40 g, 5.15 mmol), A1-1-1c (1.49 g, 5.15 mmol), and dry acetone (20 mL) were added sequentially. After complete dissolution, potassium carbonate (1.42 g, 10.30 mmol) and tetrabutylammonium iodide (1.90 g, 5.15 mmol) were added sequentially. After the addition was completed, the temperature was slowly raised to 25°C and maintained for 6 h. TLC was monitored until the reaction of the raw materials was complete. After the reaction was completed, the reaction solution was washed with water (30 mL) and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate. After concentration on a rotary evaporator, the product was separated and purified using a rapid separation column to obtain A1-4-5g (1.35 g, 2.80 mmol, yield: 54%).

[0376] Step 7

[0377] A1-4-5g (1.35g, 2.80mmol) and tetrahydrofuran (30mL) were added sequentially to a dry 100mL three-necked flask. After complete dissolution, a 1.0M aqueous lithium hydroxide solution (15mL) was slowly added dropwise. Methanol (10mL) was then added to the reaction solution to aid dissolution. After the addition was completed, the reaction was maintained at room temperature for 2h. TLC was monitored until the reaction of the raw materials was complete. After the reaction was completed, the reaction solution was adjusted to acidity (pH: 4-5) with formic acid and then extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with saturated brine (100mL), and then dried over anhydrous sodium sulfate. After concentration on a rotary evaporator, the mixture was separated and purified using a rapid separation column to obtain compound A1-4-5h (730mg, 1.56mmol, yield: 55%).

[0378] MS-ESI:[M+H] + =468.0

[0379] Step 8

[0380] Compound A1-4-5h was separated by SFC to afford A1-4-5. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30*250 mm 5 μm) (Daicel); Separation conditions: ethanol (0.2% TFA), 75% °C2; Flow rate: 45 mL / min.

[0381] Preparation Example (II) 9 Compound A2-4-5

[0382] Compound A1-4-5h was separated by SFC to afford A2-4-5. Instrument: SFC-80 (Waters); Separation column: CHIRALPAK AD (30×250 mm 5 μm) (Daicel); Separation conditions: ETOH (0.2% FATFA), 75°C; Flow rate: 45 mL / min.

[0383] The third group of preparation examples (including embodiments of the third set of technical solutions)

[0384] Preparation Example (III) 1 Compound A-1-8-1-1

[0385] first step

[0386] In a dry 100 mL three-necked flask, compound A-1-8-1-1a (5.98 g, 26.08 mmol) was dissolved in dichloromethane (20 mL), and then N, O-dimethylhydroxylamine hydrochloride (3.03 g, 31.30 mmol), triethylamine (7.5 mL, 57.34 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (11.89 g, 31.30 mmol) were added in sequence. The reactants were reacted at room temperature for 1 h. TLC was monitored until the reaction of the raw materials was complete. 40 mL of water was added to quench the reaction, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate. After concentration on a rotary evaporator, the product was separated and purified using a rapid separation column to obtain the concentrated organic phase. Forward purification (PE:EA=5:1, Rf=0.4) was performed to obtain the target product A-1-8-1-1b (6.50 g, 23.89 mmol, yield: 91.67%) as a colorless oil.

[0387] Step 2

[0388] In a dry 100mL three-necked flask, compound A-1-8-1-1b (6.50g, 23.89mmol) was dissolved in tetrahydrofuran (30mL) and protected with nitrogen. Ethylmagnesium bromide (28.66mL, 28.66mmol) was then added dropwise. The reaction was allowed to react at room temperature for 16h. The reaction solution was tested by spot plate detection and found to be complete. 20mL of saturated ammonium chloride was added to quench the reaction. 50mL×3 ethyl acetate was then added for extraction. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried and spin-dried for forward purification (PE:EA=5:1, Rf=0.6) to obtain a colorless oil as the target product A-1-8-1-1c (5.00g, 20.72mmol, yield: 86.84%).

[0389] Step 3

[0390] In a dry 100mL three-necked flask, compound A-1-8-1-1c (1g, 4.15mmol) was dissolved in tetrahydrofuran (30mL), and then pyridinium tribromide (1.99g, 6.22mmol) was added. The reaction was then allowed to react at room temperature for 16h. The reaction solution was tested by spot plate detection and found to have new spots generated (PE:EA=10:1, Rf=0.7). There was still residual raw material. H2O (20mL) was added to quench the reaction, and then ethyl acetate was added for extraction (20mL×3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried and spin-dried to obtain a yellow oil as the target product A-1-8-1-1d, which was directly used in the next step.

[0391] Step 4

[0392] In a dry 100mL three-necked flask, the crude compound A-1-8-1-1d (1.33g, 4.15mmol) was dissolved in acetone (30mL), and then A1-1-1c (0.60g, 2.07mmol) and potassium carbonate (1.14g, 8.30mmol) were added. The reaction was allowed to react at room temperature for 16h. The reaction solution was tested by spot plate detection and new spots were found to be generated (PE:EA=3:1, Rf=0.5). There was still residual raw material. 20mL of water was added to quench the reaction, and then (20mL×3) ethyl acetate was added for extraction. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was subjected to positive purification and spin-dried to obtain a yellow oil as the target product A-1-8-1-1e (0.43g, 0.81mmol, yield: 19%).

[0393] Step 5

[0394] In a dry 100mL three-necked flask, compound A-1-8-1-1e (0.43g, 0.81mmol) was dissolved in hydrochloric acid-ethyl acetate solution (3M) (10mL), and then the reaction was allowed to react at room temperature for 1h. The reaction solution was tested by spot plate detection and new spots were found to be generated, indicating that the raw material reaction was complete. 40mL of saturated sodium bicarbonate was added to quench the reaction, and then 20mL×3 ethyl acetate was added for extraction. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was subjected to forward purification (DCM:MeOH=10:1, Rf=0.5) and spin-dried to obtain a white solid as the target product A-1-8-1-1 (0.29g, 0.67mmol, yield: 83.26%, purity: 95.33%).

[0395] MS-ESI:[M+H] + =430.1

[0396] 1 H NMR(400MHz,Chloroform-d)δ7.32(ddd,J=8.4,5.5,3.0Hz,2H),7.17(t,J=8.2Hz,1H),7.02(d,J=6.9Hz ,1H),6.95–6.89(m,1H),6.87–6.77(m,1H),6.23(d,J=2.4Hz,1H),5.02–4.89(m,1H),3.73(dt,J=17.0, 8.5Hz,1H),3.57(d,J=13.2Hz,1H),3.41(t,J=13.5Hz,1H),3.00(dd,J=20.6,11.0Hz,1H),2.89(d,J=12 .9Hz,1H),2.31(s,1H),2.02–1.86(m,2H),1.59(dd,J=13.5,6.8Hz,3H),1.27(dd,J=14.8,10.8Hz,2H).

[0397] Preparation Example (III) 2 Compound A-1-10-1-30

[0398] first step

[0399] In a dry 500 mL three-necked flask, compound A-1-10-1-30a (4 g, 15.08 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11.47 g, 30.16 mmol) were dissolved in N,N-dimethylformamide (100 mL). After stirring at room temperature for 5 minutes, triethylamine (4.58 g, 45.24 mmol) and methoxymethylamine hydrochloride (1.38 g, 22.62 mmol) were added sequentially. The reaction was stirred for 16 hours, and TLC indicated completion of the reaction. Ethyl acetate (100 mL) was added, followed by three washes with 5% aqueous hydrochloric acid (50 mL) and saturated brine (100 mL). The organic phase was collected, dried, and spin-dried to afford the desired product A-1-10-1-30b (4.50 g, 14.59 mmol, yield: 96.79%), which was used directly in the next step.

[0400] Step 2

[0401] In a dry 500mL three-necked flask, A-1-10-1-30b (4.5g, 14.59mmol) was dissolved in anhydrous tetrahydrofuran (100mL). The atmosphere was replaced with nitrogen at 0°C, and a tetrahydrofuran solution of magnesium bromide (3.89g, 29.18mmol) was added. After addition, the mixture was transferred to room temperature and allowed to react for 2-3h. Acetic acid (5mL) was added, followed by water (10mL). After stirring for 5min, the mixture was concentrated to dryness, mixed with silica gel, and purified by column chromatography (PE:EA = 3:1) to obtain the desired product as a light yellow oil. HNMR (LJH-97-P1) confirmed the product to be A-1-10-1-30c (2.2g, 7.93mmol, yield: 54.36%).

[0402] Step 3

[0403] In a dry 100 mL three-necked flask, A-1-10-1-30c (2.2 g, 7.93 mmol) was dissolved in tetrahydrofuran (40 mL) and pyridinium tribromide (5.07 g, 15.86 mmol) was added. The reaction was allowed to proceed at 45°C for 16 h. TLC (PE:EA = 3:1, Rf = 0.49) indicated partial reaction. Ethyl acetate (40 mL) was added and the mixture was washed twice with water (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to afford crude A-1-10-1-30d (1.00 g, 2.81 mmol, yield: 35.39%), which was used directly in the next step.

[0404] Step 4

[0405] In a dry 100mL three-necked flask, compounds A-1-10-1-30d (1.00g, 2.81mmol) and A1-1-1c (0.82g, 2.81mmol) were dissolved in acetone (50mL) and potassium carbonate (0.78g, 5.62mmol) was added. The reaction was allowed to react at room temperature for 24h to obtain a brown-yellow suspension. The reaction solution was plated and the reaction was found to be complete (PE:EA=1:1, Rf=0.38). The reaction solution was drained and the residue was added with 50mL of ethyl acetate and 50mL of water, extracted and the organic phase was collected and dried to obtain a crude product. The crude product was purified by column chromatography twice to obtain the target product A-1-10-1-30e (1.20g, 2.12mmol, yield: 75%) as a light yellow solid.

[0406] Step 5

[0407] In a dry 100mL three-necked flask, compound A-1-10-1-30e (0.6g, 1.06mmol) was dissolved in methanol (20mL), and 350.0mg of wet palladium carbon (5%) was added. Then, the hydrogen was replaced. Under a hydrogen atmosphere, the reaction was allowed to react at room temperature for 2h. The reaction solution was tested by spot plate detection and it was found that new spots were generated, there was residual raw material, and the impurity spots increased. The reaction was stopped, filtered, and forward purification was performed (DCM:MeOH=10:1, Rf=0.5) and dried to obtain a white solid as the target product A-1-10-1-30 (0.15g, 0.35mmol, yield: 32.83%).

[0408] MS-ESI:[M+H] + =432.1

[0409] 1 H NMR (400MHz, Chloroform-d) δ = 7.36–7.29 (m, 2H), 7.16 (s, 1H), 6.98 (d, J = 8.8Hz, 1H),6.85–6.72(m,2H),6.21(s,1H),5.39(ddd,J=17.5,11.2,7.3Hz,1H),4.23(t, J=7.2Hz,1H),4.03(t,J=11.1Hz,1H),3.79–3.64(m,1H),3.26(dd,J=28.4,12.3H z,1H),3.06–2.86(m,2H),2.79(t,J=11.3Hz,1H),1.77(s,1H),1.67–1.58(m,3H).

[0410] Preparation Example (III) 3 Compound A-1-2-1-1

[0411] first step

[0412] In a dry 500mL three-necked flask, palladium acetate (0.63g, 2.82mmol) and ligand 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.63g, 2.82mmol) were added to the three-necked flask and the atmosphere was replaced with nitrogen; tert-butanol (20.87g, 281.6mmol) and A-1-2-1a (30.00g, 140.80mmol) and triethylamine (28.50g, 281.6mmol) were added and dissolved with toluene (300mL) and the atmosphere was replaced with nitrogen. After the addition was completed, a mixture of formic acid (12.96g, 281.6mmol) and acetic anhydride (28.75g, 281.6mmol) was stirred at 30°C for 1.5h and added to the reaction flask. After the addition, the temperature was raised to 80°C and the reaction was carried out for 4 hours. After the reaction, the insoluble matter in the reaction solution was filtered, and 300 mL of distilled water and 300 mL of saturated brine were added to the reaction solution for washing. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow-brown crude product; the crude product was slurried with PE and dried to obtain an orange-yellow product A-1-2-1b (20.00 g, 112.24 mmol, yield: 79.72%).

[0413] MS-ESI:[MH] - =177.1

[0414] Step 2

[0415] In a dry 500 mL three-necked flask, A-1-2-1b (20.00 g, 112.24 mmol), tert-butyloxycarbonyl anhydride (49.00 g, 224.48 mmol), and 4-dimethylaminopyridine (6.86 g, 56.12 mmol) were dissolved in tert-butanol (200 mL) and stirred at room temperature for 12 h. Potassium carbonate (62.06 g, 448.96 mmol) dissolved in water (50 mL) was added to the reaction solution and stirred for 1 h. The reaction progress was monitored by TLC. The product was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and loaded onto a column chromatography column with PE:EA = 1-20% to obtain A-1-2-1c (21.66 g, 92.45 mmol, yield: 82%) as a colorless oil.

[0416] 1 H NMR(400MHz,Chloroform-d)δ8.52(d,J=1.9Hz,1H),8.12(ddt,J=16.4,7.8,1.5Hz,2 H),7.50(t,J=7.7Hz,1H),3.02(q,J=7.2Hz,2H),1.60(s,9H),1.22(t,J=7.2Hz,3H).

[0417] Step 3

[0418] In a dry 500 mL single-necked flask, A-1-2-1c (23.50 g, 100.30 mmol) was dissolved in 200 mL of tetrahydrofuran. Pyridinium tribromide (38.49 g, 120.00 mmol) was added portionwise at 0°C. After completion of the addition, the mixture was brought to room temperature and stirred for 5 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was filtered, the filtrate was dried by rotary evaporation, and 200 mL of ethyl acetate was added. The mixture was washed sequentially with water (100 mL x 2), 100 mL of saturated sodium bicarbonate, and 100 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, rotary evaporation, and column chromatography (PE:EA = 10:1) to obtain A-1-2-1d (30.10 g, 96.11 mmol, yield: 95%) as a yellow oil.

[0419] Step 4

[0420] To a dry 100 mL three-necked flask, add diethyl carbonate (17.11 g, 144.80 mmol) and dissolve in tetrahydrofuran (50 mL). The atmosphere was then replaced with nitrogen. The reaction apparatus was cooled to 0°C in a low-temperature reaction bath. Sodium hydride (2.90 g, 72.40 mmol) was added portionwise and allowed to react for 1 h. Then, A-1-2-1e (5.00 g, 36.20 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 h (preferably 2-4 h). After TLC indicated completion of the reaction, the reaction was quenched with 1 M hydrochloric acid at 0°C to pH 1, maintaining the temperature at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to afford crude intermediate A-1-2-1f (4.20 g, 19.98 mmol, yield: 55.2%).

[0421] Step 5

[0422] In a dry 100 mL three-necked flask, A-1-2-1f (4.20 g, 19.98 mmol) and resorcinol (2.2 g, 19.98 mmol) were dissolved in methanesulfonic acid (30 mL). The temperature was raised to 50°C and the reaction was allowed to react for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL), controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1g (3.0 g, 11.71 mmol, yield: 59%).

[0423] MS-ESI:[MH] - =255.1

[0424] Step 6

[0425] To a dry 100 mL three-necked flask, add A-1-2-1g (1.64 g, 6.39 mmol), A-1-2-1d (2.0 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) in acetone (30 mL) in sequence and stir at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, filter the insoluble material, spin dry the solvent, add water (30 mL), and extract with ethyl acetate (15 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1h (0.62 g, 1.27 mmol, yield: 19.9%). MS-ESI: [MH] - =487.2

[0426] Step 7

[0427] In a dry 100 mL three-necked flask, add A-1-2-1h (0.62 g, 1.27 mmol) and dissolve it in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) and stir for 4 h (preferably 4-8 h). After LCMS shows the reaction is complete, the solvent is dried and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product A-1-2-1 (395.9 mg, 0.92 mmol, yield: 72%).

[0428] MS-ESI:[MH] - =431.1.

[0429] 1 H NMR(400MHz,Chloroform-d)δ8.80(t,J=1.7Hz,1H),8.36(dt,J=7.7,1.5Hz,1H),8.30 (dt,J=7.9,1.5Hz,1H),7.65(t,J=7.8Hz,1H),7.49(dddd,J=8.6,7.0,5.1,2.2Hz,1H), 7.30(ddd,J=8.3,6.8,1.5Hz,2H),7.21(dd,J=9.8,8.3Hz,1H),7.15(dd,J=9.1,2.4Hz ,1H),6.81(d,J=7.9Hz,2H),6.25(s,1H),5.63(q,J=6.8Hz,1H),1.80(d,J=6.9Hz,3H).

[0430] Preparation Example (III) 4 Compound A-1-2-1-2

[0431] first step

[0432] To a dry 100 mL three-necked flask, add diethyl carbonate (15.28 g, 129.36 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.59 g, 64.68 mmol) was added in batches and allowed to react for 1 hour. Then, A-1-2-1-2a (5.00 g, 32.34 mmol) was added to the flask. The temperature was then slowly raised to room temperature. The reaction was continued for 2 hours (preferably 2-4 hours). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, maintaining the temperature below 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-2b (5.60 g, 24.71 mmol, yield: 77.4%).

[0433] 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=7.7Hz,1H),7.55(d,J=4.3Hz,2H),7.47(dt,J =8.2,4.0Hz,1H),4.14(s,2H),4.09(dd,J=7.1,2.7Hz,2H),1.14(t,J=7.1Hz,3H)

[0434] Step 2

[0435] In a dry 100 mL three-necked flask, add A-1-2-1-2b (5.60 g, 24.71 mmol) and resorcinol (2.72 g, 24.71 mmol) dissolved in methanesulfonic acid (30 mL). The temperature was raised to 50°C and the reaction was allowed to react for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL), controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-2c (6.20 g, 22.74 mmol, yield: 78.2%). MS-ESI: [MH] - =271.0

[0436] Step 3

[0437] To a dry 100 mL three-necked flask, A-1-2-1-2c (1.74 g, 6.39 mmol), tert-butyl 3-(2-bromopropionyl)benzoate (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added sequentially and dissolved in acetone (30 mL). The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, the insoluble material was filtered, the solvent was dried, and water (30 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-2d (0.90 g, 1.78 mmol, yield: 27.9%).

[0438] MS-ESI:[MH] - =503.1

[0439] Step 4

[0440] In a dry 100 mL three-necked flask, add A-1-2-1-2d (0.90 g, 1.78 mmol) and dissolve it in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) and stir for 4 h (preferably 4-8 h). After LCMS shows the reaction is complete, the solvent is dried and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product A-1-2-1-2 (113 mg, 0.25 mmol, yield: 14%).

[0441] MS-ESI:[MH] - =447.2

[0442] 1 H NMR(400MHz,Chloroform-d)δ8.79(q,J=1.8Hz,1H),8.36(dq,J=7.7,1.3Hz,1H),8 .29(dt,J=8.0,1.5Hz,1H),7.65(ddd,J=8.4,7.6,1.1Hz,1H),7.52(dt,J=7.9,1.5H z,1H),7.46–7.32(m,2H),7.29–7.20(m,1H),6.97(dd,J=8.8,4.0Hz,1H),6.86–6.6 8(m,2H),6.20(d,J=1.1Hz,1H),5.63(dd,J=7.0,1.1Hz,1H),1.79(d,J=6.9Hz,3H).

[0443] Preparation Example (III) 5 Compound A-1-2-6-1

[0444] first step

[0445] In a dry 100 mL three-necked flask, compound A-1-2-6-1a (2.50 g, 16.01 mmol) and m-diphenol (1.94 g, 17.61 mmol) were weighed into the reaction flask and dissolved in methanesulfonic acid (20 mL). The reaction was incubated at 50°C for 3 h to yield a black solution. TLC indicated complete reaction. The reaction mixture was returned to room temperature and 30 mL of ethanol was added. Solid sodium bicarbonate was added to adjust the pH to 6-7. Water (200 mL) was then added and extracted with ethyl acetate (100 mL). The organic phase was collected, dried, and concentrated. The product was then purified by column chromatography (PE:EA = 3:1) to yield the desired product as a yellow oil, which was used in the next reaction. A-1-2-6-1b (3.00 g, 14.84 mmol, yield: 92.68%) was obtained.

[0446] Step 2

[0447] In a dry 100 mL three-necked flask, compounds A-1-2-6-1b (3.00 g, 14.84 mmol) and A-1-2-1-1d (5.58 g, 17.81 mmol) were dissolved in acetone (30 mL) with potassium carbonate (5.13 g, 37.1 mmol). The mixture was reacted at room temperature to yield a yellow, turbid solution. TLC indicated the formation of new spots and complete reaction of the starting materials. The reaction mixture was poured into ethyl acetate (50 mL) and washed three times with saturated brine. The organic phase was collected, dried, and concentrated. Purification by column chromatography (PE:EA = 1:1) afforded the desired product, A-1-2-6-1c (1.5 g, 3.45 mmol, yield: 23.27%), as a yellow solid. This product was used directly in the next reaction.

[0448] Step 3

[0449] In a dry 100 mL three-necked flask, compound A-1-2-6-1c (1.50 g, 3.45 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (0.79 g, 6.90 mmol) was added. The reaction was allowed to react at room temperature for 2 h to yield a yellow, clear solution. TLC indicated complete reaction. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, and the pH was adjusted to 4-5 with solid sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried to yield the crude product as a dark yellow oil. The compound was purified by adding 50 mL of ethyl acetate to the crude product. After dissolution, 25 mL of petroleum ether was slowly added and stirred for 1 hour to obtain a yellow turbid liquid. Filtering afforded a pale yellow solid. The solid was collected and completely dissolved in 50 mL of ethyl acetate, which was then refluxed for 3 hours. The solid was concentrated and mixed, and then column purification (PE:EA = 2:1) was performed to obtain the desired product. 2.5 mL of acetonitrile and 25 mL of water were added to the desired product and lyophilized to obtain the desired product A-1-2-6-1 (265 mg, 0.70 mmol, purity: 99.26%, yield: 20.2%) as a white solid. MS-ESI: [MH] - =377.1.

[0450] 1 H NMR (400MHz, DMSO-d6DMSO-D6) δ8.55(s,1H),8.31(d,J=8.0Hz,1H),8.23(d,J=7.8Hz,1H),7.97(d,J=8.8Hz,1H),7.71(t,J=7.8Hz,1H),6.9 8(dt,J=6.0,2.4Hz,2H),6.27(q,J=6.7Hz,1H),5.89(s,1H),2.29–2.18(m,1H),1.59(d,J=6.7Hz,3H),1.11–1.04(m,2H),0.90–0.82(m,2H).

[0451] Preparation Example (III) 6 Compound A-1-2-1-8

[0452] first step

[0453] To a dry 100 mL three-necked flask, add diethyl carbonate (15.73 g, 133.20 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.59 g, 66.60 mmol) was added in batches and allowed to react for 1 h. A-1-2-1-8a (5.00 g, 33.30 mmol) was then added to the flask. The temperature was then slowly raised to room temperature. The reaction was continued for 2 h (preferably 2-4 h). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, maintaining the temperature below 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-8b (7.0 g, 22.05 mmol, yield: 94.60%).

