Fluorine-containing compounds and their anti-cancer medical uses

Abstract

The present invention provides fluorine-containing compounds as shown in Formula II / III and their anti-cancer medical uses. [Formula 1] JPEG2022533346000072.jpg86170

Description

[Technical Field]

[0001] The present invention belongs to the field of research and development of anti-cancer compounds, and relates to a series of AKR1C3 enzyme-activated DNA alkylating agents obtained by further research and development of the compounds disclosed in PCT / US2016 / 021581 (WO 2016 / 145092) (corresponding to Chinese Patent Application No. 2016800150788 (Chinese Patent Application Publication No. 107530556)). [Background technology]

[0002] The contents of Chinese Patent Application No. 201910392606.7 filed by the applicant on May 13, 2019 (titled "Fluorine-containing compounds and their anti-cancer medical uses") and Chinese Patent Application No. 201911324466.6 filed by the applicant on December 20, 2019 (titled "Fluorine-containing compounds and their anti-cancer medical uses") are hereby incorporated by reference into this specification.

[0003] All of the compounds in the DNA alkylating anticancer drugs developed by our company that target overexpressed aldo-keto reductase 1C3 (AKR1C3) (DNA alkylating agents in PCT / US2016 / 021581 (International Publication No. 2016 / 145092) (corresponding to Chinese Patent Application No. 2016800150788 (Chinese Patent Application Publication No. 107530556)) are yellow oils. However, because these compounds are not solid, subsequent formulation research and development poses the following challenges:

[0004] Separation and purification are complex and expensive. Because these compounds are oils, they cannot be purified by recrystallization or slurry purification, which are highly efficient and low-cost, but can only be purified by column chromatography. This requires complex operations, which increases the cost of preparing active pharmaceutical ingredients.

[0005] This formulation is inconvenient and has poor stability. Oils cannot be conveniently transported / measured. Furthermore, it is impossible or inconvenient to develop and diversify the formulation of oils. Generally, they can only be developed as lyophilized powder for injection or as an injectable solution for administration, which limits the versatility of administration methods and makes them expensive. In addition, some patients are not well suited to injection of lyophilized powder or injectable solution. Summary of the Invention

[0006] To solve the above technical problems, the present invention designs and synthesizes a series of fluorine-containing compounds by structurally modifying the compounds disclosed in PCT / US2016 / 021581 (International Publication No. 2016 / 145092) (corresponding to Chinese Patent Application No. 2016800150788 (Chinese Patent Application Publication No. 107530556) with the title "DNA Alkylating Agents").

[0007] Therefore, the contents of PCT / US2016 / 021581 (International Publication No. 2016 / 145092) (corresponding to Chinese Patent Application No. 2016800150788 (Chinese Patent Application Publication No. 107530556)) are hereby incorporated by reference as if they were incorporated herein by reference. Where a definition or concept provided herein differs from a definition or concept provided by the aforementioned application documents, the definition or concept provided herein shall prevail. Where a concept or definition provided herein is not expressly defined or limited, it shall be defined in accordance with the aforementioned application documents. Other concepts or definitions not expressly defined or limited in either the present specification or the aforementioned application documents shall be interpreted in accordance with, inter alia, organic chemistry and medicinal chemistry textbooks and handbooks.

[0008] Compound 3424, disclosed in PCT / US2016 / 021581, PCT / US2016 / 025665, and PCT / US2016 / 062114, has been internationally proven as an original, highly tumor-selective small molecule targeted therapeutic agent, demonstrating excellent anticancer effects in various preclinical cell and animal models. As a specific substrate for the aldo-keto reductase AKR1C3, these compounds can be rapidly and effectively reduced only in cancer cells that overexpress AKR1C3, thereby releasing cytotoxins and resulting in highly selective cancer cell killing.

[0009] Literature (Literature 1: Richard B. Lock, Kathryn Evans, Raymond Yung, Tara Pritchard, Beverly A. Teicher, JianXin Duan, Yuelong Guo, Stephen W.Erickson, Malcolm A. Smith. The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound In Vivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia(T-ALL); a Pediatric Preclinical Testing Consortiu LCM Study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia(PA): AACR; Mol Cancer Ther 2018; 17 (1Suppl): Abstractnr LB-B16; Literature 2: Evans K, Duan J, Pritchard T, Jones CD, McDermottL, Gu Z, Toscan CE, El-ZeinN, MayohC, Erickson SW, Guo Y, Meng F, Jung D, Rathi KS, Roberts KG, Mullighan CG, Shia CS, Pearce T, Teicher BA, Smith MA, Lock RB. OBI-3424, a novel AKR1C3-activated prodrug, exhibits potent efficacy against preclinical models of T-ALL. Clin Cancer Res. 2019 Apr 23. pii:clin canres.0551.2019.doi:10.1158 / 1078-0432.As shown in CCR-19-0551, the compound AST-3424 (OBI-3424) (i.e., the S-isomer of compound 2870) showed favorable efficacy against cancers such as leukemia and lung cancer in phase I clinical trials.