[0454] MS-ESI:[M+H] + =223.2

[0455] Step 2

[0456] In a dry 100 mL three-necked flask, A-1-2-1-8b (7.00 g, 22.05 mmol) and resorcinol (2.43 g, 22.05 mmol) were dissolved in methanesulfonic acid (30 mL) and heated to 50°C for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-8c (5.50 g, 20.50 mmol, yield: 79.00%).

[0457] MS-ESI:[MH] - =267.0

[0458] Step 3

[0459] To a dry 100 mL three-necked flask, A-1-2-1-8c (1.54 g, 5.75 mmol), A-1-2-1-1d (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added sequentially and dissolved in acetone (30 mL). The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-8d (1.00 g, 2.00 mmol, yield: 31.29%).

[0460] MS-ESI:[M- t Bu] - =445.2

[0461] Step 4

[0462] In a dry 100 mL three-necked flask, add A-1-2-1-8d (1.00 g, 2.00 mmol) and dissolve it in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) and stir for 4 h (preferably 4-8 h). After LCMS shows the reaction is complete, the solvent is dried and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the product A-1-2-1-8 (329.5 mg, 0.74 mmol, yield: 36.80%, purity: 99.16%).

[0463] MS-ESI:[MH] - =443.1.

[0464] 1 H NMR(400MHz,Chloroform-d)δ8.80(t,J=1.8Hz,1H),8.36(dt,J=7.8,1.4Hz,1H),8.29(dt,J=7.9,1.5Hz,1H),7.64(t,J=7.8Hz,1H),7.45(ddd,J=8.4 ,7.4,1.8Hz,1H),7.18(dd,J=7.5,1.8Hz,1H),7.10–6.96(m,3H),6.76(s,2 H),6.20(s,1H),5.62(d,J=8.0Hz,1H),3.73(s,3H),1.79(d,J=6.8Hz,3H).

[0465] Preparation Example (III) 7 Compound A-1-2-1-9

[0466] first step

[0467] To a dry 100 mL three-necked flask, add diethyl carbonate (14.39 g, 121.80 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.44 g, 60.90 mmol) was added in batches and allowed to react for 1 h. Then, A-1-2-1-9a (5.00 g, 30.45 mmol) was added to the flask. The temperature was then slowly raised to room temperature. The reaction was continued for 2 h (preferably 2-4 h). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, maintaining the temperature at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-9b (7.5 g, 22.22 mmol, yield: 83.40%).

[0468] MS-ESI:[M+H] + =237.1

[0469] Step 2

[0470] In a dry 100 mL three-necked flask, A-1-2-1-9b (7.5 g, 22.22 mmol) and resorcinol (2.45 g, 22.22 mmol) were dissolved in methanesulfonic acid (30 mL) and heated to 50°C for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-9c (2.5 g, 8.86 mmol, yield: 33.88%).

[0471] MS-ESI:[MH] - =281.1

[0472] Step 3

[0473] To a dry 100 mL three-necked flask, A-1-2-1-9c (1.62 g, 5.57 mmol), A-1-2-1-1d (2.0 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added sequentially and dissolved in acetone (30 mL). The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-9d (2.00 g, 1.27 mmol, yield: 60.86%).

[0474] MS-ESI:[MH] - =513.2

[0475] Step 4

[0476] In a dry 100 mL three-necked flask, add A-1-2-1-9d (2.00 g, 1.27 mmol) and dissolve it in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) and stir for 4 h (preferably 4-8 h). After LCMS shows the reaction is complete, the solvent is dried and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product A-1-2-1-9 (905.2 mg, 0.92 mmol, yield: 48.13%, purity: 95.03%).

[0477] MS-ESI:[MH] - =457.2.

[0478] 1 H NMR(400MHz,Chloroform-d)δ8.80(t,J=1.8Hz,1H),8.35(dt,J=7.8,1.4Hz,1H),8.29(dt ,J=7.9,1.5Hz,1H),7.63(t,J=7.8Hz,1H),7.42(ddd,J=8.3,7.5,1.8Hz,1H),7.18(dd,J=7 .5,1.8Hz,1H),7.10(d,J=8.8Hz,1H),7.05–6.96(m,2H),6.76(s,2H),6.21(s,1H),5.62(d ,J=6.9Hz,1H),3.99(dq,J=10.7,7.1Hz,2H),1.79(d,J=6.8Hz,3H),1.14(t,J=7.0Hz,3H).

[0479] Preparation Example (III) 8 Compound A-2-2-1-4

[0480] first step

[0481] A-2-2-1-4a (2.00 g, 11.22 mmol) was added to a dry 100 mL three-necked flask and the atmosphere was replaced with nitrogen. Anhydrous tetrahydrofuran (20 mL) was then added to dissolve the mixture. The temperature was lowered to 0°C, and pyridinium tribromide (4.31 g, 13.46 mmol) was added portionwise. After complete addition, the temperature was raised to 25°C and the reaction was allowed to proceed for 6 h (preferably 6-8 h). After LCMS indicated completion of the reaction, the reaction mixture was filtered and the filtrate was collected. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were separated, washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to afford intermediate A-2-2-1-4b (1.10 g, 4.28 mmol, yield: 38.12%).

[0482] MS-ESI:[MH] - =255.0

[0483] Step 2

[0484] To a dry 100 mL three-necked flask, A-2-2-1-4b (1.1 g, 4.28 mmol), A1-1-1c (1.12 g, 3.85 mmol), potassium carbonate (1.18 g, 8.56 mmol), and tetrabutylammonium iodide (1.58 g, 4.28 mmol) were added in sequence and dissolved in acetone (10 mL). The mixture was stirred at room temperature overnight. After LCMS showed the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain intermediate A-2-2-1-4c (1.00 g, 2.14 mmol, yield: 50.06%).

[0485] MS-ESI:[MH] - =465.1

[0486] Step 3

[0487] A-2-2-1-4c (1.00 g, 2.14 mmol) was added to a dry 100 mL three-necked flask and dissolved in 4 mL of tetrahydrofuran. The temperature was lowered to 0°C, and 2 M sodium hydroxide solution (2 mL) was added dropwise. The reaction was stirred for 1 h (preferably 1-2 h). After LCMS indicated completion of the reaction, the mixture was diluted with water (10 mL) and quenched by adding 2 M hydrochloric acid solution at 0°C, adjusting the pH to 1. The mixture was extracted with ethyl acetate (5 mL x 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to afford the final product, A-2-2-1-4 (117.4.0 mg, 0.08 mmol, yield: 10.29%, purity: 85.01%).

[0488] MS-ESI:[MH] - =451.1

[0489] 1 H NMR (400MHz, DMSO-d6) δ8.52(t,J=1.8Hz,1H),8.25(ddt,J=10.7,7.8,1.4Hz,2H),7.76–7.64(m,2H),7.57(dd,J= 8.6, 6.1Hz, 1H), 7.44 (td, J=8.5, 2.6Hz, 1H), 7.25 (d, J=2.3Hz, 1H), 6.99–6.93 (m, 2H), 6.32 (s, 1H), 5.83 (s, 2H).

[0490] Preparation Example (III) 9 Compound A-1-2-1-33

[0491] first step

[0492] A-1-2-1-33a (20.00 g, 68.81 mmol) and ethyl (2S)-2-hydroxypropionate (9.75 g, 82.57 mmol) were added to a dry 500 mL three-necked flask and dissolved in tetrahydrofuran (300 mL). Triphenylphosphine (21.66 g, 82.57 mmol) and diisopropyl azodicarboxylate (16.70 g, 82.57 mmol) were added under ice-cooling. After stirring under ice-cooling for 2 h, the reaction was complete as monitored by TLC. The reaction was quenched by the addition of water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The organic phases were purified by silica gel column chromatography (PE:EA = 10:1) to obtain intermediate A-1-2-1-33b (30.00 g, crude product).

[0493] MS-ESI: [M+H]+=391.1

[0494] Step 2

[0495] A-1-2-1-33b (30.00 g, crude) was added to a 500 mL single-necked flask and dissolved in tetrahydrofuran (150 mL) and methanol (50 mL). Aqueous sodium hydroxide (2N, 100 mL) was added and stirred in an ice bath for 20 min. A spot plate was taken. TLC indicated complete reaction of the starting material, and the reaction was stopped. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL × 3). The aqueous phase was removed and quenched with dilute hydrochloric acid (1N, 200 mL). The mixture was adjusted to slightly acidic and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, sampled, and sent to LCMS. Purification by silica gel column chromatography (DCM:MeOH = 15:1) afforded intermediate A-1-2-1-33c (14.40 g, crude).

[0496] MS-ESI:[MH] - =361.1

[0497] Step 3

[0498] A-1-2-1-33c (450 mg, 1.24 mmol) and ((3-(2-methoxy-2-oxoethyl)phenyl)boric acid (530.0.0 mg, 2.48 mmol) were added to a dry 50 mL three-necked flask. After nitrogen was replaced, tetrakistriphenylphosphine palladium (72 mg, 0.062 mmol) was added and dissolved in 5 mL of dioxane solution. Finally, dimethyl dicarbonate (330 mg, 2.48 mmol) was added and reacted at 115 ° C for 2 h (preferably 2-4 h). After the reaction was completed by LCMS, the reaction was cooled to room temperature, filtered, and the filtrate was collected. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE: EA = 3: 1) to obtain intermediate A-1-2-1-33d (400 mg, 0.81 mmol, yield: 65.15%).

[0499] MS-ESI:[M+H] + =495.1

[0500] Step 4

[0501] A-1-2-1-33d (400 mg, 0.81 mmol) was added to a dry 50 mL three-necked flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0°C and then added with 2 mL of 2M aqueous sodium hydroxide solution. The reaction was allowed to proceed for 30 min (preferably 0.5-2 h). After TLC indicated completion of the reaction, the pH was adjusted to 1 with 1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product A-1-2-1-33 (86 mg, 0.178 mmol, yield: 22.0%).

[0502] MS-ESI:[MH] - =479.1

[0503] 1 H NMR(400MHz,Chloroform-d)δ8.01–7.94(m,2H),7.60–7.55(m,1H),7.49(td,J=7. 7,1.7Hz,1H),7.30–7.27(m,1H),7.26–7.23(m,1H),7.12(tdd,J=8.3,4.1,2.5Hz,1 H),6.94(dd,J=8.8,4.9Hz,1H),6.83–6.78(m,1H),6.77–6.71(m,1H),6.17(d,J=0. 9Hz, 1H), 5.61 (qd, J = 6.9, 3.4Hz, 1H), 3.74 (d, J = 1.9Hz, 2H), 1.75 (d, J = 6.8Hz, 3H).

[0504] Preparation Example (III) 10 Compound A-1-10-1-21

[0505] first step

[0506] A-1-2-1-33c (450 mg, 1.24 mmol) and A-1-10-1-21a (460 mg, 2.48 mmol) were added to a dry 50 mL three-necked flask. After nitrogen was replaced, tetrakistriphenylphosphine palladium (72 mg, 0.062 mmol) was added and dissolved in 2 mL of dioxane solution. Finally, dimethyl dicarbonate (0.33 g, 2.48 mmol) was added and reacted at 115 ° C for 2 h (preferably 2-4 h). After the reaction was completed, LCMS showed that the reaction was completed, and the mixture was cooled to room temperature, filtered, and the filtrate was collected. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=3:1) to obtain intermediate A-1-10-1-21b (210 mg, 0.43 mmol, yield: 34.77%).

[0507] MS-ESI:[MH] - =485.4

[0508] Step 2

[0509] A-1-10-1-21b (210 mg, 0.43 mmol) was added to a dry 50 mL three-necked flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0°C and then 2 mL of 2M aqueous sodium hydroxide solution was added. The reaction was allowed to react for 30 min (preferably 0.5-2 h). After TLC indicated completion of the reaction, the pH was adjusted to 1 with 1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product A-1-10-1-21 (52 mg, 0.109 mmol, yield: 25.3%).

[0510] MS-ESI:[MH] - =471.0

[0511] 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=4.1Hz,1H),7.83(d,J=4.0Hz,1H),7.29(dd,J=8.4,2.5Hz,1H),7.25(d,J=5.9Hz,1H),7.13(tt ,J=8.3,2.4Hz,1H),6.98(dd,J=8.4,2.5Hz,1H),6.92–6.73(m,2H),6.21(d,J=0.8Hz,1H),5.25(q,J=6.8Hz,1H),1.79(d,J=6.9Hz,3H).

[0512] Preparation Example (III) 11 Compound A-1-10-1-19

[0513] first step

[0514] A-1-2-1-33c (500 mg, 1.38 mmol) and A-1-10-1-19a (469 mg, 2.76 mmol) were added to a dry 50 mL three-necked flask. After nitrogen was replaced, tetrakistriphenylphosphine palladium (80 mg, 0.069 mmol) was added and dissolved in 5 mL of dioxane solution. Finally, dimethyl dicarbonate (463 mg, 3.45 mmol) was added and reacted at 115 ° C for 2 h (preferably 2-4 h). After the reaction was completed, LCMS showed that the reaction was completed, and the mixture was cooled to room temperature, filtered, and the filtrate was collected. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=3:1) to obtain intermediate A-1-10-1-19b (317 mg, 0.67 mmol, yield: 65.15%).

[0515] MS-ESI:[M+H] + =471.1

[0516] Step 2

[0517] To a dry 50 mL three-necked flask, add A-1-10-1-19b (317 mg, 0.67 mmol) and dissolve in 2 mL of tetrahydrofuran. Cool to 0°C, then add 2 mL of 2M aqueous sodium hydroxide solution and react for 30 min (preferably 0.5-2 h). After TLC indicates completion of the reaction, adjust the pH to 1 with 1 M aqueous hydrochloric acid. Extract with ethyl acetate (5 mL x 3), wash with saturated brine (5 mL x 2), dry over anhydrous sodium sulfate, and spin dry. Purify by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product A-1-10-1-19 (104.8 mg, 0.23 mmol, yield: 31.67%).

[0518] MS-ESI:[MH] - =455.0

[0519] 1H NMR (400MHz, DMSO-d6) δ7.76–7.65(m,2H),7.54(dd,J=8.6,6.1Hz,1H),7.41(tt,J=8.5,3.2Hz,1H),6.99(dd,J=6.6,2 .4Hz,1H),6.98–6.91(m,2H),6.87(ddd,J=8.7,5.7,2.5Hz,1H),6.31(s,1H),5.91–5.77(m,1H),1.59(d,J=6.4Hz,3H).

[0520] Preparation Example (III) 12 Compound A-1-2-1-44

[0521] first step

[0522] A-1-2-1-33c (1.00 g, 2.76 mmol) and A-1-2-1-44a (1.18 g, 5.52 mmol) were added to a dry 100 mL three-necked flask. After replacing nitrogen, tetrakistriphenylphosphine palladium (0.16 g, 0.14 mmol) was added and dissolved in 15 mL of dioxane solution. Finally, dimethyl dicarbonate (0.74 g, 5.52 mmol) was added and the reaction was continued at 115 ° C for 2 h. (5-(methoxycarbonyl)furan-2-yl)boric acid (469 mg, 2.76 mmol) was added and the nitrogen was replaced. After adding tetrakistriphenylphosphine palladium (80 mg, 0 069mmol), dissolved in 5mL of dioxane solution, and finally added dimethyl dicarbonate (463mg, 3.45mmol) and reacted at 115°C for 2h (preferably 2-4h). After the reaction was completed, LCMS showed that the reaction was complete, cooled to room temperature, filtered, and the filtrate was collected. 10mL of water was added, extracted with ethyl acetate (10mL×3), washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=3:1) to obtain intermediate A-1-2-1-44b (0.33g, 0.64mmol, yield: 23.13%).

[0523] MS-ESI:[MH] - =513.1

[0524] Step 2

[0525] A-1-2-1-44b (300 mg, 0.58 mmol) was added to a dry 50 mL three-necked flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0°C and then added with 2 mL of 2M aqueous sodium hydroxide solution. The reaction was allowed to proceed for 30 min (preferably 0.5-2 h). After TLC indicated completion of the reaction, the pH was adjusted to 1 with 1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product A-1-2-1-44 (15 mg, 0.03 mmol, yield: 4.66%).

[0526] LCMS=[MH] - =498.9

[0527] 1 H NMR(400MHz,Chloroform-d)δ8.69(s,1H),8.13(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H),7.30–7.27(m,1H),7.24(s,1H),7. 16–7.05(m,1H),6.95(dd,J=8.8,3.0Hz,1H),6.87–6.64(m,2H),6.18(s,1H),5.51(d,J=6.9Hz,1H),1.78(d,J=6.8Hz,3H).

[0528] Preparation Example (III) 13 Compound A-1-2-1-60

[0529] first step

[0530] A-1-2-1-60a (20.00 g, 76.65 mmol), tert-butyl 2-bromoacetate (1.36 g, 6.99 mmol), and potassium carbonate (1.61 g, 11.65 mmol) were added to a dry 500 mL three-necked flask and dissolved in 12 mL of acetone. The mixture was stirred at 25°C for 6 h (preferably 6-10 h). After LCMS showed completion of the reaction, 10 mL of water was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were separated and combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-60b (1.20 g, 4.54 mmol, yield: 97.40%).

[0531] MS-ESI:[M- t Bu] + =209.2

[0532] Step 2

[0533] In a dry 100 mL three-necked flask, A-1-2-1-60b (1.20 g, 4.54 mmol) and pyridinium tribromide (1.45 g, 4.54 mmol) were dissolved in 12 mL of tetrahydrofuran and stirred at 25°C for 2 h (preferably 2-4 h). After LCMS showed completion of the reaction, insoluble salts were removed by filtration, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-60c (1.20 g, 3.83 mmol, yield: 77.01%).

[0534] 1 H NMR(400MHz,Chloroform-d)δ7.62(dt,J=7.7,1.4Hz,1H),7.52(dq,J=2.7,1.5Hz,1H),7.39(tt,J=7.9,1.7Hz,1H),7.15(d dt,J=8.4,2.8,1.3Hz,1H),5.27(q,J=6.6Hz,1H),4.57(q,J=1.7Hz,2H),1.88(dt,J=6.7,1.6Hz,3H),1.49(t,J=1.5Hz,9H).

[0535] Step 3

[0536] A-1-2-1-60c (1.20 g, 3.83 mmol) was added to a dry 100 mL three-necked flask and dissolved in 10 mL of acetone. Tetrabutylammonium iodide (1.41 g, 3.83 mmol) and potassium carbonate (1.06 g, 7.66 mmol) were added and stirred to disperse. Finally, dichloromethane was added to A-1-1-1c (0.85 g, 5.75 mmol) and stirred at room temperature for overnight. After LCMS showed that the reaction was complete, the reaction solution was filtered and the filtrate was collected. The filtrate was diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were separated and combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH=15:1, 1:1000AcOH) to obtain intermediate A-1-2-1-60d (0.86 g, 1.56 mmol, yield: 44.48%).

[0537] MS-ESI:[MH] - =551.2

[0538] Step 4

[0539] A-1-2-1-60d (860 mg, 1.56 mmol) was dissolved in trifluoroacetic acid (10 mL) and 10 mL of dichloromethane in a dry 50 mL three-necked flask and allowed to react at 25°C for 2 h (preferably 2-4 h). After TLC indicated completion of the reaction, water (20 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the target product A-1-2-1-60a (386 mg, 0.78 mmol, yield: 49.53%).

[0540] MS-ESI:[MH] - =495.1

[0541] 1 H NMR(400MHz,Chloroform-d)δ7.68(d,J=7.6Hz,1H),7.56(dd,J=5.3,2.6Hz,1 H),7.44(t,J=8.0Hz,1H),7.30–7.26(m,1H),7.25–7.19(m,2H),7.12(ddd,J=1 1.5,7.8,3.2Hz,1H),6.94(dd,J=9.2,3.6Hz,1H),6.83–6.67(m,2H),6.17(s, 1H), 5.58 (q, J = 6.8Hz, 1H), 4.74 (d, J = 1.4Hz, 2H), 1.74 (dd, J = 6.7, 1.4Hz, 3H).

[0542] Preparation Example (III) 14 Compound A-1-2-1-93

[0543] first step

[0544] In a dry 100 mL three-necked flask, compound A-1-2-1-93a (4.10 g, 18.72 mmol) and methoxymethylamine hydrochloride (1.39 g, 20.59 mmol) were dissolved in N,N-dimethylformamide (40 mL). Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.81 g, 20.59 mmol), 1-hydroxybenzotriazole (2.78 g, 20.59 mmol), and N,N-diisopropylethylamine (12.1 g, 93.6 mmol) were added under ice-cooling and allowed to react at room temperature for 2 h. The reaction was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with 1 M hydrochloric acid, 1 M sodium hydroxide and saturated brine, respectively, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column chromatography (0-10% EA:PE) to give a colorless oil A-1-2-1-93b (4.85 g, 17.58 mmol, yield 93.91%, purity 95%).

[0545] MS-ESI:[M+H] + =261.9

[0546] Step 2

[0547] In a dry 100 mL three-necked flask, compound A-1-2-1-93b (4.35 g, 16.6 mmol) was dissolved in anhydrous tetrahydrofuran (87 mL). Ethylmagnesium bromide (2 M, 12.45 mL, 24.9 mmol) was added dropwise under an ice bath. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched by the addition of saturated ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 20:1) to afford A-1-2-1-93c (3.87 g, 15.91 mmol, yield: 95.86%, purity: 95%) as a white solid.

[0548] 1 H NMR(600MHz,Chloroform-d)δ7.88(t,J=1.6Hz,1H),7.58(ddd,J=8.9,2.4,1.4Hz,1 H),7.44(ddd,J=7.7,2.5,1.7Hz,1H),2.96(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H).

[0549] Step 3

[0550] In a dry 100 mL three-necked flask, compound A-1-2-1-93c (3.90 g, 16.88 mmol) was dissolved in anhydrous N,N-dimethylformamide (87 mL). Cuprous cyanide (4.54 g, 50.64 mmol) was added. The mixture was purged with nitrogen four times and refluxed at 185°C under nitrogen for three hours (a large amount of bubbling initially occurred, which disappeared upon completion). The mixture was concentrated under reduced pressure to remove the N,N-dimethylformamide. The mixture was then stirred with 50 mL of water and 120 mL of ethyl acetate for 10 minutes, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was allowed to stand and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 20:1) to afford A-1-2-1-93d (2.08 g, 11.62 mmol, 68.86% yield, 99% purity) as a white solid.

[0551] 1 H NMR(400MHz,Chloroform-d)δ8.04(t,J=1.4Hz,1H),7.89(ddd,J=8.8,2.5,1.4Hz,1 H),7.55(ddd,J=7.5,2.6,1.4Hz,1H),3.00(q,J=7.2Hz,2H),1.26(t,J=7.2Hz,3H).

[0552] Step 4

[0553] In a dry 100 mL three-necked flask, compound A-1-2-1-93d (2.08 g, 11.74 mmol) was dissolved in dioxane (17.60 mL). Aqueous sodium hydroxide (4 M, 17.6 mL, 70.44 mmol) was added and reacted at 95°C for 3 h. The mixture was cooled to room temperature, diluted with water, and washed once with ethyl acetate. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a color-coded solid, A-1-2-1-93e (2.03 g, 9.83 mmol, 83.74% yield, 95% purity).

[0554] MS-ESI:[MH] - =195.3

[0555] Step 5

[0556] In a dry 100 mL three-necked flask, compound A-1-2-1-93e (1.93 g, 9.84 mmol) was dissolved in tert-butanol (19 mL). 4-Dimethylaminopyridine (481 mg, 3.94 mmol) and di-tert-butyl dicarbonate (2.58 g, 25.58 mmol) were added and allowed to react at room temperature for 3 h. TLC confirmed the reaction was complete. The reaction solution was dried, dissolved in ethyl acetate, and washed with 1 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, respectively. Drying over anhydrous sodium sulfate resulted in the crude product being purified by silica gel column chromatography (PE:EA = 10:1) to afford A-1-2-1-93f (1.25 g, 4.71 mmol, 47.84% yield, 95% purity) as a white solid.

[0557] 1 H NMR (400MHz, Chloroform-d) δ8.34(t,J=1.4Hz,1H),7.83(dddd,J=11.9,8.9,2.6,1.4Hz,2H),3.03(q,J=7.2Hz,2H),1.62(s,9H),1.24(t,J=7.2Hz,3H).

[0558] Step 6

[0559] In a dry 50 mL three-necked flask, compound A-1-2-1-93f (100 mg, 396.38 μmol) was dissolved in dichloromethane (1 mL). 48% hydrobromic acid (4.5 μL) was added, and bromine (63 mg, 396.38 μmol, 20.4 μL) was added dropwise. The mixture was allowed to react at room temperature for 16 hours. One equivalent of bromine (63 mg, 396.38 μmol, 20.4 μL) was added, and the reaction was continued at room temperature for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was dried over anhydrous sodium sulfate and spin-dried to obtain the crude compound A-1-2-1-93f (107 mg, 350.09 μmol, 88.32% yield, 90% purity) as a pale yellow solid. MS-ESI: [MH] - =273.2.

[0560] Step 7

[0561] In a dry 50 mL three-necked flask, compound A1-1-1-1c (101 mg, 368.11 μmol) was dissolved in anhydrous acetonitrile (1 mL). Triethylamine (112 mg, 1.10 mmol) and compound A-1-2-1-93g (107 mg, 368.11 μmol) were added. The mixture was allowed to react at room temperature for 5 h. LCMS confirmed the reaction was complete. The mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The product was purified by medium-pressure reverse phase chromatography to afford A-1-2-1-93 (43 mg, 85.15 μmol, 23.13% yield, 95.34% purity) as a white solid.

[0562] MS-ESI:[M+H] + =485.4.

[0563] 1 H NMR (400MHz, DMSO-d6DMSO-D6) δ13.65(s,1H),8.37(q,J=1.3Hz,1H),8.19(dq,J =9.1,2.2Hz,1H),7.99(ddd,J=8.7,2.6,1.4Hz,1H),7.69(dt,J=8.9,2.3Hz,1H) ,7.56(ddd,J=8.6,6.1,2.6Hz,1H),7.43(tdd,J=8.5,4.1,2.5Hz,1H),7.13(dd, J=3.5,2.3Hz,1H),6.98–6.86(m,2H),6.35–6.25(m,2H),1.58(d,J=6.7Hz,3H).

[0564] Preparation Example (III) 15 Compound A-1-2-1-40

[0565] first step

[0566] In a dry 100 mL three-necked flask, compound A-1-2-1-40a (2.00 g, 9.94 mmol), methoxymethylamine (1.05 g, 10.44 mmol), triethylamine (1.06 g, 10.44 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.00 g, 10.44 mmol) were dissolved in N,N-dimethylformamide (30 mL) and allowed to react at room temperature for 3 h. The N,N-dimethylformamide was removed by concentration, and the mixture was extracted three times with ethyl acetate after adding water. The organic phases were combined and dried. The crude product was purified by silica gel column chromatography to afford A-1-2-1-40b (1.77 g, 6.17 mmol, 62.10% yield, 85% purity) as a colorless liquid.

[0567] MS-ESI:[M+H]+ =244.9.

[0568] Step 2

[0569] In a dry 10 mL three-necked flask, compound A-1-2-1-40b (1.77 g, 7.26 mmol) was dissolved in tetrahydrofuran (35 mL). Ethylmagnesium bromide (14.5 mL, 29.05 mmol) was added dropwise at 0°C and allowed to react at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution at 0°C and extracted three times with ethyl acetate. The organic phases were combined and dried. The crude product was purified by silica gel column chromatography to afford A-1-2-1-40c (718 mg, 3.37 mmol, 46.36% yield, 95% purity) as a colorless liquid.

[0570] MS-ESI:[M+H] + =214.2.

[0571] Step 3

[0572] In a dry 50 mL three-necked flask, compound A-1-2-1-40d (718 mg, 3.37 mmol) and hydrobromic acid (272 mg, 3.37 mmol) were dissolved in dichloromethane (15 mL). Bromine (538 mg, 3.37 mmol) was added at 0°C and allowed to react at room temperature for 3 h. The solvent was removed by concentration. The crude product was purified by silica gel column chromatography to afford A-1-2-1-40e (700 mg, 2.40 mmol, 71.16% yield, 100% purity) as a colorless liquid.

[0573] MS-ESI:[M+H] + =292.2.

[0574] Step 4

[0575] In a dry 50 mL three-necked flask, A1-1-1c (200 mg, 688 μmol), compound A-1-2-1-40e (201 mg, 688 μmol), and cesium carbonate (560 mg, 1.72 mmol) were dissolved in acetonitrile (10 mL) and reacted at room temperature for 2 h. The reaction mixture was filtered and purified using high-pressure reverse-phase preparative and silica gel forward chromatography to obtain a chromogenic solid A-1-2-1-40 (45 mg, 88 μmol, 12.86% yield, 98.7% purity).

[0576] 1H NMR (400MHz, DMSO-d6) δ8.42 (t, J=1.8Hz, 1H), 8.35 (ddd, J=7.0, 2.9, 1.3Hz, 1H), 8.13 (dt,J=8.1,1.2Hz,1H),7.81(t,J=7.8Hz,1H),7.69(dt,J=8.9,2.4Hz,1H),7.59–7.50( m,3H),7.42(tdd,J=8.5,4.1,2.6Hz,1H),7.09(dd,J=5.2,2.4Hz,1H),6.98–6.86(m,2 H),6.35–6.30(m,1H),6.29–6.22(m,1H),1.68–1.53(m,3H).ESI-LCMS:m:z502.0[M+H] + .

[0577] Preparation Example (III) 16 Compound A-1-2-1-94

[0578] first step

[0579] In a dry 50 mL three-necked flask, compound A-1-2-1-94a (500 mg, 2.69 mmol) and 4-dimethylaminopyridine (83 mg, 671 μmol) were dissolved in dichloromethane (20 mL). Acetyl chloride (232 mg, 2.95 mmol) was added dropwise at room temperature. The mixture was allowed to react at 25°C for 1.5 h. The dichloromethane was removed by concentration. The crude product was purified by silica gel column chromatography to obtain A-1-2-1-94b as a white solid (248 mg, 1.09 mmol, 40.46% yield, 98% purity).

[0580] MS-ESI:[M+H] + =229.0.

[0581] Step 2

[0582] In a dry 50 mL three-necked flask, compound A-1-2-1-94b (248 mg, 1.09 mmol) and hydrobromic acid (88 mg, 1.09 mmol) were dissolved in dichloromethane (8 mL). Bromine (521 mg, 3.26 mmol) was added at 0°C and allowed to react at 20°C for 16 h. The dichloromethane was removed by concentration. The crude product was purified by silica gel column chromatography to obtain A-1-2-1-94c as a yellow solid (281 mg, 915 μmol, 84.20% yield, 95% purity).

[0583] MS-ESI:[M+H] + =307.0.

[0584] Step 3

[0585] Compound A-1-2-1-94c (295 mg, 960 μmol), A1-1-1c (279 mg, 960 μmol), and cesium carbonate (782 mg, 2.40 mmol) were dissolved in acetonitrile (8 mL) in a dry 50 mL three-necked flask and reacted at 40°C for 3 h. The reaction solution was filtered and purified using high-pressure reverse-phase preparative purification to obtain A-1-2-1-94 as a white solid (52 mg, 104 μmol, yield 10.84%, purity 95.1%).

[0586] MS-ESI:[M+H] + =474.9.

[0587] 1 H NMR (600MHz, DMSO-d6) δ11.59 (s, 1H), 7.82 (dt, J = 7.4, 1.4Hz, 2H), 7.69 (dt, J=8.8,2.8Hz,1H),7.55(ddd,J=8.5,6.1,2.4Hz,1H),7.46–7.40(m,1H),7.0 2(dd,J=8.0,2.5Hz,1H),6.94(d,J=8.9Hz,1H),6.86(ddd,J=13.1,8.9,2.5H z,1H),6.31(d,J=1.3Hz,1H),6.21–6.14(m,1H),1.55(dd,J=6.7,1.6Hz,3H).

[0588] Preparation Example (III) 17 Compound A-1-11-1-1

[0589] first step

[0590] In a dry 100 mL three-necked flask, compound A-1-11-1-1a (4.00 g, 24.82 mmol) and N-methoxymethylamine hydrochloride (2.88 g, 29.78 mmol) were dissolved in N,N-dimethylformamide (30 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.26 g, 32.27 mmol) and N,N-diisopropylethylamine (9.62 g, 74.46 mmol) were added thereto in sequence. The mixture was stirred at room temperature for 2 h, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried and filtered, and the crude product was dried and purified by reverse phase to obtain A-1-11-1-1b (3.30 g, 16.16 mmol, yield: 65.10%) as a white solid.

[0591] MS-ESI:[M+H] + =205.0

[0592] Step 2

[0593] A-1-11-1-1b (2.00 g, 9.79 mmol) was dissolved in tetrahydrofuran (20 mL) in a dry 100 mL three-necked flask. Ethylmagnesium bromide (2M, 24.48 mL) was slowly added to the reaction solution under an ice bath. The temperature was raised to 50°C and the reaction was allowed to react for 10 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were dried and filtered, and purified by normal phase to give a yellow oil A-1-11-1-1c (840 mg, 4.12 mmol, yield: 42.09%).

[0594] MS-ESI:[M+H] + =174.2

[0595] Step 3

[0596] In a dry 50 mL three-necked flask, A-1-11-1-1c (860 mg, 4.97 mmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (179 mg, 7.45 mmol) was added thereto under ice bath, and stirred under ice bath for 0.5 h. Then p-toluenesulfonyl chloride (644 mg, 7.45 mmol) was added and reacted at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried and filtered, and the crude product was dried to give a yellow solid. The product was purified by normal phase to give A-1-11-1-1d (1.00 g, 3.05 mmol, yield: 61.52%) as a yellow solid.

[0597] MS-ESI:[M+H] + =328.0

[0598] Step 4

[0599] In a dry 50 mL three-necked flask, compound A-1-11-1-1d (290 mg, 885.78 μmol) was dissolved in tetrahydrofuran (3 mL), and phenyltrimethylammonium tribromide (399 mg, 1.06 mmol) was added thereto. The mixture was reacted at room temperature for 2 h, filtered and dried to obtain A-1-11-1-1e (359 mg, crude product), which was used directly in the next step.

[0600] MS-ESI:[M+H] + =405.9

[0601] Step 5

[0602] In a dry 50 mL three-necked flask, compounds A-1-11-1-1e (634 mg, crude) and A1-1-1c (381 mg, 1.30 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (180 mg, 1.30 mmol) was added thereto. The mixture was reacted at 45 °C for 2 h, filtered, and the solvent was dried by normal phase purification to obtain a gray solid A-1-11-1-1f (530 mg, 857.51 μmol, yield: 65.87%).

[0603] MS-ESI:[M+H] + =616.4

[0604] Step 6

[0605] In a dry 50 mL three-necked flask, compound A-1-11-1-1f (250 mg, 404.48 μmol) was dissolved in methanol (10 mL) and tetrahydrofuran (5 mL), and cesium carbonate (263 mg, 808.97 μmol) was added. The reaction was carried out at 55 ° C for 2 h, and the solvent was filtered and dried. The white solid A-1-11-1-1 (70 mg, 150.90 μmol, yield: 37.31%) was obtained by reverse phase purification.

[0606] MS-ESI:[M+H] + =462.4

[0607] 1 H NMR (600MHz, DMSO-d6) δ11.59(br.s,1H),8.51(t,J=2.1Hz,1H),7.80(dd,J=8.5,1.7Hz,1H),7.68(ddd,J=8.9,4.4,2.6Hz,1H), 7.57–7.49(m,3H),7.41(qd,J=8.3,2.6Hz,1H),7.01–6.85(m,3H),6.65(s,1H),6.34–6.22(m,2H),1.61(dd,J=6.7,1.7Hz,3H).

[0608] Preparation Example (III) 18 Compound A-1-10-1-4

[0609] first step

[0610] In a dry 50 mL three-necked flask, compound A-1-10-1-4a (1.20 g, 9.9 mmol) was dissolved in chloroform (15 mL) and ethyl acetate (15 mL). Copper dibromide (4.40 g, 19.9 mmol) was added at room temperature. The temperature was raised to 65 ° C and the reaction was carried out for 5 h. The solvent was dried and the crude product was purified by reverse phase to obtain a gray solid A-1-10-1-4b (500 mg, 2.47 mmol, yield: 24.78%).

[0611] MS-ESI:[M+H] + =202.0

[0612] Step 2

[0613] In a dry 50 mL three-necked flask, compounds A-1-10-1-4b (100 mg, 494.92 μmol) and A1-1-1c (110 mg, 380.7 μmol) were dissolved in acetonitrile (5 mL), potassium carbonate (131 mg, 0.95 mmol) was added, and the mixture was reacted at 45 ° C for 10 h. The mixture was filtered and dried to obtain the crude product, which was then purified by reverse phase to obtain a pink solid A-1-10-1-4 (66 mg, 160.27 μmol, yield: 42.1%, purity 95%).

[0614] 1 H NMR (400MHz, DMSO-d6) δ12.00 (s, 1H), 7.68 (dt, J = 8.9, 2.4Hz, 1H), 7.54 (ddd, J=8.7,6.1,1.3Hz,1H),7.41(tdd,J=8.5,3.6,2.5Hz,1H),7.33(ddt,J=4.8,3. 5,2.0Hz,1H),7.26–7.11(m,1H),7.01–6.91(m,2H),6.88(ddd,J=8.9,3.7,2.4 Hz,1H),6.37–6.23(m,2H),5.76(p,J=6.5Hz,1H),1.58(dd,J=6.6,1.3Hz,3H).

[0615] MS-ESI:[M+H] + =412.0

[0616] Preparation Example (III) 19 Compound A-1-10-1-5

[0617] first step

[0618] In a dry 50 mL three-necked flask, compound A-1-10-1-5a (1.00 g, 9.00 mmol) and N-methoxymethylamine (1.13 g, 11.70 mmol, hydrochloride) were dissolved in N,N-dimethylformamide (15 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.42 g, 11.70 mmol) and N,N-diisopropylethylamine (3.49 g, 27.00 mmol) were added in sequence. The temperature was slowly raised to 60 ° C overnight, and the reaction was quenched by adding water. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, filtered and spin-dried to give the crude product, which was then purified by reverse phase to give A-1-10-1-5b (1.20 g, 4.67 mmol, yield: 51.89%, purity: 60%) as a white solid.

[0619] MS-ESI:[M+H] + =155.1

[0620] Step 2

[0621] In a dry 50 mL three-necked flask, compound A-1-10-1-5b (1.10 g, 4.28 mmol) was dissolved in dichloromethane (20 mL). Di-tert-butyl dicarbonate (1.39 g, 6.42 mmol), triethylamine (650 mg, 6.42 mmol), and 4-dimethylaminopyridine (52 mg, 428.11 μmol) were added sequentially. The reaction was allowed to proceed at room temperature for 2 h. The solvent was then dried and purified by normal phase purification to obtain a white oil, A-1-10-1-5c (410 mg, 1.61 mmol, yield: 37.66%).

[0622] MS-ESI:[M+H] + =255.0

[0623] Step 3

[0624] Compound A-1-10-1-5c (410 mg, 1.61 mmol) was dissolved in tetrahydrofuran (5 mL) in a dry 50 mL three-necked flask. Ethylmagnesium bromide (2 M, 2.42 mL) was added under ice bath. After addition, the temperature was raised to room temperature and the reaction was allowed to react for 2 h. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phases were combined, dried, filtered, and spin-dried. Purification with normal phase gave a colorless oil A-1-10-1-5d (270 mg, 1.21 mmol, yield: 75.00%).

[0625] MS-ESI:[M+H] + =224.4

[0626] Step 4

[0627] In a dry 50 mL three-necked flask, compound A-1-10-1-5d (352 mg, 1.58 mmol) was dissolved in chloroform (5 mL) and ethyl acetate (5 mL), and copper bromide (703 mg, 3.15 mmol) was added thereto. The mixture was heated to 65 ° C and reacted for 2 h. LCMS showed that the main product was obtained. The product was filtered and dried to give A-1-10-1-5e (318 mg, crude product) which was used directly in the next step.

[0628] MS-ESI:[M+H] + =201.9

[0629] Step 5

[0630] In a dry 50 mL three-necked flask, compounds A-1-10-1-5e (318 mg, 1.57 mmol) and A1-1-1c (458 mg, 1.57 mmol) were dissolved in acetonitrile (10 mL). Potassium carbonate (434 mg, 3.15 mmol) was added and reacted at 45°C for 10 h. The mixture was filtered and dried. The crude product was purified by reverse phase chromatography and HPLC to afford A-1-10-1-5c (60 mg, 144.97 μmol, yield: 9.23%, purity: 99.5%).

[0631] MS-ESI:[M+H] + =412.0

[0632] 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),7.86(tt,J=3.4,1.6Hz,1H),7.68(dt,J=8.9,2.3Hz,1H),7.54(ddd,J=8.6,6.1,1.2Hz,1H),7.41(td d,J=8.5,3.7,2.5Hz,1H),7.00–6.78(m,4H),6.56(q,J=2.3Hz,1H),6.29(d,J=1.4Hz,1H),5.77–5.63(m,1H),1.55(dd,J=6.6,1.1Hz,3H).

[0633] Preparation Example (III) 20 Compound A-2-2-1-1

[0634] first step

[0635] To a dry 50 mL three-necked flask, tetrahydrofuran (10 mL) and pentamethylene magnesium bromide (1.23 g, 4.4 mmol) were added. A solution of cuprous cyanide bis(lithium chloride) complex (589 mg, 4.4 mL, 4.4 mmol) was added dropwise to the flask at -78°C. After a 0.5 h reaction, A-2-2-1-1a (1.00 g, 4.37 mmol) was added at -78°C. After a 1 h reaction at room temperature, isobutyryl chloride (698 mg, 6.55 mmol) was added. After a 0.5 h reaction, the sample was sent for monitoring. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted three times with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain A-2-2-1-1b (560 mg, 2.91 mmol, yield: 66.64%).

[0636] MS-ESI:[M+H] + =174.3

[0637] Step 2

[0638] In a dry 50 mL three-necked flask, A-2-2-1-1b (560 mg, 2.91 mmol) was added to the reaction flask and dissolved in methanol (10 mL). Concentrated sulfuric acid (2.1 mL) was added and the temperature was raised to 70°C for 2 h before sampling and monitoring. After the reaction was complete, 1N sodium hydroxide solution was added to adjust the pH to neutral, the reaction was poured into water, and the reaction mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the crude product A-2-2-1-1c (471 mg, crude product).

[0639] MS-ESI:[M+H] + =207.3

[0640] Step 3

[0641] In a dry 50 mL three-necked flask, A-2-2-1-1c (400 mg, crude) was added to the reaction flask and dissolved in tetrahydrofuran (5 mL). Lithium hydroxide (93 mg, 0.29 mmol), methanol (4 mL), and water (2 mL) were then added. After reacting for 2 h, the sample was sent for monitoring. After the reaction, HCl was added to adjust the pH, the mixture was poured into water, extracted with dichloromethane three times, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product A-2-2-1-1d (364 mg, crude).

[0642] MS-ESI:[M+H] + =193.3

[0643] Step 4

[0644] In a dry 50 mL three-necked flask, compound A-2-2-1-1d (364 mg, crude) was added to the reaction flask and dissolved in dichloromethane (5 mL). Di-tert-butyl dicarbonate (455 mg, 2.08 mmol) and 4-dimethylaminopyridine (231 mg, 1.89 mmol) were then added. After reacting for 2 h, the sample was sent for monitoring. After the reaction was complete, the product was poured into water, extracted with dichloromethane three times, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product A-2-2-1-1e (520 mg, crude).

[0645] MS-ESI:[M+H] + =249.1

[0646] Step 5

[0647] In a dry 50 mL three-necked flask, add A-2-2-1-1e (520 mg, crude) and dissolve in dichloromethane (5 mL). Add hydrobromic acid (35 mg, 0.20 mmol) and bromine (397 mg, 2.51 mmol) at 0°C. React at room temperature for 2 h before sampling and monitoring. After completion of the reaction, concentrate and dry the mixture to obtain the crude product A-2-2-1-1f (635 mg, crude).

[0648] MS-ESI:[M+H] + =327.3

[0649] Step 6

[0650] In a dry 50 mL three-necked flask, compound A-2-2-1-1f (600 mg, crude) was added to the reaction flask. N,N-dimethylformamide (10 mL) was added to dissolve the mixture. A1-1-1c (596 mg, 2.02 mmol) and cesium carbonate (1.49 g, 4.58 mmol) were then added. The mixture was allowed to react for 16 h before sampling. After completion of the reaction, the mixture was poured into water, extracted three times with EA, washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product. The crude product was purified on a silica gel column (DCM:MeOH = 10:1) to obtain A-2-2-1-1g (110 mg, 0.20 mmol, yield: 11.14%).

[0651] MS-ESI:[M+H] + =495.1

[0652] Step 7

[0653] Compound A-2-2-1-1g (80 mg, 0.15 mmol) was added to a dry 50 mL three-necked flask and dissolved in dichloromethane (2.5 mL). TFA (2.5 mL) was then added and allowed to react at room temperature for 2 h before sampling and monitoring. After completion of the reaction, the mixture was concentrated and dried to give a crude product, which was then purified by MPLC to give compound A-2-2-1-1 (52 mg, 0.10 mmol, yield: 66.6%).

[0654] MS-ESI:[M+H] + =481.2

[0655] 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),8.71(t,J=1.8Hz,1H),8.36(d,J=7.9Hz,1H),8.12(dt,J=7.8,1.4Hz,1 H),7.74–7.56(m,2H),7.58–7.34(m,2H),6.89(d,J=8.8Hz,1H),6.82–6.66(m,2H),6.30(s,1H),1.76(s,6H).