[0010] Since all of the compounds in this series are oils which have many drawbacks, such as not being able to be conveniently stored, transported, or metered, it is necessary to develop similar compounds which are solids at room temperature.

[0011] The research group considered using a solution of converting oil into a solid salt by salt formation. However, experiments showed that the desired salt could not be obtained from the salt formation reaction of inorganic acids such as sulfuric acid / hydrochloric acid with a nitrogen-containing three-membered ring, and that the nitrogen-containing three-membered ring of the compound disclosed in the Chinese Patent Publication No. 107530556 formed a ring-opening by-product under acidic conditions. The results of numerous experiments showed that the above-mentioned traditional method was not feasible.

[0012] Based on their experience and experimental results, the research group creatively introduced fluorine-containing groups, such as specific trifluoromethyl groups, fluorine-substituted aryl groups, or heteroaryl groups, into specific positions in the structure of the above compounds (between the nitrobenzene ring and the phosphate amine group). After this modification, all of the resulting compounds were found to be solids (including solids and waxes).

[0013] Further in vitro experiments have shown that these compounds have strong inhibitory activity on cancer cell proliferation in vitro.Furthermore, the combination of the compounds with AKR1C3 inhibitor TH3021 has shown that the inhibitory activity is reduced.This demonstrates that by introducing specific fluorine-containing groups into specific positions, the compounds can be made solid, which makes it easier to prepare formulations, and facilitates measurement and storage, and also provides AKR1C3 enzyme-activated DNA alkylating agents.

[0014] A compound of formula I, II or III, or a pharmaceutically acceptable salt or solvate thereof [ka] And, R1 is C6-C 10 aryl or Z-substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 membered heteroaryl or Z-substituted heteroaryl, or 7-15 membered fused ring, or Z-substituted fused ring; R2 is hydrogen, halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs , OLCMS, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4- to 15-membered heterocycle or Z-substituted heterocycle, 5- to 15-membered heteroaryl or Z-substituted heteroaryl, ether having 1 to 6 carbon atoms or Z-substituted alkoxy having 1 to 6 carbon atoms, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6 , -OCOO-R 6 , -COOR 6、 -NR 6 COR 7 , -OCOR 6 , -NR 6 SO2R 7 or -NR 6 SO2NR 6 R 7 or R 2 forms, together with the group R1 to which it is attached, a 7- to 15-membered fused ring or a Z-substituted fused ring; R3 is hydrogen, halogen, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OLCMS, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4- to 15-membered heterocycle or Z-substituted heterocycle, 5- to 15-membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6 , -OCO-R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , or -NR 6 SO2R 7 and; R4 and R5 each independently represent a hydrogen atom, a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs , OLCMS, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4- to 15-membered heterocycle or Z-substituted heterocycle, 5- to 15-membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 6 , -OCOR 6 or -NR 6 SO2R 7or R4 and R5 together with the atoms of the benzene ring to which they are attached form a 7- to 15-membered fused ring or a Z-substituted fused ring; R 6 and R 7 are each independently hydrogen, cyano or isocyano, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 aryl or Z-substituted aryl, 4- to 15-membered heterocycle or Z-substituted heterocycle, 5- to 15-membered heteroaryl or Z-substituted heteroaryl, or C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, or R 6 and R 7 together with the atom to which they are attached form a 5- to 7-membered heterocyclyl or Z-substituted 5- to 7-membered heterocyclyl; R8 and R 10 are each independently hydrogen, deuterium, aryl or Z-substituted aryl, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, R8 and R 10 at least one of is hydrogen or deuterium; R9 is a substituted C6-C 10 aryl, a substituted 4-15 membered heterocycle substituted with at least one fluorine atom or nitro group, or a substituted 5-15 membered heteroaryl substituted with at least one fluorine atom or nitro group; The substituent Z is a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OLCMS, C1-C3 alkyl or substituted alkyl, C1-C3 alkoxy or substituted alkoxy, C2-C3 alkenyl or substituted alkenyl, C2-C3 alkynyl or substituted alkynyl, C3-C8 cycloalkyl or substituted cycloalkyl, aromatic ring, heterocyclic ring, aromatic heterocyclic ring and fused ring or substituted aromatic ring, heterocyclic ring, or aromatic heterocyclic ring and fused ring, and the substitution pattern is mono- or di-substituted; Substitution C6-C in R9 10 Substituents in the aryl, substituted 4- to 15-membered heterocycle, or substituted 5- to 15-membered heteroaryl are halogen atoms, nitro, cyano or isocyano, hydroxy, amino, C1-C3 alkyl or alkoxy, alkenyl, alkynyl, cycloalkyl or benzene ring, substituted benzene ring, C1-C3 alkoxy, or halogen atom-substituted alkoxy.

[0015] The substitution has a broad meaning and can be single (only one H on a C atom in the benzene ring can be substituted) or polysubstituted (multiple substitutions on a specific C atom, i.e., di- and tri-substitutions (e.g., gem-difluoromethyl and gem-trifluoromethyl) or separate substitutions on different C atoms in the ring (e.g., perfluorobenzene).

[0016] Heterocycles and heteroaryls include 3-, 4-, 5-, 6-, and 7-membered rings, examples of which are as follows:

[0017] The three-membered rings include ethylene oxide, azirane, and ethylene sulfide; the four-membered rings include azetidine, oxaethidine, thiaethidine, and ethidine; and the five-membered rings include pyrrolidine, pyrroline, 1-pyrroline, 3-pyrroline, 2-pyrroline, pyrrole, pyrazolidine, 2-pyrazoline, imidazole, pyrazole, furan, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, thiophene, sulfolane, phosphole, oxazole, 1,2,3 The six-membered rings include piperidine, tetrahydropyran, tetrahydrothiopyran, pyridine, pyran, thiopyran, dihydropyridine, morpholine, piperazine, pyridazine, pyrazine, 1,3,5-triazine, and 1,3,5-trithiane; the seven-membered rings include azepane (azacycloheptane), oxaheptane, thiaheptane, azepine, oxepine, and thiepine.

[0018] The fused ring is defined as the fusion of the heterocycle and heteroaryl, or the fusion of the heterocycle and heteroaryl with a cycloalkane structure. The fusion can be via a single bond or a bond sharing one, two, or three atoms (i.e., spirocyclic, fused, or bridged rings). Common fused ring structures include naphthalene, quinoline, indole, isoindole, isoquinoline, cinnoline, quinoxaline, biphenyl, coumarin, fluorene, diphenylcarane, carbazole, anthracene, acridine, thiophenazine, adamantane, azulene, phenanthrene, anthraquinone, flavonoid, and isoflavone.

[0019] The above compounds also include compounds substituted with isotopes Z, and a typical pattern of substitution with Z is that a hydrogen halogen atom H is substituted with a deuterium atom deuterium (D).

[0020] In particular, the deuterium substituted position is on Ph-C* of Formulas II and III as shown in the following formula: [ka] .

[0021] In addition, in the above compounds, R1 is phenyl or Z-substituted phenyl, a 6-membered nitrogen-containing heterocycle or Z-substituted heterocycle, a 6-membered nitrogen-containing heteroaryl or Z-substituted heteroaryl, or a 9- to 14-membered fused ring or Z-substituted fused ring; R2 is hydrogen, a halogen atom, cyano or isocyano, hydroxy, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4- to 15-membered nitrogen-containing heterocycle or Z-substituted nitrogen-containing heterocycle, 5- to 15-membered nitrogen-containing heteroaryl or substituted nitrogen-containing heteroaryl, C1-C6 alkoxy or fluorine-substituted C1-C6 alkoxy, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , -NR 6 SO2R 7 or -NR 6 SO2NR 6 R 7 and; R 6 and R 7 are each independently C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 aryl or Z-substituted aryl, 4- to 15-membered heterocycle or Z-substituted heterocycle, 5- to 15-membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or fluorine-substituted C1-C6 alkoxy, or R 6 and R7 are bonded together with the nitrogen atom to form a 5- to 7-membered heterocyclic group or a Z-substituted 5- to 7-membered heterocyclic group.