[0656] Preparation Example (III) 21 Compound A-1-2-1-83

[0657] first step

[0658] To a 200 mL single-necked flask, A-1-2-1-83a (1.50 g, 9.99 mmol), N,N-dimethylformamide (20 mL), imidazole (2.04 g, 30 mmol), and tert-butyldimethylsilyl chloride (3.01 g, 19.98 mmol) were added sequentially. After the addition was complete, the mixture was stirred at room temperature for 6 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-83b (2.00 g, 7.56 mmol, yield: 76%).

[0659] MS-ESI:[M+H] + =265.2

[0660] Step 2

[0661] To a 100 mL single-necked flask, compound A-1-2-1-83b (500 mg, 1.89 mmol), tetrahydrofuran (10 mL), pyrrolidone tribromide (1.23 g, 3.78 mmol), and 2-pyrrolidone (322 mg, 3.78 mmol) were added sequentially. The mixture was reacted at 60°C for 6 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-83c (400 mg, 1.17 mmol, yield: 62%).

[0662] MS-ESI:[M+H] + =343.1

[0663] Step 3

[0664] In a 100 mL single-necked flask, compound A-1-2-1-83c (380 mg, 1.11 mmol), intermediate A1-1-1c (355 mg, 1.22 mmol), tetrabutylammonium iodide (820 mg, 2.22 mmol), potassium carbonate (307 mg, 2.22 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After the addition was complete, the reaction mixture was allowed to react at room temperature overnight. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-83d (110 mg, 0.25 mmol, yield: 23%).

[0665] MS-ESI:[M+H] + =439.1

[0666] 1 H NMR (400MHz, DMSO-d6) δ10.76(d,J=1.7Hz,1H),7.97(dd,J=8.8,1.3Hz,2H),7.68(dt,J=8.9,2.6Hz,1H),7.54(dd,J=8.6,6.1Hz,1H),7.41(tdd, J=8.5,4.4,2.5Hz,1H),6.98–6.89(m,4H),6.84(ddd,J=9.1,7.0,2.5Hz,1H),6.29(d,J=1.1Hz,1H),6.12(p,J=6.7Hz,1H),1.54(d,J=6.7Hz,3H).

[0667] Step 4

[0668] In a 50 mL single-necked flask, intermediate A-1-2-1-83d (40 mg, 0.09 mmol) and N,N-diisopropylethylamine (24 mg, 0.18 mmol) were dissolved in dichloromethane (2 mL). Acetyl chloride (11 mg, 0.14 mmol) was slowly added dropwise to the solution at room temperature. The reaction was allowed to react at room temperature for 2 h. LCMS was used to monitor the reaction until completion. The reaction solution was diluted with dichloromethane (50 mL) and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by prep-TLC to obtain compound A-1-2-1-83 (20 mg, 0.04 mmol, yield: 44%).

[0669] MS-ESI:[M+H] + =481.1

[0670] 1 H NMR(400MHz,Chloroform-d)δ8.10(d,J=8.8Hz,2H),7.35–7.26(m,2H),7.26–7.21(m,2H),7.12(tt,J=8.2,2.8Hz,1H), 6.94(dd,J=8.8,3.9Hz,1H),6.85–6.68(m,2H),6.17(s,1H),5.55(q,J=6.8Hz,1H),2.34(s,3H),1.76(d,J=6.8Hz,3H).

[0671] Preparation Example (III) 22 Compound A-1-2-1-89

[0672] first step

[0673] To a 100 mL single-necked flask, A-1-2-1-89a (360 mg, 2 mmol), tetrahydrofuran (10 mL), pyrrolidone tribromide (1.30 g, 4 mmol), and 2-pyrrolidone (340 mg, 4 mmol) were added sequentially. The mixture was reacted at 60°C for 6 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-89b (400 mg, 1.55 mmol, yield: 77%).

[0674] MS-ESI:[MH] - =256.0

[0675] Step 2

[0676] In a 100 mL single-necked flask, compound A-1-2-1-89b (380 mg, 1.47 mmol), A1-1-1c (470 mg, 1.62 mmol), tetrabutylammonium iodide (1.09 g, 2.94 mmol), potassium carbonate (406 mg, 2.94 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. The mixture was allowed to react at room temperature overnight. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-89 (140 mg, 0.30 mmol, yield: 20%).

[0677] MS-ESI:[M+H] + =468.1

[0678] 1 H NMR (400MHz, Chloroform-d) δ8.91(q,J=1.9Hz,1H),8.47(ddd,J=8.2,2.3,1.0Hz,1H),8.38(dd,J=7.8,1.4Hz,1H),7.72(t,J=8.0Hz,1H),7.32–7.23( m,2H),7.13(tt,J=7.8,2.3Hz,1H),6.97(dd,J=8.8,2.6Hz,1H),6.85–6.74 (m,2H),6.19(d,J=1.0Hz,1H),5.55(q,J=6.9Hz,1H),1.81(d,J=6.8Hz,3H).

[0679] Preparation Example (III) 23 Compound A-1-10-1-39

[0680] first step

[0681] To a 50 mL single-necked flask, A-1-10-1-39a (150 mg, 1.05 mmol), tetrahydrofuran (5 mL), pyrrolidone tribromide (684 mg, 2.10 mmol), and 2-pyrrolidone (179 mg, 2.10 mmol) were added sequentially. The mixture was reacted at 60°C for 6 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-39b (400 mg, 1.55 mmol, 77% yield).

[0682] 1 H NMR(400MHz,Chloroform-d)δ4.55(q,J=6.7Hz,1H),4.02(dtd,J=11.5,4.5,2.3Hz,2H),3.46( td,J=11.0,2.4Hz,2H),3.09(tt,J=11.4,3.9Hz,1H),1.96–1.62(m,4H),1.75(d,J=6.8Hz,3H).

[0683] Step 2

[0684] To a 50 mL single-necked flask, A-1-10-1-39b (190.0 mg, 0.86 mmol), intermediate A1-1-1c (225.0 mg, 0.77 mmol), tetrabutylammonium iodide (635.0 mg, 1.72 mmol), potassium carbonate (238.0 mg, 1.72 mmol), and N,N-dimethylformamide (5 mL) were added sequentially. After the addition was complete, the reaction mixture was allowed to react at room temperature overnight. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by prep-TLC to obtain compound A-1-10-1-39 (110.0 mg, 0.26 mmol, 30% yield).

[0685] MS-ESI:[M+H] + =431.1

[0686] 1 H NMR(400MHz,Chloroform-d)δ7.33(dd,J=8.5,2.7Hz,2H),7.17(td,J=8.3,2.6Hz,1H),7.01(d,J=8.7Hz,1H),6.86–6.73(m,2H),6.24(s,1H) ,4.86(q,J=6.8Hz,1H),4.07–3.94(m,2H),3.45(ddt,J=25.8,13.8,7.5Hz,2H),3.09–2.98(m,1H),1.89–1.68(m,4H),1.59(d,J=6.8Hz,3H).

[0687] Preparation Example (III) 24 Compound A-1-1-1-15

[0688] first step

[0689] To a 50 mL single-necked flask, add A-1-1-1-15a (450.0 mg, 3.16 mmol), tetrahydrofuran (5 mL), pyrrolidone tribromide (1.03 g, 3.16 mmol), and 2-pyrrolidone (269.0 mg, 3.16 mmol) in sequence. After the addition is complete, react at room temperature for 4 h. After TLC monitoring indicates the reaction is complete, dilute the reaction solution with water and extract with ethyl acetate (50 mL x 3). The organic layers are combined and washed with saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product A-1-1-1-15b (500.0 mg), which is used directly in the next reaction.

[0690] Step 2

[0691] In a 100 mL single-necked flask, intermediate A-1-1-1-15a (500.0 mg, 2.26 mmol, crude), intermediate A-1-1-1c (657.0 mg, 2.26 mmol), tetrabutylammonium iodide (1.25 g, 3.39 mmol), potassium carbonate (625.0 mg, 4.52 mmol), and N,N-dimethylformamide (10 mL) were added sequentially and reacted at room temperature for 3 h. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-1-1-15 (110.0 mg, 0.26 mmol, yield: 11%).

[0692] MS-ESI:[MH] - =429.2.

[0693] 1 H NMR(400MHz,Chloroform-d)δ7.32(dt,J=8.7,2.7Hz,2H),7.17(td,J=8.2,2.4Hz,1H),7.00(d,J=8.7Hz,1H),6.86–6.69(m,2H),6.22(s,1H),4. 74(q,J=6.8Hz,1H),2.65(dt,J=18.5,7.4Hz,1H),2.45(dt,J=17.9,7.3 Hz,1H),1.57(t,J=6.1Hz,5H),1.31–1.19(m,6H),0.88(t,J=6.6Hz,3H).

[0694] Preparation Example (III) 25 Compound A-1-2-1-73

[0695] first step

[0696] In a 100 mL single-necked flask, compound A-1-2-1-73a (213.0 mg, 1 mmol), tetrahydrofuran (5 mL), pyrrolidone tribromide (652.0 mg, 2 mmol), and 2-pyrrolidone (170.0 mg, 2 mmol) were added sequentially. After the addition was complete, the mixture was reacted at 60°C for 2 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-73b (250.0 mg, 0.86 mmol, 86% yield).

[0697] MS-ESI:[M+H] + =292.9.

[0698] Step 2

[0699] In a 100 mL single-necked flask, compound A-1-2-1-73b (250.0 mg, 0.86 mmol), intermediate A1-1-1c (165.0 mg, 0.57 mmol), tetrabutylammonium iodide (211.0 mg, 0.57 mmol), potassium carbonate (158.0 mg, 1.14 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After the addition was complete, the mixture was reacted at room temperature for 3 h. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-73 (226.0 mg, 0.45 mmol, 52% yield).

[0700] MS-ESI:[M+H] + =501.0

[0701] 1H NMR (400MHz, DMSO-d6) δ8.23(d,J=1.9Hz,1H),8.08(dd,J=8.0,1.5Hz,1H),7.93(dd,J=7.8,2.0Hz,1H),7.70(dt,J=8.9,2.4Hz,1 H),7.60–7.53(m,2H),7.48–7.37(m,1H),7.09(dd,J=5.0,2.4Hz,1H),6.95(d,J=8.9Hz,1H),6.89(td,J=8.5,2.4Hz,1H),6.32(s, 1H),6.30–6.21(m,1H),1.56(d,J=6.7Hz,3H).

[0702] Preparation Example (III) 26 Compound A-1-2-1-90

[0703] first step

[0704] In a 100 mL single-necked flask, compound A-1-2-1-90a (100.0 mg, 0.63 mmol), tetrahydrofuran (5 mL), pyrrolidone tribromide (411.0 mg, 1.26 mmol), and 2-pyrrolidone (107.0 mg, 1.26 mmol) were added sequentially. After the addition was completed, the mixture was reacted at 60°C for 2 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-9b (118.0 mg, 0.50 mmol, yield: 79%).

[0705] MS-ESI:[M+H] + =237.9

[0706] Step 2

[0707] In a 100 mL single-necked flask, compound A-1-2-1-90b (118.0 mg, 0.50 mmol), intermediate A1-1-1c (145.0 mg, 0.50 mmol), tetrabutylammonium iodide (185.0 mg, 0.50 mmol), potassium carbonate (138.0 mg, 1 mmol), and N,N-dimethylformamide (2.5 mL) were added sequentially and allowed to react at room temperature for 3 h. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-90 (30.5.0 mg, 0.07 mmol, yield: 14%).

[0708] MS-ESI:[M+H] + =448.1

[0709] 1 H NMR(400MHz, DMSO-d6)δ8.58(q,J=1.6Hz,1H),8.31(dt,J=8.0,1.5Hz,1H),8.18(dt,J=7.7, 1.4Hz,1H),7.80(t,J=7.8Hz,1H),7.69(dt,J=8.9,2.3Hz,1H),7.56(ddd,J=8.5,6.1,2.4Hz ,1H),7.42(tdd,J=8.5,4.1,2.6Hz,1H),7.11(dd,J=3.9,2.3Hz,1H),6.94(d,J=8.7Hz,1H), 6.92–6.87(m,1H),6.32(d,J=0.9Hz,1H),6.29(td,J=6.8,4.0Hz,1H),1.57(d,J=6.8Hz,3H).

[0710] Preparation Example (III) 27 Compound A-1-10-1-3

[0711] first step

[0712] To a 50 mL single-necked flask, A-1-10-1-3a (200.0 mg, 1.47 mmol), tetrahydrofuran (5 mL), pyrrolidone tribromide (951.0 mg, 2.92 mmol), and 2-pyrrolidone (248.0 mg, 2.92 mmol) were added sequentially. After the addition was complete, the mixture was reacted at 60°C for 6 h. After TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-3b (182.0 mg, 0.85 mmol, yield: 58%).

[0713] MS-ESI:[M+H] + =215.0

[0714] Step 2

[0715] In a 50 mL single-necked flask, compound A-1-10-1-3b (182.0 mg, 0.85 mmol), intermediate A1-1-1c (163.0 mg, 0.56 mmol), tetrabutylammonium iodide (310.0 mg, 0.84 mmol), potassium carbonate (232.0 mg, 1.68 mmol), and N,N-dimethylformamide (5 mL) were added sequentially. After the addition was complete, the mixture was allowed to react at room temperature overnight. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-3 (39.0 mg, 0.09 mmol, yield: 16%).

[0716] MS-ESI:[M+H] + =425.1.

[0717] 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),9.00(d,J=2.4Hz,1H),8.89(s,1H),7.69(dt,J=8.9,2.5Hz,1H),7.55(ddd,J=8.7,6.2,2.7Hz, 1H),7.46–7.38(m,1H),7.00(dd,J=6.8,2.2Hz,1H),6.88(ddd,J=12.3,11.0,5.5Hz,2H),6.34–6.27(m,2H),1.65(d,J=6.8Hz,3H).

[0718] Preparation Example (III) 28 Compound A-1-10-1-6

[0719] first step

[0720] To a 100 mL single-necked flask, A-1-10-1-6a (2.00 g, 17.84 mmol), dichloromethane (50 mL), dimethylhydroxylamine hydrochloride (3.50 g, 35.88 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.10 g, 26.60 mmol), and 1-hydroxybenzotriazole (3.60 g, 26.64 mmol) were added sequentially. The mixture was allowed to react at 25°C for 16 h. After TLC and LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-6b (1.80 g, 11.60 mmol, yield: 65%).

[0721] MS-ESI:[M+H] + =156.1

[0722] Step 2

[0723] In a 100 mL single-necked flask, compound A-1-10-1-6c (1.80 g, 11.60 mmol) and tetrahydrofuran (20 mL) were added. The atmosphere was purged with nitrogen and the temperature was lowered to -15°C. A solution of ethylmagnesium bromide in tetrahydrofuran (2 M, 11.6 mL, 23.2 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and allowed to react for 4 h. After LCMS and TLC monitoring indicated completion of the reaction, saturated aqueous ammonium chloride (100 mL) was added for quenching. The mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to afford compound A-1-10-1-6c (1.10 g, 8.86 mmol, yield: 76%).

[0724] MS-ESI:[M+H] + =125.1

[0725] Step 3

[0726] In a 100 mL single-necked flask, compound A-1-10-1-6c (400.0 mg, 3.22 mmol), tetrahydrofuran (10 mL), pyrrolidone tribromide (2.10 g, 6.44 mmol), and 2-pyrrolidone (548.0 mg, 6.44 mmol) were added. After addition, the mixture was allowed to react at room temperature for 6 h. After completion of the reaction as monitored by LCMS and TLC, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to afford compound A-1-10-1-6d (210.0 mg, 1.03 mmol, yield: 32%).

[0727] MS-ESI:[M+H] + =203.0

[0728] Step 4

[0729] In a 50 mL single-necked flask, compound A-1-10-1-6d (210.0 mg, 1.03 mmol), intermediate A1-1-1c (198.0 mg, 0.68 mmol), tetrabutylammonium iodide (380.0 mg, 1.03 mmol), potassium carbonate (285.0 mg, 2.06 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After the addition was complete, the mixture was allowed to react at room temperature overnight. After LCMS and TLC monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-6 (43.0 mg, 0.10 mmol, yield: 15%).

[0730] MS-ESI:[M+H] + =413.1

[0731] 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),9.00(d,J=2.4Hz,1H),8.89(s,1H),7.69(dt,J=8.9,2.5Hz,1H),7.55(ddd,J=8.7,6.2,2.7Hz, 1H),7.46–7.38(m,1H),7.00(dd,J=6.8,2.2Hz,1H),6.88(ddd,J=12.3,11.0,5.5Hz,2H),6.34–6.27(m,2H),1.65(d,J=6.8Hz,3H).

[0732] Preparation Example (III) 29 Compound A-1-2-1-78

[0733] first step

[0734] A-1-2-1-78a (1.00 g, 6.70 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask. After thorough stirring, di-tert-butyl dicarbonate (1.61 g, 7.38 mmol) and 4-dimethylaminopyridine (0.08 g, 0.67 mmol) were added sequentially to the reaction system and allowed to react overnight at room temperature. The reaction was monitored by LCMS and TLC. After completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-78b (0.56 g, 2.25 mmol, yield: 34%).

[0735] MS-ESI:[M+H] + =250.1

[0736] Step 2

[0737] A-1-2-1-78b (0.40 g, 1.60 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask. After complete dissolution, pyrrolidone (0.16 g, 1.92 mmol) and pyrrolidone tribromide (0.78 g, 2.40 mmol) were added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS and TLC, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-78c (0.32 g, 0.97 mmol, yield: 61%).

[0738] MS-ESI:[M+H] + =328.1

[0739] Step 3

[0740] Compounds A-1-2-1-78c (0.20 g, 0.61 mmol) and A1-1-1c (0.16 g, 0.55 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.17 g, 1.22 mmol) and tetrabutylammonium iodide (0.23 g, 0.61 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-2-1-78d (0.16 g, 0.30 mmol, yield: 49%).

[0741] MS-ESI:[M+H] + =538.1

[0742] Step 4

[0743] Compound A-1-2-1-78d (0.10 g, 0.19 mmol) and dichloromethane (3 mL) were added to a 50 mL three-necked flask. After thorough stirring, trifluoroacetic acid (3 mL) was added dropwise to the solution. The reaction was allowed to react at room temperature for 10 minutes. After completion, as monitored by TLC and LCMS, the reaction was quenched with saturated bicarbonate (20 mL), diluted with water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-78 (0.05 g, 0.11 mmol, 58% yield).

[0744] MS-ESI:[M+H] + =438.2

[0745] 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J=8.6Hz, 2H), 7.73–7.64 (m, 1H), 7.55 (dd, J= 8.5,6.2Hz,1H),7.43(m,J=4.3Hz,1H),6.92(d,J=8.9Hz,1H),6.89(dd,J=5.3,2.4Hz,1H),6. 86–6.80(m,1H),6.61(d,J=8.7Hz,2H),6.30(s,3H),6.06–5.93(m,1H),1.54(d,J=6.6Hz,3H).

[0746] Preparation Example (III) 30 Compound A-1-2-1-72

[0747] Compounds A-1-2-1-72a (0.50 g, 2.02 mmol) and A1-1-1c (0.53 g, 1.82 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.56 g, 4.04 mmol) and tetrabutylammonium iodide (0.75 g, 2.02 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to yield compound A-1-2-1-72 (0.16 g, 0.35 mmol, yield: 20%).

[0748] MS-ESI:[M+H] + =457.1

[0749] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),8.03(d,J=7.7Hz,1H),7.79(d,J=7.9Hz,1H),7.69(dd,J=8.9,2.1Hz,1H),7.63(t,J=7.9Hz,1H),7.55(t,J=7.3Hz, 1H),7.46–7.37(m,1H),7.08(dd,J=4.5,2.3Hz,1H),6.93(t,J=7.9Hz,1H),6 .88(t,1H),6.31(s,1H),6.27(dd,J=9.2,4.2Hz,1H),1.55(d,J=6.7Hz,3H).

[0750] Preparation Example (III) 31 Compound A-1-2-1-84

[0751] Compound A-1-2-1-84a (0.10 g, 0.23 mmol) and tetrahydrofuran (3 mL) were added to a 50 mL three-necked flask. After sufficient dissolution, acetic anhydride (0.03 g, 0.28 mmol) was added dropwise to the reaction solution. The reaction was allowed to react overnight at room temperature. After completion of the reaction monitored by TLC and LCMS, ethyl acetate (30 mL) was added to the reaction solution, and the mixture was washed with aqueous hydrochloric acid solution (1.0 M). The aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined and washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-84 (0.06 g, 0.13 mmol, yield: 57%).

[0752] MS-ESI:[M+H] + =480.2

[0753] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.06(d,J=8.4Hz,2H),7.77(d,J=8.7Hz,2H),7.69(d,J=8.9Hz,1H),7.59–7.51(m,1H),7.47–7.35(m,1H) ,6.98(dd,J=5.9,2.1Hz,1H),6.93(d,J=8.9Hz,1H),6.89–6.81(m,1H),6.31(s,1H),6.16(t,J=6.7Hz,1H),2.10(s,3H),1.57(d,J=6.5Hz,3H).

[0754] Preparation Example (III) 32 Compound A-1-2-1-79

[0755] Compound A-1-2-1-79a (0.50 g, 1.14 mmol) and acetone (10 mL) were added to a 50 mL three-necked flask. After complete dissolution, iodomethane (1.62 g, 11.40 mmol) and sodium carbonate (0.36 g, 3.42 mmol) were added to the reaction mixture. The mixture was allowed to react at room temperature for 24 h. After completion, the reaction was monitored by TLC and LCMS. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound P06 (0.13 g, 0.29 mmol, yield: 25%).

[0756] MS-ESI:[M+H] + =452.3

[0757] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.5Hz,2H),7.69(dt,J=8.8,2.6Hz,1H),7.54(dd,J=8.5,6.2Hz,1H),7.46–7.37(m,1H),6.92(d,J=8.9Hz,1H ), 6.88(dd,J=5.2,2.4Hz,1H),6.86–6.80(m,1H),6.60(d,J=8.9Hz,2H),6.29(s,1H),6.02(t,J=6.9Hz,1H),2.76(s,3H),1.54(d,J=6.5Hz,3H).

[0758] Preparation Example (III) 33 Compound A-1-2-1-80

[0759] Compound A-1-2-1-80a (0.50 g, 1.14 mmol) and acetone (10 mL) were added to a 50 mL three-necked flask. After complete dissolution, iodomethane (1.62 g, 11.40 mmol) and sodium carbonate (0.36 g, 3.42 mmol) were added to the reaction mixture. The mixture was allowed to react at room temperature for 24 h. After completion, the reaction was monitored by TLC and LCMS. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-80 (0.08 g, 0.17 mmol, yield: 15%).

[0760] MS-ESI:[M+H] + =466.2

[0761] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=8.2Hz,2H),7.69(d,J=8.9Hz,1H),7.54(dd,J=8. 5,6.2Hz,1H),7.46–7.35(m,1H),6.92(d,J=8.9Hz,1H),6.89(dd,J=5.4,2.4Hz,1H), 6.86–6.81(m,1H),6.77(d,J=9.0Hz,2H),6.29(s,1H),6.05(p,J=6.6Hz,1H),3.05(s,6H),1.54(d,J=6.5Hz,3H).