[0022] In addition, in the above compound, R1 is phenyl or Z-substituted phenyl, a 6-membered nitrogen-containing heterocycle or Z-substituted heterocycle, a 6-membered nitrogen-containing heteroaryl or Z-substituted heteroaryl, or a 9-14 membered fused ring or Z-substituted fused ring; R2 is hydrogen, a halogen atom, cyano or isocyano, hydroxy, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4- to 15-membered nitrogen-containing heterocycle or Z-substituted nitrogen-containing heterocycle, 5- to 15-membered nitrogen-containing heteroaryl or substituted nitrogen-containing heteroaryl, C1-C6 alkoxy or fluorine-substituted C1-C6 alkoxy, -CONR 6 R 7 , -SO2R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 6 , -OCOR 6 , -NR 6 SO2R 6 or -NR 6 SO2NR 6 R 7 and; R 6 and R 7 are each independently C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 aryl or Z-substituted aryl, 4- to 15-membered heterocycle or Z-substituted heterocycle, 5- to 15-membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or fluorine-substituted C1-C6 alkoxy, or R 6 and R 7form, together with the nitrogen atom to which they are attached, a 5- to 7-membered heterocyclic group or a Z-substituted 5- to 7-membered heterocyclic group.

[0023] In addition, in the above compound, R1 is phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran, pyridine, furan, pyran, thiopyran, thiazole, dihydropyridine, morpholine, piperazine, pyridazine, pyrazine, 1,3,5-triazine, naphthalene, quinine, benzothiazole, benzothiopyran, benzofuran, benzimidazole, indole, imidazopyridine or Z-substituted phenyl, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran, pyridine, furan, pyran, thiopyran, thiazole, dihydropyridine, morpholine, piperazine, pyridazine, pyrazine, 1,3,5-triazine, naphthalene, quinine, benzothiazole, benzothiopyran, benzofuran, benzimidazole, indole, or imidazopyridine; R2 is -CON(CH3)2, -SO2CH3, -OCOO-CH3, -COOCH3, -NHCOCH3, -NMeCOCH3, -NHCOCF3, -OCOCH3, -NHSO2CH3, -NMeSO2CH3, -NHSO2CF3, -NMeSO2CF3, -CF3, F, Cl, Me, benzene, fluorobenzene, chlorobenzene, -OCF3, pyridyl, fluoropyridyl, chloropyridyl, furyl, thiopyran, thiazole, -CONMePh, C5-C6 cycloalkyl or F-substituted C5-C6 cycloalkyl; [ka] is. The wavy line represents a chemical bond, to the left of which connects another atom, any atom in the ring, at the position where the connected atom is located.

[0024] Also in formula I, R2 is H.

[0025] Additionally, R3, R4, and R5 are each independently H.

[0026] Also, R8 and R 10 are each independently H.

[0027] Also, R9 is monofluoro, fluorochloro, difluoro, or tetrafluoro substituted phenyl. Furthermore, the R9 [ka] is. Note that the solid lines cut by the wavy lines above represent chemical bonds, one end of which connects any atom in the ring to another atom, or connects atoms to form any stereochemistry (E / Z or R / S).

[0028] Also, the compound is selected from the following compounds: [ka] [ka] [ka]

[0029] In addition, the salts of the above compounds may be basic salts or acid salts.

[0030] The compounds described herein may also include salt forms of Formula II or Formula III. That is, the present invention provides pharmaceutically acceptable salts of the compounds described herein. The salts may be basic salts, including salts of the compounds with inorganic bases (such as alkali metal hydroxides and alkaline earth metal hydroxides) or organic bases (such as monoethanolamine, diethanolamine, or triethanolamine). Alternatively, the salts may be acidic salts, including salts of the compounds with inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid) or organic acids (such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, and citric acid). The selection and preparation of acceptable salts, solvates, and the like of compounds are well known in the art.

[0031] In addition, in the above compounds, the solvates include hydrates, alcoholates, and the like.

[0032] The compounds described herein may also be used in the form of solvates. That is, the present invention provides pharmaceutically acceptable solvates of the compounds of Formula II or III shown herein. The solvates include hydrates, alcoholates, etc., and alcoholates include ethanolates.

[0033] The present invention also provides the use of a compound of Formula II or Formula III in the manufacture of a medicament for treating tumors and cancer.

[0034] The present invention also provides a medicament or formulation comprising a compound of Formula II or Formula III for use in treating tumors and cancer diseases in a patient.