[0762] Preparation Example (III) 34 Compound A-1-1-1-13

[0763] Compound 3-bromo-2-butanone (0.20 g, 1.32 mmol) and A1-1-1c (0.35 g, 1.19 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.36 g, 2.64 mmol) and tetrabutylammonium iodide (0.48 g, 1.32 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-1-1-13 (0.26 g, 0.72 mmol, yield: 62%).

[0764] MS-ESI:[M+H] + =361.1

[0765] 1 H NMR (400MHz, DMSO-d6) δ7.75–7.69(m,1H),7.61–7.54(m,1H),7.48–7.41(m,1H),7.04(dd,J=6.5,2.4Hz,1H),6.95 (d,J=8.9Hz,1H),6.91–6.86(m,1H),6.33(s,1H),5.25–5.14(m,1H),2.23(d,J=1.2Hz,3H),1.49(d,J=6.8Hz,3H).

[0766] Preparation Example (III) 35 Compound A-1-2-1-75

[0767] first step

[0768] A-1-2-1-75a (0.50 g, 3.37 mmol) and tetrahydrofuran (15 mL) were added to a 50 mL three-necked flask. After complete dissolution, pyrrolidone (0.34 g, 4 mmol) and pyrrolidone tribromide (1.65 g, 5.06 mmol) were added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-75b (0.71 g, 3.13 mmol, yield: 93%).

[0769] Step 2

[0770] Compounds A-1-2-1-75b (0.15 g, 0.66 mmol) and A1-1-1c (0.17 g, 0.59 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.18 g, 1.32 mmol) and tetrabutylammonium iodide (0.24 g, 0.66 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to yield compound A-1-2-1-75 (0.12 g, 0.27 mmol, yield: 47%).

[0771] MS-ESI:[MH] - =435.1

[0772] 1H NMR (400MHz, DMSO-d6) δ7.93(d,J=7.3Hz,2H),7.73(dt,J=8.9,2.6Hz,1H),7.61–7.55(m,2H),7.53(d,J=7.9Hz,1H),7.50–7.42(m,1H),7.04( dd,J=6.9,2.4Hz,1H),6.98(d,J=8.9Hz,1H),6.94–6.87(m,1H),6.35(d,J=1.2Hz,1H),6.31–6.23(m,1H),2.44(s,3H),1.60(d,J=6.4Hz,3H).

[0773] Preparation Example (III) 36 Compound A-1-2-1-76

[0774] first step

[0775] A-1-2-1-76a (0.20 g, 1.22 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask. After complete dissolution, pyrrolidone (0.12 g, 1.46 mmol) and pyrrolidone tribromide (0.59 g, 1.83 mmol) were added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-76b (0.22 g, 0.90 mmol, yield: 74%).

[0776] Step 2

[0777] Compounds A-1-2-1-76b (0.20 g, 0.82 mmol) and A1-1-1c (0.22 g, 0.74 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.23 g, 1.64 mmol) and tetrabutylammonium iodide (0.30 g, 0.82 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-2-1-76 (0.16 g, 0.35 mmol, yield: 46%).

[0778] MS-ESI:[M+H] + =453.2

[0779] 1H NMR (400MHz, DMSO-d6) δ7.74–7.65(m,2H),7.59–7.47(m,3H),7.47–7.36(m,1H),7.30(dd,J=8.3,2.0Hz,1H),7.02(dd,J=6.8,2 .2Hz,1H),6.94(d,J=8.9Hz,1H),6.88(td,J=8.6,2.3Hz,1H),6.31(s,1H),6.27(dd,J=13.2,6.6Hz,1H),3.83(d,J=5.5Hz,3H), 1.56(d,J=6.7Hz,3H).

[0780] Preparation Example (III) 37 Compound A-1-2-1-70

[0781] first step

[0782] A-1-2-1-70a (0.30 g, 2.20 mmol) and dichloromethane (15 mL) were added to a 50 mL three-necked flask. After complete dissolution, Dess-Martin periodinane (1.40 g, 3.30 mmol) was slowly added to the reaction system and allowed to react at room temperature for 1 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with ethyl acetate (30 mL). The reaction solution was then filtered and the filtrate was washed once with water. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-70b (0.23 g, 1.71 mmol, yield: 78%).

[0783] Step 2

[0784] A-1-2-1-70b (0.23 g, 1.71 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask and dissolved thoroughly. Pyrrolidone (0.17 g, 2.05 mmol) and pyrrolidone tribromide (0.83 g, 2.56 mmol) were then added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-70c (0.20 g, 0.94 mmol, yield: 55%).

[0785] Step 3

[0786] Compounds A-1-2-1-70c (0.10 g, 0.47 mmol) and A1-1-1c (0.12 g, 0.42 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.13 g, 0.94 mmol) and tetrabutylammonium iodide (0.17 g, 0.47 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-2-1-70 (0.11 g, 0.26 mmol, 56% yield).

[0787] MS-ESI:[MH] - =421.1

[0788] 1 H NMR(400MHz, DMSO-d6)δ8.09(d,J=7.8Hz,2H),7.71(dd,J=16.6,8.4Hz,2H),7.64–7.52(m,3H),7.43(dt,J=6.7,4.2Hz,1H),7.03( dd,J=6.0,1.8Hz,1H),6.95(d,J=8.9Hz,1H),6.91–6.84(m,1H),6.31(s,1H),6.25(dd,J=13.0,6.5Hz,1H),1.58(d,J=6.6Hz,3H).

[0789] Preparation Example (III) 38 Compound A-1-11-1-10

[0790] first step

[0791] A-1-11-1-10a (0.50 g, 2.81 mmol) and tetrahydrofuran (15 mL) were added to a 50 mL three-necked flask. After complete dissolution, pyrrolidone (0.29 g, 3.37 mmol) and pyrrolidone tribromide (1.37 g, 4.22 mmol) were added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound A-1-11-1-10b (0.42 g, 1.63 mmol, yield: 58%).

[0792] Step 2

[0793] Compounds A-1-11-1-10b (0.20 g, 0.78 mmol) and A1-1-1c (0.20 g, 0.70 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.22 g, 1.56 mmol) and tetrabutylammonium iodide (0.29 g, 0.78 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-11-1-10 (0.18 g, 0.39 mmol, yield: 50%).

[0794] MS-ESI:[MH] - =465.1

[0795] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.2Hz,1H),7.69(d,J=8.8Hz,1H),7.57(s,1H),7.54(d,J=6.6Hz,1H),7.43(dd,J=10.5,6.5Hz,1H) ,7.12(d,J=8.2Hz,1H),7.00–6.94(m,1H),6.93(s,1H),6.86(t,J=8.1Hz,1H),6.31(s,1H),6.21–6.13(m,3H),1.55(d,J=6.6Hz,3H).

[0796] Preparation Example (III) 39 Compound A-1-2-1-71

[0797] first step

[0798] A-1-2-1-71a (1.00 g, 6.57 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask. After complete dissolution, pyrrolidone (0.67 g, 7.88 mmol) and pyrrolidone tribromide (3.21 g, 9.86 mmol) were added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-71b (0.90 g, 3.90 mmol, yield: 59%).

[0799] Step 2

[0800] Compounds A-1-2-1-71b (0.20 g, 0.87 mmol) and A1-1-1c (0.23 g, 0.78 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.24 g, 1.74 mmol) and tetrabutylammonium iodide (0.32 g, 0.87 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to yield compound A-1-2-1-71 (0.12 g, 0.27 mmol, yield: 31%).

[0801] MS-ESI:[M+H] + =441.1

[0802] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=7.7Hz,1H),7.89(d,J=9.8Hz,1H),7.73–7.51(m,4H),7.47–7.38(m,1H),7.06(dd,J=4. 8,2.3Hz,1H),6.94(t,J=8.9Hz,1H),6.92–6.85(t,1H),6.31(s,1H),6.27(dt,J=11.9,6.0Hz,1H),1.56(d,J=6.6Hz,3H).

[0803] Preparation Example (III) 40 Compound A-1-2-1-88

[0804] first step

[0805] A-1-2-1-88a (1.00 g, 4.95 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask. After complete dissolution, pyrrolidone (0.51 g, 5.94 mmol) and pyrrolidone tribromide (2.42 g, 7.43 mmol) were added sequentially to the reaction system. The temperature was raised to 50°C and the reaction was allowed to react for 6 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound A-1-2-1-88b (0.90 g, 3.20 mmol, yield: 65%).

[0806] Step 2

[0807] Compound A-1-2-1-88b (0.30 g, 1.07 mmol) and A1-1-1c (0.28 g, 0.96 mmol) were added to a 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.30 g, 2.14 mmol) and tetrabutylammonium iodide (0.39 g, 1.07 mmol) were then added sequentially. The mixture was heated to 60°C. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-2-1-88 (0.40 g, 0.81 mmol, yield: 76%).

[0808] MS-ESI:[M+H] + =491.1

[0809] 1 H NMR (400MHz, DMSO-d6) δ7.91(dd,J=15.0,8.7Hz,2H),7.73–7.51(m,4H),7.47–7.38(m,1H),7.06(dd,J=4.8,2. 3Hz, 1H), 6.90 (ddd, J=12.8, 11.3, 5.7Hz, 2H), 6.31 (s, 1H), 6.27 (dt, J=11.9, 6.0Hz, 1H), 1.56 (d, J=6.6Hz, 3H).

[0810] Preparation Example (III) 41 Compound A-1-7-1-1

[0811] A-1-7-1-1a (0.15 g, 0.32 mmol), formic acid (5 mL), and 37% formaldehyde (5 mL) were added to a 50 mL reaction flask and heated to 80°C with stirring. After completion of the reaction, monitored by TLC and LCMS, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-7-1-1 (0.13 g, 0.29 mmol, yield: 91%).

[0812] MS-ESI:[M+H] + =444.1

[0813] 1H NMR(400MHz,DMSO-d6)δ7.72(d,J=8.8Hz,1H),7.57(dd,J=8.6,6.1Hz,1H),7 .49–7.40(m,1H),7.03(dd,J=5.1,2.4Hz,1H),6.96(dd,J=8.8,1.4Hz,1H),6. 91–6.83(m,1H),6.34(s,1H),5.48–5.28(m,1H),2.99–2.71(m,3H),2.24(s, 3H), 1.99 (dd, J=38.5, 26.3Hz, 3H), 1.73–1.51 (m, 3H), 1.49 (d, J=6.8Hz, 3H).

[0814] Preparation Example (III) 42 Compound A-1-7-1-4

[0815] A-1-7-1-4a (0.15 g, 0.32 mmol), 2-chloroethanol (0.14 g, 1.12 mmol), triethylamine (2 mL), and dioxane (10 mL) were added to a 50 mL three-necked flask and stirred at room temperature. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-7-1-4 (0.12 g, 0.25 mmol, yield: 78.5%).

[0816] MS-ESI:[M+H] + =474.1

[0817] 1 H NMR (400MHz, DMSO-d6) δ7.71(d,J=8.8Hz,1H),7.57(t,1H),7.44(t,J=8.4Hz,1H),7. 00(dd,J=5.6,2.4Hz,1H),6.95(dd,J=8.9,1.8Hz,1H),6.88–6.82(m,1H),6.32(s,1H ),5.44–5.29(m,1H),4.35(t,J=5.4Hz,1H),3.46(dd,J=11.7,6.1Hz,2H),2.96–2.61 (m,4H),2.35(t,J=6.3Hz,2H),1.96(dt,J=20.8,11.6Hz,4H),1.46(d,J=10.8Hz,3H).

[0818] Preparation Example (III) 43 Compound A-1-7-1-3

[0819] In a dry 50 mL three-necked flask, A-1-7-1-3a (0.15 g, 0.32 mmol), 2,2-dichloroacetic acid (0.10 g, 0.80 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.14 g, 0.38 mmol), triethylamine (1 mL), and dichloromethane (20 mL) were added to a 100 mL three-necked flask and stirred at room temperature. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-7-1-3 (0.13 g, 0.24 mmol, yield: 74%).

[0820] MS-ESI:[M+H] + =540.1

[0821] 1 H NMR (400MHz, CD3OD) δ7.50–7.42(m,2H),7.29(td,J=8.1,1.9Hz,1H),7.04(d,J= 8.8Hz,1H),6.99–6.95(m,1H),6.88(t,J=5.7Hz,2H),6.23(s,1H),5.20(td,J=6. 8,4.1Hz,1H),4.50–4.33(m,1H),4.09(dd,J=23.4,13.9Hz,1H),3.22(ddd,J=14. 2,12.4,3.0Hz,2H),3.01–2.77(m,1H),2.06(d,J=13.0Hz,1H),1.81–1.46(m,6H)

[0822] Preparation Example (III) 44 Compound A-1-10-1-7

[0823] first step

[0824] In a dry 50 mL three-necked flask, A-1-10-1-7a (2.56 g, 19.96 mmol), 2-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.11 g, 23.95 mmol), triethylamine (5.05 g, 49.90 mmol), and methoxyamine hydrochloride (2.14 g, 21.96 mmol) were added to dichloromethane (80 mL) and stirred at room temperature overnight. TLC showed that the raw materials were reacted completely. The reaction solution was washed with 1.0 M hydrochloric acid (50 mL), 0.5% aqueous sodium carbonate solution (50 mL), and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-7b (3.24 g, 18.92 mmol, yield: 95%).

[0825] Step 2

[0826] In a dry 50mL three-necked flask, compound A-1-10-1-7b (3.24g, 18.92mmol) was added to a 50mL three-necked flask, and then tetrahydrofuran (40mL) was added. The temperature was lowered to -10°C, and 18mL of ethylmagnesium bromide (2.0M) was slowly added dropwise. The temperature was kept for half an hour, and the temperature was slowly raised to room temperature. TLC showed that the raw material disappeared. Ethyl acetate (150mL) and 5% ammonium chloride solution (50mL) were added. The organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-7c (1.40g, 9.99mmol, yield: 53%).

[0827] Step 3

[0828] In a dry 50 mL three-necked flask, A-1-10-1-7c (1.40 g, 9.99 mmol) and tribromopyridine (4.79 g, 14.99 mmol) were added to 20 mL of tetrahydrofuran and heated to 60°C under nitrogen protection. The starting material disappeared after TLC detection. Ethyl acetate (150 mL) and 5% sodium dithionite solution (50 mL) were added, and the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-7d (2.00 g, 9.13 mmol, yield: 91%).

[0829] Step 4

[0830] Compounds A-1-10-1-7d (0.12 g, 0.55 mmol) and A1-1-1c (0.15 g, 0.50 mmol) were added to a dry 50 mL three-necked flask. Acetone (10 mL) was then added and dissolved. Potassium carbonate (0.15 g, 1.10 mmol) and tetrabutylammonium iodide (0.20 g, 0.55 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-10-1-7 (0.15 g, 0.35 mmol, yield: 64%).

[0831] MS-ESI:[M+H] + =429.0

[0832] 1 H NMR(400MHz, DMSO-d6)δ8.80(td,J=2.9,1.2Hz,1H),7.77–7.67(m,2H),7.60(d,J=4.5Hz,1H),7.56(dd,J=8.6,6.1Hz,1H),7.47–7.37(m,1H),7 .00(dd,J=7.5,2.4Hz,1H),6.96(d,J=9.3Hz,1H),6.92–6.85(m,1H),6.33(d,J=1.0Hz,1H),6.00(t,J=6.8Hz,1H),1.60(dd,J=6.7,0.9Hz,3H).

[0833] Preparation Example (III) 45 Compound A-1-10-1-47

[0834] first step

[0835] In a dry 50 mL three-necked flask, A-1-10-1-47a (15.00 g, 65.42 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29.85 g, 78.50 mmol), triethylamine (16.55 g, 163.55 mmol), and methoxymethylamine hydrochloride (7.02 g, 71.96 mmol) were added to 200 mL of dichloromethane and stirred at room temperature overnight. TLC showed that the raw materials were completely reacted. The product was washed with 1.0 M hydrochloric acid (200 mL), 0.5% sodium carbonate water (150 mL), and water, dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain compound A-1-10-1-47b (16.00 g, 58.75 mmol, yield: 90%).

[0836] Step 2

[0837] Compound A-1-10-1-47b (16.00 g, 58.75 mmol) was added to a dry 50 mL three-necked flask, followed by tetrahydrofuran (100 mL). The temperature was lowered to -10°C, and 50 mL of ethylmagnesium bromide (2.0 M) was slowly added dropwise. After incubation for half an hour, the temperature was slowly raised to room temperature. TLC indicated the disappearance of the starting material. 50 mL of ethyl acetate and 5% ammonium chloride solution (50 mL) were added, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford A-1-10-1-47c (10.00 g, 41.44 mmol, yield: 71%).

[0838] Step 3

[0839] In a dry 50 mL three-necked flask, A-1-10-1-47c (10.00 g, 41.44 mmol) and pyridine tribromide (19.88 g, 62.16 mmol) were added to 150 mL of tetrahydrofuran. Under nitrogen protection, the mixture was heated to 60°C. TLC confirmed the disappearance of the starting material. Ethyl acetate (100 mL) and 5% sodium dithionite solution (100 mL) were added. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain A-1-10-1-47d (6.73 g, 21.02 mmol, yield: 51%).

[0840] Step 4

[0841] Compounds A-1-10-1-47d (6.73 g, 21.02 mmol) and A1-1-1c (5.49 g, 18.92 mmol) were added to a 100 mL three-necked flask. Acetone (50 mL) was then added and dissolved thoroughly. Potassium carbonate (5.81 g, 42.04 mmol) and tetrabutylammonium iodide (7.76 g, 21.02 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, as monitored by TLC and LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford compound A-1-10-1-47e (2.68 g, 5.06 mmol, yield: 24%).

[0842] Step 5

[0843] In a dry 50mL three-necked flask, compound A-1-10-1-47e (2.68g, 5.06mmol) and ethyl acetate (50mL) were added to a 100mL three-necked flask, and then 10mL of hydrogen chloride dioxane solution (4.0M) was added. The mixture was heated to 50°C. After TLC monitoring, the temperature was lowered to 0°C and filtered to obtain A-1-10-1-47f hydrochloride (2.00g, 4.66mmol, yield: 85%).

[0844] MS-ESI:[M+H] + =430.1

[0845] Step 6

[0846] In a dry 50mL three-necked flask, compound A-1-10-1-47f (0.10g, 0.22mmol), potassium carbonate (0.15g, 1.1mmol) and dichloromethane (5mL) were added to a 50mL three-necked flask and stirred at room temperature for 2h. The mixture was filtered and concentrated. The crude product was purified by flash column chromatography to obtain compound A-1-10-1-47 (0.08g, 0.19mmol, yield: 87%).

[0847] MS-ESI:[M+H] + =430.1

[0848] 1 H NMR(400MHz, DMSO-d6)δ7.71(dd,J=8.9,2.2Hz,1H),7.56(dd,J=8.6,6.1Hz,1H),7.44(t ,J=9.1,7.9Hz,1H),7.02(dd,J=6.0,2.4Hz,1H),6.95(d,J=9.0Hz,1H),6.87(ddd,J=8.9 ,6.5,2.4Hz,1H),6.33(s,1H),5.40(qd,J=6.6,2.9Hz,1H),3.22–2.95(m,4H),2.82–2.6 7(m,2H),2.01(d,1H),1.69(d,J=12.1Hz,1H),1.61–1.50(m,2H),1.48(d,J=6.7Hz,3H).

[0849] Preparation Example (III) 46 Compound A-1-2-1-104

[0850] first step

[0851] In a 100 mL single-necked flask, A-1-2-1-104a (800.0 mg, 4.90 mmol) and 2-bromopropionyl chloride (1.68 g, 9.80 mmol) were dissolved in dichloromethane (10 mL). Anhydrous aluminum chloride (1.96 g, 14.70 mmol) was slowly added to the solution at 0°C. After the addition was complete, the mixture was reacted at 40°C for 1 h. After LCMS monitoring indicated the reaction was complete, the reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-104b (700.0 mg, 2.35 mmol, yield: 48%).

[0852] MS-ESI:[M+H] + =298.0

[0853] Step 2

[0854] To a 100 mL single-necked flask, intermediate A-1-2-1-104b (650.0 mg, 2.18 mmol), intermediate A1-1-1c (506.0 mg, 1.74 mmol), tetrabutylammonium iodide (1.21 g, 3.27 mmol), potassium carbonate (603.0 mg, 4.36 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After the addition was complete, the mixture was reacted at room temperature for 3 h. After LCMS monitoring indicated the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash column chromatography to obtain compound A-1-2-1-104 (200.0 mg, 0.39 mmol, yield: 18%).

[0855] MS-ESI:[M+H] + 508.1

[0856] 1H NMR(400MHz, DMSO-d6)δ8.03(d,J=7.8Hz,2H),7.95(t,J=5.7Hz,1H),7.68(ddd,J=10.6, 5.2,2.7Hz,1H),7.54(dd,J=8.5,5.9Hz,1H),7.42(d,J=8.3Hz,3H),6.98(dd,J=6.6,2.4H z,1H),6.93(d,J=8.9Hz,1H),6.90–6.84(m,1H),6.30(q,J=1.2Hz,1H),6.23(qd,J=6.7, 4.6Hz,1H),3.33–3.26(m,2H),2.80(t,J=7.2Hz,2H),1.78(s,3H),1.56(d,J=6.6Hz,3H).

[0857] Preparation Example (III) 47 Compound A-1-2-1-98

[0858] first step

[0859] To a dry 250 mL three-necked flask, add diethyl carbonate (17.61 g, 149.04 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.98 g, 74.52 mmol) was added in batches and allowed to react for 1 h. A-1-2-1-98a (5.00 g, 37.26 mmol) was then added to the flask. The temperature was then slowly raised to room temperature. The reaction was continued for 2 h (preferably 2-4 h). After TLC indicated the reaction was complete, the reaction was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, maintaining the temperature at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-98b (6.00 g, 33.94 mmol, yield: 54.7%).

[0860] Step 2

[0861] A-1-2-1-98b (6.00 g, 20.36 mmol) and resorcinol (2.24 g, 20.36 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 250 mL three-necked flask and heated to 50°C for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-98c (5.50 g, 21.80 mmol, yield: 91%).

[0862] MS-ESI:[M+H] + =253.2

[0863] 1 H NMR (400MHz, DMSO-d6) δ7.41–7.31(m,3H),7.21(d,J=7.7Hz,1H),6.83–6.77(m,2H),6.72(dd,J=8.7,2.2Hz,1H),6.07(d,J=1.9Hz,1H),2.09(s,3H).

[0864] Step 3

[0865] To a dry 100 mL three-necked flask, A-1-2-1-98c (1.61 g, 6.39 mmol), A-1-2-1-1d (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added sequentially and dissolved in acetone (30 mL). The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-98d (0.50 g, 1.03 mmol, yield: 16.20%).

[0866] MS-ESI:[M- t Bu] + =429.2

[0867] Step 4

[0868] In a dry 100 mL three-necked flask, add A-1-2-1-98d (0.50 g, 1.03 mmol) and dissolve it in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) and stir for 4 h (preferably 4-8 h). After LCMS shows the reaction is complete, the solvent is dried and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the product A-1-2-1-98 (335.3.0 mg, 0.78 mmol, yield: 75.0%).

[0869] MS-ESI:[MH] - =427.2

[0870] 1 H NMR(400MHz,Chloroform-d)δ8.79(t,J=1.7Hz,1H),8.36(dq,J=7.8,1.5Hz,1H),8.29(dq,J=7.9,1.5Hz,1H),7.65(td,J=7.8,1.8Hz ,1H),7.37(td,J=7.5,1.5Hz,1H),7.32–7.27(m,2H),7.15–7.10(m,1H),6.94(dd,J=8.7,0.9Hz,1H),6.87–6.60(m,2H),6.15(s,1H), 5.63(dd,J=6.9,4.4Hz,1H),2.13(s,3H),1.79(d,J=6.9Hz,3H).

[0871] Preparation Example (III) 48 Compound A-1-2-1-99

[0872] first step

[0873] To a dry 250 mL three-necked flask, add diethyl carbonate (17.61 g, 149.04 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.98 g, 74.52 mmol) was added in batches and allowed to react for 1 h. A-1-2-1-99a (5.00 g, 37.26 mmol) was then added to the flask. The temperature was then slowly raised to room temperature. The reaction was continued for 2 h (preferably 2-4 h). After TLC indicated the reaction was complete, the reaction was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, maintaining the temperature at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-99b (7.00 g, 33.94 mmol, yield: 91.1%).

[0874] Step 2

[0875] In a dry 100 mL three-necked flask, A-1-2-1-99b (6.00 g, 33.94 mmol) and resorcinol (3.74 g, 19.98 mmol) were dissolved in methanesulfonic acid (30 mL) and heated to 50°C for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-99c (5.50 g, 11.71 mmol, yield: 54.6%).

[0876] MS-ESI:[M+H] + =253.2

[0877] Step 3

[0878] To a dry 100 mL three-necked flask, A-1-2-1-99c (1.61 g, 6.39 mmol), A-1-2-1-98c (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added sequentially and dissolved in acetone (30 mL). The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-99d (0.35 g, 0.72 mmol, yield: 11.31%).

[0879] MS-ESI:[M- t Bu] + =429.2

[0880] Step 4

[0881] In a dry 50 mL three-necked flask, A-1-2-1-99d (0.35 g, 0.72 mmol) was added and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added and stirred for 4 h (preferably 4-8 h). After LCMS showed the reaction was complete, the solvent was dried and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the product A-1-2-1-99 (238.6.0 mg, 0.56 mmol, 74.0% yield).

[0882] MS-ESI:[MH] - =427.2

[0883] 1 H NMR(400MHz,Chloroform-d)δ8.80(t,J=1.8Hz,1H),8.36(dt,J=7.7,1.4Hz,1H),8.30(dt,J=7.9,1.5Hz,1H),7.65(t,J=7.8Hz,1 H),7.41(d,J=8.7Hz,1H),7.30(s,4H),6.86–6.76(m,2H),6.20(s,1H),5.64(d,J=6.9Hz,1H),2.43(s,3H),1.80(d,J=6.9Hz,3H).

[0884] Preparation Example (III) 49 Compound A-1-2-1-100

[0885] first step

[0886] To a dry 100 mL three-necked flask, add diethyl carbonate (8.80 g, 74.52 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (1.49 g, 37.26 mmol) was added in batches and allowed to react for 1 h. A-1-2-1-100a (2.50 g, 18.63 mmol) was then added to the flask. The temperature was then slowly raised to room temperature. The reaction was continued for 2 h (preferably 2-4 h). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, maintaining the temperature below 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-100b (3.00 g, 33.94 mmol, yield: 78.1%).

[0887] Step 2

[0888] In a dry 100 mL three-necked flask, A-1-2-1-100b (3.00 g, 14.55 mmol) and resorcinol (1.60 g, 14.55 mmol) were dissolved in methanesulfonic acid (30 mL) and heated to 50°C for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-100c (3.50 g, 13.88 mmol, yield: 81.1%).

[0889] MS-ESI:[M+H] + =253.2

[0890] 1 H NMR (400MHz, DMSO-d6) δ7.41–7.31(m,3H),7.21(d,J=7.7Hz,1H),6.83–6.77 (m,2H),6.72(dd,J=8.7,2.2Hz,1H),6.07(d,J=1.9Hz,1H),2.09(s,3H).

[0891] Step 3

[0892] To a dry 100 mL three-necked flask, A-1-2-1-100c (1.61 g, 6.39 mmol), A1-2-1-98c (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added sequentially and dissolved in acetone (30 mL). The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed completion of the reaction, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-100d (0.60 g, 1.24 mmol, yield: 19.40%).

[0893] MS-ESI:[M- t Bu] + =429.2

[0894] Step 4

[0895] In a dry 50 mL three-necked flask, add A-1-2-1-100d (0.60 g, 1.24 mmol) and dissolve it in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) and stir to react for 4 h (preferably 4-8 h). After LCMS shows the reaction is complete, the solvent is dried and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product A-1-2-1-100 (331.6.0 mg, 0.77 mmol, yield: 60.0%).

[0896] MS-ESI:[MH] - =427.2

[0897] 1 H NMR(400MHz,Chloroform-d)δ8.80(t,J=1.8Hz,1H),8.36(dt,J=7.8,1.4Hz,1H),8.30(dt,J=7.9,1.5Hz,1H),7.65(t,J=7.8Hz,1H),7.43–7 .32(m,2H),7.32–7.28(m,1H),7.21–7.14(m,2H),6.89–6.76(m,2H),6 .20(s,1H),5.64(q,J=6.9Hz,1H),2.41(s,3H),1.80(d,J=6.9Hz,3H).

[0898] Preparation Example (III) 50 Compound A-1-2-1-101

[0899] first step

[0900] To a dry 100 mL three-necked flask, add diethyl carbonate (11.87 g, 100.48 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.01 g, 50.24 mmol) was added in batches and allowed to react for 1 hour. Then, A-1-2-1-101a (5.00 g, 25.12 mmol) was added to the flask. The temperature was then slowly raised to room temperature. The reaction was allowed to proceed for 2 hours (preferably 2-4 hours). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, with the temperature maintained at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-101b (6.50 g, 23.98 mmol, yield: 95.44%).

[0901] MS-ESI:[MH] - =268.9

[0902] Step 2

[0903] In a dry 100 mL three-necked flask, A-1-2-1-101b (6.50 g, 23.98 mmol) and resorcinol (2.64 g, 23.98 mmol) were dissolved in methanesulfonic acid (30 mL) and heated to 50°C for 4 h (preferably 4-8 h). After completion of the reaction (LCMS indicated), the reaction solution was slowly added to ethanol (100 mL), with the quenching temperature controlled. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-101c (7.20 g, 19.30 mmol, yield: 80.49%).

[0904] MS-ESI:[MH] - =314.9

[0905] Step 3

[0906] In a dry 100mL three-necked flask, A-1-2-1-101c (2.00g, 6.31mmol), ethylboric acid (2.33g, 31.55mmol), and potassium phosphate (4.02g, 18.93mmol) were added in sequence and dissolved in 20mL of toluene and 4mL of water. The nitrogen was replaced, and palladium acetate (0.071g, 0.32mmol) and tricyclohexylphosphine (0.18g, 0.63mmol) were added. The reaction was carried out at 100°C for 6h (preferably 6 to 8h). After LCMS showed that the reaction was completed, the insoluble material was filtered, the solvent was dried, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5:1) to give intermediate A-1-2-1-101d (1.15 g, 4.31 mmol, yield: 68.48%).

[0907] MS-ESI:[MH] - =265.1

[0908] Step 4

[0909] A-1-2-1-101d (1.15 g, 4.31 mmol) and A1-2-1-98c (1.50 g, 4.79 mmol) were added to a dry 100 mL three-necked flask and dissolved in 10 mL of acetone. Tetrabutylammonium iodide (1.77 g, 4.79 mmol) and potassium carbonate (1.32 g, 9.58 mmol) were added and stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed that the reaction was complete, the insoluble matter was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-101e (580.0 mg, 1.16 mmol, yield: 24.29%).

[0910] MS-ESI:[MH] - =497.2

[0911] Step 5

[0912] In a dry 50 mL three-necked flask, A-1-2-1-101e (580.0 mg, 1.16 mmol) was added and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added and stirred for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the solvent was dried and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the product A-1-2-1-101 (336.2.0 mg, 0.76 mmol, yield: 36.27%).

[0913] MS-ESI:[MH] - =441.2.

[0914] 1H NMR(400MHz,Chloroform-d)δ8.79(t,J=1.6Hz,1H),8.36(dq,J=7.8,1.6Hz,1H),8.33–8.26( m,1H),7.65(td,J=7.8,2.1Hz,1H),7.41(td,J=7.5,1.4Hz,1H),7.35(dd,J=7.8,1.4Hz,1H),7 .30–7.24(m,1H),7.10(dt,J=7.6,1.6Hz,1H),6.94(dd,J=8.8,1.4Hz,1H),6.81–6.72(m,2H) ,6.17(s,1H),5.66–5.53(m,1H),2.54–2.27(m,2H),1.79(d,J=6.8Hz,3H),1.14–0.95(m,3H).

[0915] Preparation Example (III) 51 Compound A-1-2-1-102

[0916] first step

[0917] To a dry 100 mL three-necked flask, add diethyl carbonate (11.87 g, 100.48 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.01 g, 50.24 mmol) was added in batches and allowed to react for 1 hour. A-1-2-1-102a (5.00 g, 25.12 mmol) was then added to the flask. The temperature was then slowly raised to room temperature. The reaction was allowed to proceed for 2 hours (preferably 2-4 hours). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, with the temperature maintained at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-102b (6.50 g, 23.98 mmol, yield 95.44%).

[0918] MS-ESI:[MH] - =268.9

[0919] Step 2

[0920] A-1-2-1-102b (6.50 g, 23.98 mmol) and resorcinol (2.64 g, 23.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-necked flask and heated to 50°C for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-102c (7.20 g, 19.30 mmol, yield 80.49%).

[0921] MS-ESI:[MH] - =314.9

[0922] Step 3

[0923] In a dry 100mL three-necked flask, A-1-2-1-102c (4.00g, 12.61mmol), cyclopropylboronic acid (15.13g, 7.57mmol), and potassium phosphate (8.03g, 37.83mmol) were added in sequence and dissolved in 40mL of toluene and 8mL of water. The nitrogen was replaced, and palladium acetate (0.14g, 0.63mmol) and tricyclohexylphosphine (0.35g, 1.26mmol) were added, and the reaction was carried out at 100℃ for 6h. After LCMS showed that the reaction was completed, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were separated, and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5:1) to give intermediate A-1-2-1-102d (1.75 g, 5.75 mmol, yield 48.43%).

[0924] MS-ESI:[MH] - =277.0

[0925] Step 4

[0926] In a dry 100 mL three-necked flask, tert-butyl 3-(2-bromopropionyl)benzoate was dissolved in 20 mL of acetone. Tetrabutylammonium iodide (2.95 g, 7.98 mmol) and potassium carbonate (2.21 g, 15.96 mmol) were added and stirred to disperse. Finally, A-1-2-1-102d (1.75 g, 6.29 mmol) was added and stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed that the reaction was completed, the insoluble material was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were separated, and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5:1) to give intermediate A-1-2-1-102e (1.30 g, 2.55 mmol, yield 31.90%).

[0927] MS-ESI:[M- t Bu] + =455.2

[0928] Step 5

[0929] In a dry 100 mL three-necked flask, A-1-2-1-102e (1.30 g, 2.55 mmol) was added and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added and stirred for 4 h (preferably 4-8 h). After LCMS showed completion of the reaction, the solvent was dried and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product A-1-2-1-102 (679.3.0 mg, 1.38 mmol, yield: 54.33%).

[0930] MS-ESI:[M+H] + =455.2

[0931] 1H NMR(400MHz,Chloroform-d)δ8.79(d,J=1.7Hz,1H),8.36(dt,J=7.7,1.4Hz,1H),8.30(d t,J=7.8,1.5Hz,1H),7.65(t,J=7.8Hz,1H),7.42–7.29(m,2H),7.19–7.12(m,2H),7.09( t,J=1.8Hz,1H),6.85–6.77(m,2H),6.19(s,1H),5.63(d,J=6.9Hz,1H),1.94(ddd,J=8.5 ,5.1,3.4Hz,1H),1.80(d,J=6.8Hz,3H),1.08–0.95(m,2H),0.72(dt,J=6.7,4.7Hz,2H).

[0932] Preparation Example (III) 52 Compound A-1-2-1-103

[0933] first step

[0934] To a dry 100 mL three-necked flask, add diethyl carbonate (11.87 g, 100.48 mmol) and tetrahydrofuran (50 mL) to dissolve the mixture. The atmosphere was then replaced with nitrogen. The reaction apparatus was placed in a low-temperature reaction bath and cooled to 0°C. Sodium hydride (2.01 g, 50.24 mmol) was added in batches and allowed to react for 1 h. A-1-2-1-103a (5.00 g, 25.12 mmol) was then added to the flask. The temperature was then slowly raised to room temperature. The reaction was allowed to proceed for 2 h (preferably 2-4 h). After TLC indicated the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0°C to a pH of 1, with the temperature maintained at no more than 10°C. The reaction solution was extracted with ethyl acetate (100 mL × 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-103b (6.50 g, 23.98 mmol, yield: 95.44%).

[0935] MS-ESI:[MH] - =268.9

[0936] Step 2

[0937] A-1-2-1-103b (6.50 g, 23.98 mmol) and resorcinol (2.64 g, 23.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-necked flask and heated to 50°C for 4 h (preferably 4-8 h). After LCMS indicated completion of the reaction, the reaction solution was slowly added to ethanol (100 mL) while controlling the quenching temperature. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude intermediate A-1-2-1-103c (7.20 g, 19.30 mmol, yield: 80.49%).

[0938] MS-ESI:[MH] - =314.9

[0939] Step 3

[0940] In a dry 100mL three-necked flask, A-1-2-1-103c (2.00g, 6.31mmol), palladium acetate (0.071g, 0.32mmol), triphenylphosphine (0.17g, 0.63mmol), cesium carbonate (6.17g, 18.93mmol) and potassium ethylene trifluoroborate (1.27g, 9.46mmol) were added in sequence to replace nitrogen. The mixture was dissolved in 20mL of dioxane and 2mL of water and reacted at 100℃ for 6h (preferably 6-8h). After LCMS showed that the reaction was completed, the insoluble material was filtered, the solvent was dried, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The liquids were separated, and the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5:1) to give intermediate A-1-2-1-103d (1.30 g, 4.60 mmol, yield: 54.90%).

[0941] Step 4

[0942] A-1-2-1-103d (1.22 g, 4.60 mmol) and A-1-2-1-1d (1.60 g, 5.11 mmol) were added to a dry 100 mL three-necked flask and dissolved in 20 mL of acetone. Tetrabutylammonium iodide (1.89 g, 5.11 mmol) and potassium carbonate (1.41 g, 10.22 mmol) were added and stirred for dispersion. The mixture was stirred at room temperature for 8 h (preferably 8-12 h). After LCMS showed that the reaction was complete, the insoluble matter was filtered, the solvent was dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5:1) to obtain intermediate A-1-2-1-103e (860.0 mg, 1.73 mmol, yield: 33.90%).

[0943] MS-ESI:[MH] - =495.2

[0944] Step 5

[0945] A-1-2-1-103e (860.0 mg, 1.73 mmol) was added to a dry 50 mL three-necked flask and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added and stirred for 4 h (preferably 4-8 h). After LCMS showed the reaction was complete, the solvent was dried and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product A-1-2-1-103 (383.0.0 mg, 0.87 mmol, yield: 41.22%).

[0946] MS-ESI:[MH] - =439.2

[0947] 1 H NMR (400MHz, Chloroform-d) = δ8.79 (t, J = 1.7Hz, 1H), 8.36 (dq, J = 7.8, 1.6Hz, 1H), 8.32–8.26 ( m,1H),7.72–7.63(m,2H),7.45(td,J=7.7,1.5Hz,1H),7.36(tt,J=7.4,1.0Hz,1H),7.17(dt,J =7.5,1.6Hz,1H),7.02–6.94(m,1H),6.83–6.71(m,2H),6.51–6.33(m,1H),6.17(s,1H),5.71( dd,J=17.3,1.0Hz,1H),5.65–5.57(m,1H),5.18(dd,J=10.9,1.0Hz,1H),1.79(d,J=6.9Hz,3H).

[0948] Preparation Example (III) 53 Compound A-1-2-2-2

[0949] first step

[0950] In a dry 100mL three-necked flask, compound A-1-2-2-2a (5.00g, 36.2mmol) and phenylacetyl chloride (6.16g, 39.8mmol, 5.31mL) were dissolved in acetone (360mL), potassium carbonate (17.5g, 126mmol) was added at 25°C, and the mixture was stirred at 60°C for 6h. LCMS monitored the reaction progress. After the reaction was completed, the reaction solution was poured into water (300mL) and extracted with ethyl acetate (200mL×3). The organic phases were combined, washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was used directly in the next step. Compound A-1-2-2-2b (7.26g, 29.7mmol, yield: 82.1%, purity: 97.5%) was obtained as a yellow solid.

[0951] MS-ESI:[M+H] + =239.1

[0952] 1 H NMR(400MHz,DMSO-d6)=δ10.61(br s,1H),8.15(s,1H),7.71-7.69(m,1H),7.68(s,1H),7.60(d,J=8.4Hz,1H),7.46- 7.41(m,2H),7.40-7.35(m,1H),6.82(dd,J=2.4,8.8Hz,1H),6.76(d,J=2.4Hz,1H)

[0953] Step 2

[0954] In a dry 100mL three-necked flask, compound A-1-2-2-2b (1.50g, 6.14mmol, 97.5%) and methyl 2-bromopropionate (1.23g, 7.37mmol) were dissolved in N,N-dimethylformamide (15mL), cesium carbonate (4.00g, 12.3mmol) was added at 25°C, and the mixture was stirred at 70°C for 2h. LCMS monitored the reaction progress. After the reaction was completed, the reaction solution was poured into water (100mL) and extracted with ethyl acetate (100mL×3). The combined organic phases were washed with saturated brine (150mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was used directly in the next step. Compound A-1-2-2-2c (1.77g, 5.24mmol, yield: 85.3%, purity: 96.0%) was obtained as a yellow solid.

[0955] MS-ESI:[M+H] + =325.0

[0956] 1 H NMR (400MHz, DMSO-d6)=δ8.20(s,1H),7.72-7.69(m,3H),7.48-7.37(m,3H),6.98 (dd,J=2.4,4.4Hz,2H),5.24(q,J=6.8Hz,1H),3.70(s,3H),1.56(d,J=6.8Hz,3H)

[0957] Step 3

[0958] In a dry 100mL three-necked flask, compound A-1-2-2-2c (1.77g, 5.24mmol, purity: 96.0%) was dissolved in tetrahydrofuran (90mL) and water (30mL), lithium hydroxide monohydrate (219.0mg, 5.24mmol, 1.00eq) was added at 0°C, and the mixture was stirred at 0°C for 2h. LCMS monitored the reaction progress. After the reaction was completed, the pH of the mixture was adjusted to 8 with 1M HCl, and then the mixture was extracted with ethyl acetate (100mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (HCl conditions). White solid compound A-1-2-2-2d (200.0mg, 524μmol, yield: 10.0%, purity: 81.3%) was obtained.

[0959] MS-ESI:[M+H] + =311.1

[0960] Step 4

[0961] In a dry 100 mL three-necked flask, compound A-1-2-2-2d (200.0 mg, 524 μmol, purity: 81.3%), 3-piperidinecarbonitrile (57.7.0 mg, 524 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (239.0 mg, 628 μmol), and N,N-diisopropylethylamine (101.0 mg, 786 μmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at 20°C for 16 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomene*C18 150*25m*10μm; mobile phase: [water(ammonium bicarbonate)-acetonitrile; B%: 30%-60%, 8 min). Freeze-dried to obtain A-1-2-2-2 as a white solid (70.0 mg, 172 μmol, yield: 32.8%, purity: 99.0%).

[0962] MS-ESI:[M+H] + =403.0

[0963] Preparation Example (III) 54 Compound A-1-2-6-22

[0964] first step

[0965] In a dry 100mL three-necked flask, a solution of compound A-1-2-6-22a (4.50g, 23.4mmol, 1.00eq) in POBr3 (8.73g, 30.4mmol, 3.09mL, 1.30eq) was stirred at 130°C for 1h. LCMS monitored the reaction progress. After the reaction was completed, the reaction mixture was cooled to 20°C and poured into water (50mL), and the pH was adjusted to 9 with saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted with ethyl acetate (20mL×3). The combined organic phases were washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and concentrated to give a crude product. The product was used directly in the next step. Compound A-1-2-6-22b (3.00g, 7.47mmol, yield: 31.9%, purity: 63.5%) was obtained as a yellow solid.

[0966] MS-ESI:[M+H] + =254.8

[0967] Step 2

[0968] Compound A-1-2-6-22b (3.00 g, 11.8 mmol, 1.00 eq) was added to a dry 100 mL three-necked flask, dissolved in dichloromethane (100 mL), and the reaction temperature was controlled to 20 ° C after nitrogen replacement. Boron tribromide (8.84 g, 35.3 mmol, 3.40 mL, 3.00 eq) was added and continued to stir at 20 ° C for 1 h. LCMS monitored the reaction progress. After the reaction was completed, the reaction mixture was poured into 20 ° C water (300 mL) and adjusted to pH = 9 with saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was used directly in the next step. Compound A-1-2-6-22c (2.70 g, 1.04 mmol, yield: 8.83%, purity: 9.27%) was obtained as a yellow solid.

[0969] MS-ESI:[M+H] + =240.8

[0970] Step 3

[0971] In a dry 100 mL three-necked flask, compound a-1-2-6-22c (2.54 g, 10.5 mmol, 1.00 eq), methyl 2-bromopropionate (1.85 g, 11.1 mmol, 1.23 mL, 1.05 eq), and cesium carbonate (5.15 g, 15.8 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (26 mL), and the mixture was stirred at 20°C for 2 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into water (100 mL). The reaction mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The product was used directly in the next step. Compound A-1-2-6-22d (2.45 g, 4.28 mmol, yield: 40.7%, purity: 57.2%) was obtained as a yellow solid.

[0972] MS-ESI:[M+H] + =326.8

[0973] Step 4

[0974] In a dry 100mL three-necked flask, compound A-1-2-6-22d (2.45g, 7.49mmol, 1.00eq) was dissolved in hydrochloric acid solution (25mL) (37% purity) and stirred at 20°C for 12h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into 1M hydrochloric acid solution (100mL) at 20°C. The reaction mixture was extracted with ethyl acetate (20mL×3). The combined organic phases were washed with saturated brine (100mL×2), dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was used directly in the next step. Compound A-1-2-6-22e (2.37g, 4.97mmol, yield: 66.3%, purity: 65.6%) was obtained as a yellow solid.

[0975] MS-ESI:[M+H] + =312.8

[0976] Step 5

[0977] To a dry 100 mL three-necked flask, compound a-1-2-6-22e (150.0 mg, 479 μmol, 1.00 eq), tributyl(2-pyridyl)stannane (229.0 mg, 621 μmol), cuprous iodide (45.6.0 mg, 240 μmol), and triphenylphosphine (25.1.0 mg, 95.8 μmol) were added. After nitrogen purge, trisdibenzylideneacetone dipalladium (43.9.0 mg, 47.9 μmol) was added, followed by dioxane (7 mL) as solvent. The mixture was again degassed under vacuum and purged with nitrogen three times, then stirred at 50°C for 12 h. Reaction progress was monitored by LCMS. After completion of the reaction, the mixture was cooled to 25°C and filtered through a pad of celite. The filtrate was washed with ethyl acetate (10 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. This product was used directly in the next step. Compound A-1-2-6-22f (530.0 mg, crude product) was obtained as a yellow oil.

[0978] MS-ESI:[M+H] + =311.9

[0979] Step 6

[0980] In a dry 100 mL three-necked flask, compound a-1-2-6-6-22f (530.0 mg, 1.70 mmol), 3-piperidinecarbonitrile (225.0 mg, 2.04 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (971.0 mg, 2.55 mmol, 1.50 eq), and N,N-diisopropylethylamine (440.0 mg, 3.41 mmol, 593 μL, 2.00 eq) were dissolved in N,N-diisopropylethylamine (5 mL) and stirred at 20°C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column: Phenome ne*C18 250*50mm*10μm; mobile phase: [water(ammonium bicarbonate)-acetonitrile; B%: 15%-4.6%, 9 minutes). A yellow solid A-1-2-6-22 (84.0 mg, 206 μmol, yield: 12.1%, purity: 99.0%) was obtained.

[0981] MS-ESI:[M+H] + =404.1

[0982] 1 H NMR: (400MHz, DMSO-d6)=δ8.78(d,J=4.0Hz,1H),8.11-7.94(m,1H),7.78(d,J= 7.6Hz,1H),7.73-7.65(m,1H),7.72-7.66(m,1H),7.03-6.91(m,1H),6.90-6.86 (m,1H),6.44(s,1H),5.63-5.53(m,1H),4.02-3.82(m,1H),3.80-3.63(m,1H), 3.60-3.46(m,2H),3.17-3.01(m,1H),1.89(d,J=4.8Hz,2H),1.68-1.43(m,5H).

[0983] Preparation Example (III) 55 Compound A-1-2-6-23

[0984] first step

[0985] In a dry 100 mL three-necked flask, compound a-1-2-6-23a (600.0 mg, 1.92 mmol) and 3-pyridylboronic acid (283.0 mg, 2.30 mmol) were dissolved in a mixture of dioxane (6 mL) and water (2 mL). After replacing the nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (140.0 mg, 192 μmol) and potassium acetate (376 mg, 3.83 mmol) were added. The mixture was degassed and purged with nitrogen three times. The mixture was stirred at 90°C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the mixture was cooled to 25°C and filtered through a pad of celite. The filtrate was washed with ethyl acetate (10 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was used directly in the next step to obtain yellow oily compound A-1-2-6-23b (722.0 mg, 993 μmol, yield: 51.8%, purity: 42.8%)

[0986] MS-ESI:[M+H] + =311.8

[0987] Step 2

[0988] In a dry 100 mL three-necked flask, compound A-1-2-6-23b (722.0 mg, 2.32 mmol), 3-piperidinecarbonitrile (306.0 mg, 2.78 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.32 g, 3.48 mmol), and N,N-diisopropylethylamine (600.0 mg, 4.64 mmol) were dissolved in N,N-dimethylformamide (8 mL). The mixture was stirred at 20°C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenome ne*C18 250*50mm*10μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile; B%: 15%-45%, 8 minutes). A-1-2-6-23 (96.6.0 mg, 233 μmol, yield: 10.0%, purity: 97.1%) was obtained as an off-white solid.

[0989] MS-ESI:[M+H] + =404.0

[0990] 1H NMR: (400MHz, DMSO-d6)=δ8.81-8.67(m,2H),7.98(d,J=8.0Hz,1H),7.62-7.59(m,1H),7.36-7.19(m,1H),7.08-6.92(m,1H),6. 88(d,J=8.8Hz,1H),6.37(s,1H),5.62-5.45(m,1H),4.04-3.83(m,1H),3.80-3.63(m,1H),3.59-3.37(m,2H),3.18-3.00(m,1H), 2.02-1.79(m,2H),1.78-1.40(m,5H).

[0991] Preparation Example (III) 56 Compound A-1-2-6-24

[0992] first step

[0993] In a dry 100 mL three-necked flask, compound a-1-2-6-24a (400 mg, 1.28 mmol) and 4-pyridylboronic acid (188.0 mg, 1.53 mmol, 1.20 eq) were dissolved in a mixture of dioxane (4.00 mL) and water (1.00 mL). After replacing the atmosphere with nitrogen, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (93.5 mg, 128 umol) and potassium acetate (251 mg, 2.56 mmol) were added. The mixture was degassed again and purged with nitrogen three times. The mixture was stirred at 90°C for 1 h. The reaction progress was monitored by LCMS. After the reaction was completed, the mixture was cooled to 25°C and poured into a saturated ammonium chloride solution (20.0 mL) at 0-5°C. The mixture was extracted with ethyl acetate (10.0 mL*3). The combined organic phases were washed with saturated brine (10.0 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude product. The crude product was used directly in the next step. Compound A-1-2-6-24b (250.0 mg, 426 μmol, yield: 33.3%, purity: 53.0%) was obtained as a yellow oil.

[0994] MS-ESI:[M+H] + =311.9

[0995] Step 2

[0996] In a dry 100 mL three-necked flask, compound A-1-2-6-24b (247.0 mg, 793 umol), 3-piperidinecarbonitrile (105.0 mg, 952 umol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (453.0 mg, 1.19 mmol), and N,N-diisopropylethylamine (205.0 mg, 1.59 mmol) were dissolved in N,N-dimethylformamide (2.50 mL). The mixture was stirred at 20°C for 1 h. The reaction progress was monitored by LCMS. After the reaction, the reaction mixture was poured into ice water (20.0 mL) and adjusted to pH = 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (10.0 mL*3). The combined organic phases were washed with saturated brine (10.0 mL*2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters*bridge 150*25mm 10um; mobile phase: [water(ammonium bicarbonate)-acetonitrile; B%: 16%-46%, 8 minutes) to obtain compound A-1-2-6-24 (31.4.0 mg, 76.3 umol, yield: 9.61%, purity: 98.0%).

[0997] MS-ESI:[M+H] + =404.0.

[0998] 1 H NMR: (400MHz, DMSO-d6) δ8.81-8.73(m,2H),7.58-7.51(m,2H),7.31-7.20(m,1H),7.08–6.92(m,1H),6.91-6.81(m,1H),6.35(s,1H),5 .59-5.46(m,1H),4.03-3.83(m,1H),3.80-3.64(m,1H),3.56-3.35(m,2H),3.25-3.02(m,1H),1.89(d,J=4.8Hz,2H),1.76-1.41(m,5H).

[0999] Preparation Example (III) 57 Compound A-7-1-1-1

[1000] first step

[1001] In a dry 100 mL three-necked flask, A-7-1-1-1a (444.0 mg, 5.15 mmol), triphenylphosphine (1.56 g, 5.95 mmol), and A-1-2-1-98c (1.00 g, 3.96 mmol, 1.00 eq) were dissolved in tetrahydrofuran (10 mL). The atmosphere was replaced with nitrogen and diisopropyl azodicarboxylate (1.28 g, 6.34 mmol) was added dropwise at 0°C to control the reaction temperature to no more than 5°C. After the addition was complete, the mixture was stirred at 20°C for 12 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reactants were poured into a saturated sodium sulfite solution (10 mL) and the pH was adjusted to 9 using a saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain the product (petroleum ether: ethyl acetate = 10:1, Rf = 0.60), giving yellow compound A-7-1-1-1b (1.10 g, 3.43 mmol, yield: 86.6%, purity: 100%)

[1002] MS-ESI:[M+H] + =321.1

[1003] 1 H NMR: (400MHz, DMSO-d6) δ7.46-7.31(m,3H),7.24(d,J=7.6Hz,1H),7.09(s,1H),6.85(d,J=1.2Hz,2H),6.16(s,1H ),5.84-5.79(m,1H),5.19-5.02(m,2H),4.72-4.67(m,1H),2.48-2.31(m,2H),2.11(s,3H)1.27(d,J=6.0Hz,3H).

[1004] Step 2

[1005] In a dry 100mL three-necked flask, sodium periodate (3.30g, 15.5mmol) and ruthenium trichloride monohydrate (15.5.0mg, 68.7μmol) were dissolved in a mixed solvent of dichloromethane (2mL), acetonitrile (2mL), and water (6mL). The temperature was lowered to 0°C, and A-7-1-1-1b (1.10g, 3.43mmol) dissolved in dichloromethane (2mL) and acetonitrile (2mL) was added. The mixture was stirred at -5-0°C for 3h. The reaction progress was monitored by LCMS. After the reaction was completed, the reactant was poured into a saturated sodium sulfite solution (30mL), adjusted to pH = 9 with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (10mL×3), and the combined organic phases were washed with saturated brine (30mL×2), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by Pre-HPLC (column: Phenome ne*Luna C18 200*40mm*10μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 40%-70%, 10 minutes). Compound A-7-1-1-1c (70.0 mg, 203 μmol, yield: 5.92%, purity: 98.2%)

[1006] MS-ESI:[M+H] + =339.0

[1007] Step 3

[1008] In a dry 100 mL three-necked flask, compound A-7-1-1-1c (70.0 mg, 207 μmol), dimethylamine (10.3.0 mg, 228 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118.0 mg, 310 μmol), and N,N-diisopropylethylamine (80.2 mg, 621 μmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 20°C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenome ne*Luna C18 150*25mm*10μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 43%-72%, 10 minutes). A-7-1-1-1 (40.0 mg, 98.8 μmol, yield: 47.7%, purity: 95.8%) was a yellow solid.

[1009] MS-ESI:[M+H] + =366.1

[1010] 1 H NMR(400MHz, DMSO-d6)δ7.48-7.30(m,3H),7.23(d,J=7.6Hz,1H),7.07-6.98(m,1H),6.90-6.77(m,2H),6.17(s,1H),5 .06-4.93(m,1H),2.98(s,3H),2.85-2.82(m,1H),2.80(s,3H),2.63-2.53(m,1H),2.12(s,3H),1.32(d,J=6.0Hz,3H).

[1011] Preparation Example (III) 58 Compound A-7-1-1-2

[1012] first step

[1013] In a dry 100 mL three-necked flask, A-1-2-1-98c (1.00 g, 3.96 mmol), cesium carbonate (2.58 g, 7.93 mmol), and compound A-7-1-1-2a (851.0 mg, 4.76 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the mixture was stirred at 20°C for 2 h. The reaction progress was monitored by LCMS. After the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was used directly in the next step. Compound A-7-1-1-2b (1.35 g, 3.68 mmol, yield: 93.0%, purity: 95.6%) was obtained as a yellow oil.

[1014] MS-ESI:[M+H] + =351.1

[1015] 1 H NMR (400MHz, DMSO-d6) δ7.46-7.31(m,3H),7.24(d,J=7.6Hz,1H),7.15(d,J=2.0Hz,1 H),6.97-6.84(m,2H),6.34(s,1H),6.20(s,1H),6.06(d,J=0.8Hz,1H),4.87(s,2H), 3.74(s,3H),2.11(s,3H)

[1016] Step 2

[1017] In a dry 100mL three-necked flask, compound A-7-1-1-2b (1.05g, 3.00mmol) was dissolved in ethyl acetate (5mL), nitrogen was replaced, and a solution of wet palladium carbon (0.16g, 30.0μmol, purity: 10.0%) in ethyl acetate was added. The mixture was degassed under vacuum and purged with nitrogen several times, filled with hydrogen (15.0Psi), and stirred at 20°C for 12h. LCMS monitored the reaction progress. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the product. The crude product was used directly in the next step. Compound A-7-1-1-2c (0.85g, 1.21mmol, yield: 40.2%, purity: 50.0%) was obtained as a yellow oil.

[1018] MS-ESI:[M+H] + =353.1

[1019] Step 3

[1020] In a dry 100 mL three-necked flask, compound A-7-1-1-2c (0.85 g, 2.41 mmol) was dissolved in tetrahydrofuran (10 mL) and concentrated hydrochloric acid (10 mL) (37% purity) was added. The mixture was stirred at 20°C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenome ne*Luna C18 250*50mm*10μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: %-67%, 20 minutes). Compound A-7-1-1-2d (300.0 mg, 887 μmol, yield: 36.8%, purity: 100%) was obtained as a yellow oil.

[1021] MS-ESI:[M+H] + =339.0

[1022] Step 4

[1023] In a dry 100 mL three-necked flask, compound A-7-1-1-2d (287.0 mg, 848 μmol, 1.00 equiv), dimethylamine (42.1.0 mg, 933 μmol, 47.3 μL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (484.0 mg, 1.27 mmol), and N,N-diisopropylethylamine (329.0 mg, 2.54 mmol) were dissolved in N,N-dimethylformamide (1 mL). The mixture was stirred at 20°C for 2 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by Pre-HPLC (column: Phenome ne*Luna C18 200*40mm*10μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 40%-70%, 10 minutes). A-7-1-1-2 (207.0 mg, 543 μmol, yield: 64.0%, purity: 95.8%) was obtained as a yellow solid.

[1024] MS-ESI:[M+H] + =366.1

[1025] 1 H NMR (400MHz, DMSO-d6) δ7.46-7.31(m,3H),7.24(d,J=7.2Hz,1H),7.08(d,J=1.6Hz,1H),6.86(t,J=1.2Hz,2H),6.18(s,1 H),4.26–4.22(m,1H),3.99–3.96(m,1H),3.68–3.55(m,1H),3.05(s,3H),2.83(s,3H),2.10(s,3H),1.08(d,J=6.8Hz,3H)

[1026] Preparation Example (III) 59 Compound A-1-2-1-42

[1027] first step

[1028] A-1-2-1-33c (1.00 g, 2.76 mmol) and A-1-2-1-42a (1.09 g, 2.76 mmol) were added to a dry 50 mL three-necked flask. After nitrogen was replaced, tetrakistriphenylphosphine palladium (79.7 mg, 0.05 mmol) was added and dissolved in 5 mL of dioxane. Finally, dimethyl dicarbonate (462.6 mg, 3.45 mmol) was added and reacted at 115 ° C for 2 h (recommended time 2-4 h). After the reaction was completed, LCMS detection showed that the reaction was completed, and the reaction was cooled to room temperature, filtered, and the filtrate was collected. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5%~30%) to obtain intermediate A-1-2-1-42b (930.0 mg, 1.86 mmol, yield: 67.62%).

[1029] MS-ESI:[M+H] + =499.1

[1030] Step 2

[1031] To a dry 50 mL three-necked flask, add A-1-2-1-42a (800.0 mg, 1.60 mmol) and dissolve in 5 mL of tetrahydrofuran. Cool to 0°C, then add 5 mL of 2M aqueous sodium hydroxide solution and react for 30 min (recommended time 0.5-2 h). After TLC indicates completion of the reaction, adjust the pH to 1 with 1 M aqueous hydrochloric acid. Extract with ethyl acetate (5 mL x 3), wash with saturated brine (5 mL x 2), dry over anhydrous sodium sulfate, and purify by spin-drying. Purify by silica gel column chromatography (DCM:MeOH = 50:1) to obtain the desired product A-1-2-1-42 (237.0 mg, 0.489 mmol, yield: 30.48%).

[1032] MS-ESI:[MH] - =483.1

[1033] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 7.0, 2.4 Hz, 1H), 8.37–8.32 (m, 1H), 7.68 (dd, J = 8.7, 2.1 Hz, 1H), 7.59–7.48 (m, 2H), 7.42 (dq, J = 8.4, 5.5, 4.4 Hz, 1H), 7.09 (dd, J = 4.0, 2.4 Hz, 1H), 6.96–6.86 (m, 2H), 6.31 (s, 1H), 6.26 (qd, J = 6.7, 4.0 Hz, 1H), 1.58 (d, J = 6.7 Hz, 3H). Preparation Example (III) 60 Compound A-1-10-1-20

[1034] first step

[1035] A-1-2-1-98c (500.0 mg, 1.38 mmol) and A-1-10-1-20a (530.0 mg, 2.48 mmol) were added to a dry 50 mL three-necked flask. After replacing the nitrogen, tetrakistriphenylphosphine palladium (79.7.0 mg, 0.07 mmol) was added and dissolved in 5 mL of dioxane solution. Finally, dimethyl dicarbonate (462.6 mg, 3.45 mmol) was added and reacted at 115 ° C for 2 h (preferably 2-4 h). After the reaction was completed, LCMS showed that the reaction was completed, and the mixture was cooled to room temperature, filtered, and the filtrate was collected. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=3:1) to obtain intermediate A-1-10-1-20b (590.0 mg, 1.26 mmol, yield: 91.10%).

[1036] MS-ESI:[M+H] + =470.0

[1037] Step 2

[1038] To a dry 50 mL three-necked flask, add A-1-10-1-20b (400.0 mg, 0.85 mmol) and dissolve in 5 mL of tetrahydrofuran. The mixture was cooled to 0°C and then added with 2 mL of 2M aqueous sodium hydroxide solution. The reaction was allowed to proceed for 30 min (preferably 0.5-2 h). After TLC showed completion of the reaction, the pH was adjusted to 1 with 1M aqueous hydrochloric acid. The mixture was extracted with 5 mL of ethyl acetate (3 times), washed with 5 mL of saturated brine (2 times), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 50:1) and further isolated on a preparative plate (DCM:MeOH = 10%) to afford the desired product A-1-10-1-20 (102.0 mg, 0.178 mmol, yield: 22.0%).

[1039] MS-ESI:[MH] - =454.1

[1040] Preparation Example (III) 61 Compound A-1-2-1-45

[1041] first step:

[1042] A-1-2-1-45a (20.00 g, 76.65 mmol) was added to a dry 500 mL three-necked flask and replaced with nitrogen. Anhydrous tetrahydrofuran (200 mL) was then added to dissolve the solution. The temperature was lowered to 0°C and isopropylmagnesium chloride (2M, 42.16 mL, 84.32 mmol) was slowly added dropwise, with the reaction temperature controlled to not exceed 5°C. After the addition was complete, stirring was continued at 0°C for 1 h. N-methoxy-N-methylpropionamide (9.88 mL, 84.32 mmol) diluted with anhydrous tetrahydrofuran (30 mL) was added dropwise. After the addition was complete, the mixture was transferred to a 25°C container and the reaction continued for 2 h. After LCMS showed that the reaction was completed, the temperature was lowered to 0°C and the product was slowly quenched with saturated NH4Cl solution. The quenching temperature was controlled not to exceed 5°C. After the quenching was completed, the product was extracted with ethyl acetate (100 mL × 3). The liquids were separated, and the organic phases were combined, washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-45b (18.70 g, 70.69 mmol, yield: 85.0%).

[1043] MS-ESI:[M+H] + =237.9

[1044] 1 H NMR (400MHz, Chloroform-d) δ8.29(t,J=1.7Hz,1H),8.15(d,J=1.7Hz,1H),7.96(t,J=1.7Hz,1H),3.10–2.89(m,2H),1.24(td,J=7.2,1.6Hz,3H).

[1045] Step 2

[1046] To a dry 500 mL three-necked flask, add palladium acetate (0.48 g, 2.12 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.23 g, 2.12 mmol) and replace the atmosphere with nitrogen. Then, add A-1-2-1-45b (18.70 g, 70.69 mmol) and dicyclohexylcarbodiimide (2.92 g, 14.14 mmol), dissolve in N,N-dimethylformamide (200 mL), and replace the atmosphere with nitrogen again. Then, slowly add formic acid (18.67 mL, 494.83 mmol) and triethylamine (19.65 mL, 141.38 mmol). Heat the mixture to 80°C (preferably 80-100°C) and stir for 4 h (preferably 4-8 h). After LCMS showed that the reaction was completed, it was cooled to room temperature and quenched by adding water (200 mL). The reaction solution was filtered through celite to remove insoluble matter, and then extracted with methyl tert-butyl ether (150 mL×3). The layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH=15:1) to give intermediate A-1-2-1-45c (9.50 g, 46.75 mmol, yield: 59.5%).

[1047] MS-ESI:[MH] - =202.1

[1048] 1 H NMR (400MHz, DMSO-d6) δ8.63 (d, J = 5.0Hz, 2H), 8.51 (s, 1H), 3.15 (q, J = 7.0Hz, 2H), 1.10 (t, J = 7.1Hz, 3H).

[1049] Step 3

[1050] A-1-2-1-45c (9.50 g, 46.75 mmol) was added to a dry 100 mL three-necked flask and the atmosphere was replaced with nitrogen. 20 mL of 3.3 M potassium hydroxide solution and 30 mL of methanol were added to dissolve the mixture. The temperature was raised to 80°C (preferably 60-80°C) and stirred for 2 h (preferably 2-4 h). After completion of the reaction by LCMS, the mixture was cooled to room temperature, filtered, and the filtrate collected. The pH of the filtrate was adjusted to 1 with 2 M hydrochloric acid solution and extracted with ethyl acetate (50 mL x 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1, 1:1000 AcOH) to afford intermediate A-1-2-1-45d (4.30 g, 19.35 mmol, yield: 48.47%).

[1051] MS-ESI:[MH]- =221.1

[1052] 1 H NMR (400MHz, DMSO-d6) δ8.75–8.61(m,3H),5.01(t,J=6.5Hz,2H),1.32(t,J=6.2Hz,3H).

[1053] Step 4

[1054] A-1-2-1-45d (4.30 g, 19.35 mmol) was added to a dry 100 mL three-necked flask and the atmosphere was replaced with nitrogen. N,N-dimethylformamide (40 mL) was added to dissolve the mixture and the temperature was lowered to 0°C. Potassium carbonate (10.70 g, 77.4 mmol) was added portionwise. After complete addition, the mixture was maintained at 0°C and stirred for 1 hour. Methyl iodide (4.82 mL, 77.4 mmol) was added dropwise. After complete addition, the mixture was stirred for 15 minutes before being heated to 25°C. The reaction was allowed to proceed for 2 hours (preferably 2-4 hours). After TLC indicated completion of the reaction, water (50 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain intermediate A-1-2-1-45e (1.20 g, 4.80 mmol, yield: 25.0%).

[1055] 1 H NMR (400MHz, DMSO-d6) δ8.63(dd,J=7.6,1.7Hz,3H),3.93(s,6H),3.17(q,J=7.0Hz,2H),1.11(t,J=7.0Hz,3H).

[1056] Step 5

[1057] A-1-2-1-45e (1.20 g, 4.80 mmol) was added to a dry 50 mL three-necked flask and the atmosphere was replaced with nitrogen. Anhydrous tetrahydrofuran (10 mL) was then added to dissolve the mixture. The temperature was lowered to 0°C, and pyridinium tribromide (1.84 g, 5.76 mmol) was added portionwise. After complete addition, the temperature was raised to 25°C and the reaction was allowed to proceed for 6 h (preferably 6-8 h). After LCMS indicated completion of the reaction, the reaction mixture was filtered and the filtrate was collected. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were separated, washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to afford intermediate A-1-2-1-45f (1.20 g, 3.65 mmol, yield: 76.03%).

[1058] Step 6

[1059] To a dry 50 mL three-necked flask, A-1-2-1-45f (1.20 g, 3.65 mmol), A1-1-1c (1.06 g, 3.65 mmol), potassium carbonate (1.01 g, 7.30 mmol), and tetrabutylammonium iodide (1.35 g, 3.65 mmol) were added in sequence and dissolved in acetone (10 mL). The mixture was stirred at room temperature overnight. After LCMS showed the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were separated, combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain intermediate A-1-2-1-45g (0.98 g, 1.82 mmol, yield: 49.88%).

[1060] MS-ESI:[M+H] + =539.0

[1061] Step 7

[1062] A-1-2-1-45g (0.20g, 0.37mmol) was added to a dry 50mL three-necked flask and dissolved in 4mL of tetrahydrofuran. The temperature was lowered to 0°C, and 2M sodium hydroxide solution (2mL) was added dropwise. The reaction was stirred for 1h (preferably 1-2h). After LCMS showed completion, the reaction was diluted with water (10mL) and quenched by adding 2M hydrochloric acid solution at 0°C, adjusting the pH to 1. The mixture was extracted with ethyl acetate (5mL x 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1, 1:1000 AcOH) to obtain the final product A-1-2-1-45 (42.60mg, 0.08mmol, yield: 21.1%).

[1063] MS-ESI:[MH] - =509.0

[1064] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=1.7Hz,2H),8.63(t,J=1.6Hz,1H),7.64–7.61(m,1H),7.51–7.47(m,1H),7. 39–7.33(m,1H),7.10–7.09(m,1H),6.89–6.82(m,2H),6.33–6.26(m,1H),6.25(s,1H),1.54(d,J=6.8Hz,3H).

[1065] Preparation Example (III) 62 Compound A-1-2-1-105

[1066] first step

[1067] Compound α-9 (500.0 mg, 1.07 mmol) was dissolved in N,N-dimethylformamide (5 mL) in a dry 50 mL three-necked flask. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (308.0 mg, 1.60 mmol) and 1-hydroxybenzotriazole (217.0 mg, 1.60 mmol) were then added and stirred at room temperature for 1 h. Triethylamine (325.0 mg, 3.21 mmol) was then added dropwise. The reaction mixture was allowed to react at room temperature for 2 h, with the reaction progress monitored by TLC. After TLC indicated completion of the reaction, water (10 mL) was added to quench the reaction. Ethyl acetate (10 mL) was then added for extraction and separation. The aqueous phase was further extracted with ethyl acetate (10 mL × 2), and the organic phases were collected and combined, washed with saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The resulting crude product was purified by silica gel column chromatography (PE:EA=3:1) to obtain pure compound A-1-2-1-105 (80.0 mg, 0.153 mmol, yield: 14.3%).

[1068] MS-ESI:[M+H] + =522.2

[1069] 1 H NMR(400MHz,Chloroform-d)δ8.12–8.03(m,2H),7.64(dq,J=7.6,1.5Hz,1H),7. 56(t,J=7.7Hz,1H),7.34–7.23(m,2H),7.13(tt,J=8.3,2.8Hz,1H),6.95(dd,J= 8.8,3.9Hz,1H),6.83–6.71(m,2H),6.17(d,J=1.3Hz,1H),5.61(qd,J=6.9,2.8H z,1H),3.60–3.52(m,2H),3.26(s,2H),1.76(d,J=6.8Hz,3H),1.32–1.14(m,6H).

[1070] Preparation Example (III) 63 Compound A-1-2-1-106

[1071] first step

[1072] A-1-2-1-33c (500.0 mg, 1.38 mmol) and A-1-2-1-106a (579.6 mg, 2.76 mmol) were added to a dry 50 mL three-necked flask. After nitrogen was replaced, tetrakistriphenylphosphine palladium (79.7 mg, 0.05 mmol) was added and dissolved in 5 mL of dioxane solution. Finally, dimethyl dicarbonate (462.6 mg, 3.45 mmol) was added and reacted at 115 ° C for 2 h (preferably 2-4 h). After the reaction was completed, LCMS showed that the reaction was completed, and the mixture was cooled to room temperature, filtered, and the filtrate was collected. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=3:1) to obtain intermediate A-1-2-1-106b (704.0 mg, 1.26 mmol, yield: 93.02%).

[1073] MS-ESI:[M+H] + =511.0

[1074] Step 2

[1075] To a dry 50 mL three-necked flask, add A-1-2-1-106b (712.0 mg, 1.39 mmol) and dissolve in 5 mL of tetrahydrofuran. Cool to 0°C, then add 5 mL of 2M aqueous sodium hydroxide solution and react for 30 min (preferably 0.5-2 h). After TLC indicates completion of the reaction, adjust the pH to 1 with 1 M aqueous hydrochloric acid. Extract with ethyl acetate (5 mL x 3), wash with saturated brine (5 mL x 2), dry over anhydrous sodium sulfate, and spin dry. Purify by silica gel column chromatography (DCM:MeOH = 50:1). Re-isolate on a preparative plate (DCM:MeOH = 10:1) to obtain the desired product A-1-2-1-106 (312.0 mg, 0.628 mmol, yield: 45.1%).

[1076] MS-ESI:[MH] - =495.1

[1077] 1 H NMR(400MHz,Chloroform-d)δ8.86(t,J=2.4Hz,1H),8.30(dt,J=9.0,2.3Hz,1H),7.31–7.23(m,2H),7.19(d,J=8.9Hz,1H),7.12(tt,J= 8.3, 2.4Hz, 1H), 6.94 (dd, J = 8.8, 2.9Hz, 1H), 6.84–6.70 (m, 2H), 6.17 (s, 1H), 5.60 (q, J = 6.8Hz, 1H), 4.16 (s, 3H), 1.77 (d, J = 6.9Hz, 3H).

[1078] Preparation Example (III) 64 Compound A-1-2-1-49

[1079] In a dry 50 mL three-necked flask, compound α-9 (500.0 mg, 1.07 mmol) and potassium carbonate (295.77.0 mg, 2.14 mmol) were dissolved in N,N-dimethylformamide (5 mL) and the suspension was stirred. Methyl iodide (227.81.0 mg, 1.60 mmol) was then added dropwise and allowed to react at room temperature for 2 h. The reaction progress was monitored by TLC. After TLC indicated completion of the reaction, water (10 mL) was added to quench the reaction. Ethyl acetate (10 mL) was then added for extraction and the layers separated. The aqueous phase was further extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The resulting crude product was purified by silica gel column chromatography to afford pure compound A-1-2-1-49 (305.0 mg, 0.634 mmol, yield: 58.3%).

[1080] MS-ESI:[M+H] + =481.0

[1081] 1 H NMR (400MHz, DMSO-d6) δ8.54 (t, J=1.8Hz, 1H), 8.36 (dq, J=7.9, 1.5Hz, 1H), 8. 23(dt,J=7.8,1.4Hz,1H),7.74(t,J=7.8Hz,1H),7.65(dt,J=8.8,2.5Hz,1H),7 .53(ddd,J=8.3,6.1,1.9Hz,1H),7.44–7.36(m,1H),7.09(dd,J=5.7,2.3Hz,1 H),6.96–6.85(m,2H),6.29(t,J=2.0Hz,2H),3.88(s,3H),1.59(d,J=6.6,3H).

[1082] Preparation Example (III) 65 Compound A-1-7-1-2

[1083] Compound α-9 (250.0 mg, 0.54 mmol) was dissolved in dichloroethane (5 mL) in a dry 50 mL three-necked flask. Cyclopropylboronic acid (93.0 mg, 1.08 mmol), bipyridine (169.0 mg, 1.08 mmol), copper acetate (196.0 mg, 1.08 mmol), and sodium carbonate (172.0 mg, 1.62 mmol) were then added sequentially. The mixture was reacted at 80°C for 4 h, and the reaction progress was monitored by TLC. Aft...

Claims

1. A benzopyrone compound represented by formula (I), or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, in, X1 and X2 are each independently selected from an O or NH group; Y is selected from a CR group or N, wherein R is H or a C1-C3 alkyl group; R1 and R1' may be the same or different and are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group; L1 and L3 are each independently selected from -O-, -S-, -NR3-, -CR2R3-, -CR2(R3), -CO-, -SO- or -SO2- groups; L2 is directly linked, -CR2R3-, -CR2(R3)- or -C(R2R3)-, wherein R2 is selected from H or a C1-C4 chain alkyl group; R3 is selected from H or a C1-C4 chain alkyl group; or R2 and R3 in a group of -CR2(R3) together form an oxygen subunit; R4, R5 and R6 are each independently selected from H, halogen, -C-OR8(R9), -CR8(R9), -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SO2R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, olefin, alkynyl, aryl or heteroaryl or aromatic heterocyclic group, wherein R8, R9, R 10 are independently selected from H, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be independently replaced by one or more R 11 Replacement, R 11 R4 and R5 are selected from the group consisting of halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, acyloxy, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic heterocyclic group, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic heterocyclic group can be substituted with one or more halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl, or haloalkyl; or R4 and R5 together form an oxysubyl group; Alternatively, any two or three of R4, R5 and R6 together with the carbon atom connected to L3 form a cyclic group A connected to L3: Wherein, the ring group A is selected from any one of the following ring groups: aromatic ring group, saturated cycloalkyl group or unsaturated cycloalkyl group, single heterocyclic group, condensed heterocyclic group, benzoheterocyclic group, spirocyclic group, bridged ring group and the like. 11 substituted ring groups; W is selected from hydrogen, H, alkyl, -CR 8a R 9a R 10a 、-NR 8a R 9a 、-OR 10a , or can be 1 or more R7 Substituted ring group B1 containing a carbon atom and connected to the benzopyrone ring via the carbon atom: or a ring group B2 containing a nitrogen atom and connected to a benzopyrone ring through the nitrogen atom: Here, R 8a 、R 9a and R 10a Each is independently selected from H, halogen, alkyl, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, acyloxy, amide, sulfonate, sulfonamide, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group; the ring group B1 and the ring group B2 are each independently selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl. wherein R7 is selected from H, halogen, -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SO2R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group, preferably selected from halogen, alkyl, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, acyloxy, sulfonate, sulfonamide, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or aromatic heterocyclic group is independently composed of one or more R 11 Replacement, R8, R9 and R 10 The meaning of R8, R9 and R appears in R4, R5 and R6 10 The meaning is exactly the same; In addition, formula (I) does not contain the following compounds:

2. The compound according to claim 1, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, wherein: X1 is an -O- group, X2 is an -O- group, Y is a -CR- group, and R1 and R1' are both hydrogen; Alternatively, X1 is a -NH- group, X2 is a -O- group, Y is a -CR- group, and R1 and R1' are both hydrogen; Alternatively, X1 is an -O- group, X2 is an -NH- group, Y is a -CR- group, and R1 and R1' are both hydrogen; Alternatively, X1 is an -O- group, X2 is an -O- group, Y is an -N- group, and R1 and R1' are both hydrogen;.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated substance thereof, or a hydrate thereof, or a solvate thereof, wherein -L1-L2-L3- as a whole is any one group selected from the following group: -O-CR2(R3)-CO-, -O-CR2R3-CO-, -CR2(R3)-CR2(R3)-CO-, -NR3-CR2(R3)-CO-, -S-CR2(R3)-CO-, -SO2-CR2(R3)-CO-, -O-CR2(R3)-CR2R3-, -O-CR2(R3)-SO2- and -CR2(R3)-NR3-CO-; in, The R2 is preferably one of H, methyl and ethyl, more preferably methyl; R3 is preferably methyl or H, More preferably, it is H.

4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, wherein -L1-L2-L3- as a whole is any one group selected from the following groups: -O-CH(CH3)-CO-, -O-CR2(R3)-CO-, -CR2R3-CH(CH3)-CO-, -NR3-CH(CH3)-CO-, -S-CH(CH3)-CO-, -SO2-CH(CH3)-CO-, -O-CR2(R3)-CR2(R3)-, and -O-CH(CH3)-SO2- or -CR2(R3)-NR3-CO-.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, or its salt, or its prodrug, or its deuterated product, or its hydrate, or its solvate, wherein the ring group A is selected from any one of the following ring groups: C3-C 12 Cycloalkyl, C3-C 12 Heterocycloalkyl, C5-C 12 Aryl and C5-C 12 Heteroaryl, preferably selected from C3-C 12 cycloalkyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, anthraquinonyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, indolyl, benzimidazolyl, carbazolyl, thiolinyl, quinoline, isoquinolinyl, purinyl, acridinyl, phenazinyl, and phenothiazinyl; More preferably, the ring group A is selected from any one of the following ring groups: Wherein these ring groups A can be substituted by one or more groups selected from halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

6. A compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, wherein R4, R5 and R6 are each independently selected from -CR8(R9), R8 is H, a chain alkyl group, a cyano group or a cycloalkyl group, and R9 is a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group substituted with halogen, cyano group, hydroxyl group, sulfhydryl group, ether group, nitro group, alkoxy group, amino group, amine group, carboxyl group, sulfonic acid group, ester group, acyl group, amide group, sulfonate group or sulfonamide group, and R9 is connected to the carbon atom connected to L3 through an oxygen atom, a nitrogen atom or a carbon atom on the substituent.

7. The compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, wherein the substituted ring group B1 and the substituted ring group B2 are each independently selected from the group consisting of: a halogenated cycloalkyl group, a halogenated heterocycloalkyl group, a halogenated aryl group, and a halogenated heteroaryl group; Further preferably, the substituted ring group B1 and the substituted ring group B2 are each independently 2-chloro-4-fluorophenyl, chlorophenyl, methyl-substituted phenyl, amide-substituted phenyl, amino-substituted phenyl or phenylalkyl.

8. The compound according to any one of claims 1 to 7, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate, wherein: The ring group B1 is C5-C 10 Aryl, C5-C 10 Heteroaryl, C3-C 10 Cycloalkyl or C3-C 10 Heterocycloalkyl.

9. The compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated substance thereof, or a hydrate thereof, or a solvate thereof, wherein: The compound of formula (I) is selected from the compounds represented by any of the following structural formulas: Wherein, the R7 is preferably F, Cl, Br, I, OH, OR2, C 1-3 Any one or more of alkyl, sulfonic acid, nitro, amino, and amine; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy; wherein R2 is the same as defined in claim 1; n is an integer of 0-5; Wherein R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-3 Any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, or an amine group; R 11 Preferably, F, Cl, Br, I, C 1-4 Alkoxy, acyl, or C 1-3 Alkyl, sulfonic acid, nitro, amino, cyano, amine, -C 0-4 Alkyl-COOH, ester group, acyloxy group, ether group, amide group, aminoacyl group, cycloalkyl substituted aminoacyl group, or aralkyl substituted aminoacyl group, carboxyl substituted C 1-3 Alkoxy, carboxyl substituted amino, cycloalkyl substituted C 1-3 Alkoxy, acyloxy-containing C 3-5 Cycloalkyl, or Any one or more groups in 11 The benzene ring connected thereto may form a benzene ring and nitrogen heterocyclic or oxygen heterocyclic structure; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkyloxy; R 2a is selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy-substituted C1-C4 alkyl, C1-C4 alkyl-substituted formyl; n is an integer of 0-5; Among them, R 11 Preferably -C 0-4 Alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; in, Preferably C 1-4 Alkyl, C 1-4 Alkylphenyl, more preferably methyl, isobutyl or benzyl; R 11 Preferably -C 0-4 Alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, R 10 Preferably C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or hydroxy substituted C 1-4 Alkoxy, R 11 Preferably -C0-C4 alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; wherein R8 and R9 are independently selected from hydrogen or C 1-4 Alkyl; R 11 Preferably -C0-C4 alkyl-COOH; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; The cyclic group, ie, the cyclic group B1, is preferably selected from: 3-12 cycloalkyl, four to ten-membered heterocyclic group, or five to ten-membered aryl group; R 11 Preferably, it is -C0-C4 alkyl-COOH; the heterocyclic group is further preferably any one of furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, indolyl, benzimidazolyl, carbazolyl, thiolinyl, quinoline, isoquinolyl, purinyl, acridinyl, phenazinyl and phenothiazinyl; R1 and R1' are preferably hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; the ring group B1 is optionally substituted by 1 or 2 or more hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-substituted hydroxy, amino, amine, or unsubstituted; The cyclic group B2 is preferably selected from: 3-12 cycloalkyl, four to ten-membered heterocyclic group, or five to ten-membered aryl group; R 11 Preferably -C 0-4 alkylcarboxyl; the heterocyclic group is further preferably any one of furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, indolyl, benzimidazolyl, carbazolyl, thiolinyl, quinolyl, isoquinolyl, purinyl, acridinyl, phenazinyl and phenothiazinyl; R1 and R1' are preferably hydrogen; the ring group B2 is optionally replaced by one or more hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-substituted hydroxyl, amino, amine, or unsubstituted; Wherein R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 The benzene ring in the structural formula is substituted by any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-3 Alkoxy or alkyl, cycloalkyl, sulfonic acid alkyl, nitro, amino, cyano, amine, -C 0-4 Any one or more of alkyl-carboxyl, ester, acyloxy, and ether groups; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl; The R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 The benzene ring in the structural formula is substituted by any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group or an amine group, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C 0-4 Any one or more of alkyl-carboxyl groups; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl; Wherein, the R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 The benzene ring in the structural formula is substituted by any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group or an amine group, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, hydroxyl, hydroxyl substituted C 1-6 Alkyl, nitro, amino, cyano, amine or -C 0-4 Any one or more of alkylcarboxyl groups; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl; Wherein, the R7 is preferably F, Cl, Br, I, OH, OR 2a 、C 1-6 Alkyl, C 3-10 The benzene ring in the structural formula is substituted by any one or more of cycloalkyl, sulfonic acid, nitro, amino or amine, more preferably chlorine and fluorine; R 11 Preferably, it is substituted with F, Cl, Br, I, oxo, C 1-3 Alkoxy or alkyl, cycloalkyl, sulfonic acid, hydroxy, nitro, amino, cyano, amine, -C 0-4 Any one or more groups of alkylcarboxyl; n is an integer of 0-5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl; Among them, wherein, the R7 is preferably F, Cl, Br, I, OH, OR 2a or any one or more of C1-3 alkyl, sulfonic acid, nitro, amino, and amine, more preferably chlorine and fluorine together replace the benzene ring in the structural formula; R 11 It can be hydrogen or replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, hydroxyl, nitro, amino, cyano, amine, -C 0-4 Any one or more of alkylcarboxyl groups; n is an integer from 0 to 5; R 2a Selected from C1-C4 alkyl, C1-C4 alkenyl, C1-C2 alkoxy substituted C1-C4 alkyl, C1-C4 alkyl substituted formyl; Wherein, the ring group A can be selected from halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, amine, -C 0-4 Alkyl-carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl and heterocycloalkyl substituted or unsubstituted aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; wherein the cycloalkyl is preferably C 3-6 The heterocycloalkyl group is preferably oxirane, oxetane, aziridine, azetidine any one of thietanyl and thietanyl; heteroaryl includes a five-membered heteroaryl group such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyrazolyl, or an oxygen-containing imidazolyl or pyrazolyl, a six-membered heteroaryl such as a pyridyl, pyrimidinyl, pyranyl, pyridazinyl, pyrazinyl, a group formed by pyrone or pyranyl, a benzoheterocyclic group such as benzofuranyl, benzothienyl, benzopyrrolyl, indolyl, quinolyl, isoquinolyl, benzopyranyl, a group formed by benzo-γ-pyrone, a heterocyclic and heterocyclic group such as purinyl; W is preferably 2-chloro-4-fluoro substituted phenyl, or 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Wherein, the ring group A is preferably a condensed ring or an aromatic heterocyclic group, more preferably a benzoheterocyclic group is a benzofuranyl, benzothienyl, benzopyrrolyl, a benzoheterocyclic group such as an indolyl, quinolyl, isoquinolyl, benzopyranyl, or a group formed by benzo-γ-pyrone, W is preferably a 2-chloro-4-fluoro substituted phenyl or a 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Wherein, the ring group A is preferably selected from a spiro ring or a bridged ring group; W is preferably 2-chloro-4-fluoro substituted benzene or 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Wherein, the ring group A is preferably phenyl, halogenated phenyl, -C 0-4 Alkylcarboxyl substituted phenyl, more preferably phenyl or carboxyl substituted phenyl; W is preferably 2-chloro-4-fluoro substituted benzene or 2-methylphenyl, R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C 0-4 Any one or more of alkyl-carboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C 0-4 Any one or more of alkyl-carboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C 0-4 Any one or more of alkyl-carboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or -C 0-4 Any one or more of the alkylcarboxyl groups as R 11 Substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; wherein R7 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy; n is an integer of 0-5; R2, R3 are independently selected from hydrogen, C 1-4 Alkyl; R4 and R5 together form an oxygen subunit; Wherein, R2 and R3 are each independently preferably hydrogen, C 1-6 or one group of R2, R3 together to form an oxygen subunit, the other group of R2, R3 are independently preferably hydrogen, C 1-6 Alkyl; R1 and R1' are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, the ring group A is preferably substituted by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 A phenyl group which is substituted or unsubstituted with any one or more of cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or carboxyl groups; further, the ring group A is preferably replaced by R as a carboxyl group. 11 substituted phenyl; W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are preferably hydrogen; Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C 0-4 Any one or more of the alkylcarboxyl groups as R 11 Substituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; The ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C 0-4 any one or more of the alkyl carboxyl groups substituted or unsubstituted phenyl; further ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; Among them, the ring group A is preferably replaced by F, Cl, Br, I, oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C 0-4 A phenyl group substituted by any one or more of the alkylcarboxyl groups; further, the ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl; as well as Among them, the ring group A is preferably F, Cl, Br, I, Oxo, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, sulfonic acid, nitro, amino, cyano, amine or C 0-4 A phenyl group substituted by any one or more of the alkylcarboxyl groups; further, the ring group A is preferably R as a carboxyl group 11 W is preferably 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl, R1 and R1 'are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylphenyl.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated substance thereof, or a hydrate thereof, or a solvate thereof; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate; or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 10 in the preparation of a POLRMT inhibitor drug.

12. Use of the compound according to any one of claims 1 to 9, or its stereoisomer, or its salt, or its prodrug, or its deuterated form, or its hydrate, or its solvate; or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 3 in the preparation of a medicament for a disease associated with abnormally high expression of POLRMT oxidative phosphorylation.

13. The use according to claim 12, characterized in that The disease is cancer; preferably, the cancer is melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, multiple myeloma, breast cancer, glioma, glioblastoma, cervical cancer, kidney cancer, colorectal cancer or ovarian cancer.

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