[0035] The tumors and cancers include lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, bone cell carcinoma, epithelial carcinoma, bile duct carcinoma, choroidal carcinoma, embryonal carcinoma, seminoma, Wilms' tumor, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemoblastoma, vocal cord nerve tumor, and the like. tumor, meningioma, neuroblastoma, optic neuroblastoma, retinoblastoma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, fibroadenoma, fibrochondroma, fibrocyst, fibromyxoma, fibroostoma, fibromyxoid sarcoma, fibropapilloma, myxosarcoma, myxocyst, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxoadenoma, myxoblastoma, liposarcoma, lipoma, lipoadenoma, lipoblastoma, lipochondroma, lipofibroma, lipoangioma, myxolipoma, chondrosarcoma, chondroma, chondromyxoid fibroma, chordoma, choriocarcinoma, chorioepithelioma , choriocarcinoma, osteosarcoma, osteoblastoma, osteochondrofibroma, osteochondroma, osteochondroma, bone cyst, bone dentinoma, osteofibroma, osteofibrosarcoma, angiosarcoma, hemangioma, angiolipoma, hemangiochondroma, hemangioblastoma, angiokeratosis, hemangioglioma, hemangioendothelioma, angiofibroma, angiomyoma, angiolipoma, angiolymphangioma, angiolipoleiomyoma, angiomyolipoma, angiomyoneuroma, angiomyxoma, hemangioblastoma, lymphangiosarcoma, lymphogranuloma, lymphangiocarcinoma, lymphoma, lymphoma, lymphangiofibroma, lymphoma The cancer or tumor may be a cancer or tumor of the central nervous system, preferably a cancer or tumor of the central nervous system, including a leiomyoma, lymphoepithelioma, lymphoblastoma, endothelioma, endodermal tumor, synovium, synovial sarcoma, mesothelioma, connective tissue tumor, Ewing's tumor, leiomyoma, leiomyosarcoma, leiomyomatous asthma, leiomyofibrilloma, rhabdomyosarcoma, acute lymphocytic leukemia, acute myeloid leukemia, anemia of chronic disease, polycythemia, lymphoma, endometrial cancer, glioma, colorectal cancer, thyroid cancer, urothelial carcinoma or multiple myeloma.

[0036] Experiments have confirmed that some compounds of the present invention have relatively good cell membrane permeability, and may be able to pass through the blood-brain barrier relatively well and enter the central nervous system.Therefore, these compounds can more easily act on the tumors and cancers in the cranial cavity of the brain and the spinal cord of the central nervous system.

[0037] The present invention provides a method for treating cancer or tumors, comprising the steps of applying the pharmaceutical or preparation and determining the AKR1C3 reductase content or expression level of cancer cells in a patient using an AKR1C3 antibody, and administering the pharmaceutical or preparation to the patient if the measured AKR1C3 reductase content or expression level is equal to or greater than a predetermined value.

[0038] The AKR1C3 reductase content can be determined using methods including ELISA and ICH methods.

[0039] Liquid samples such as plasma and blood can be directly detected using commercially available human aldo-keto reductase 1c3 (AKR1C3) ELISA assay kits. Other samples are detected after processing.

[0040] Immunohistochemistry (ICH) methods are suitable for detecting solid tumor samples.

[0041] The present invention provides a method for treating cancer or tumors, comprising the steps of applying the pharmaceutical or formulation and adjusting the AKR1C3 reductase content, and administering the pharmaceutical or formulation to a patient when the AKR1C3 reductase content has been adjusted to be equal to or greater than a predetermined value.

[0042] Research has shown that the content of AKR1C3 enzyme in tumor tissues of head and neck cancer patients increases after radiation therapy. Therefore, the expression level of AKR1C3 enzyme can be increased by irradiating tumor tissues with radioactive rays used in radiation therapy. Radiation includes alpha rays, beta rays, and gamma rays generated by radioisotopes, as well as X-rays, electron beams, proton beams, and other particle beams generated by various X-ray therapy machines or accelerators.

[0043] This method is mainly for the situation where the content of AKR1C3 reductase in the patient is relatively low, and is carried out by adjusting the content level of AKR1C3 reductase in the patient to an appropriate level through a specific adjustment treatment / administration process.

[0044] The present invention also provides schemes for the preparation of the following compounds: Compounds V and VI are subjected to a condensation reaction to close the ring and provide compounds of formula II and III above: [ka] wherein Y is a leaving group and the remaining variables are defined as in the compounds of formulas II and III.

[0045] In addition, in the above-mentioned preparation method, Y is Cl, Br, I, - OTs , -ONO2, -OLCMS or -OTf, Although organic amines are used as acid-binding agents in the condensation reaction, it is clear that inorganic bases can also be used as acid-binding agents, including alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and bicarbonates.

[0046] In the above preparation method, Y is Br, and N,N-diisopropylethylamine (DIPEA) is used as an acid binder and silver oxide (Ag2O) is used as a catalyst in the condensation reaction.

[0047] The present invention also provides the following preparation scheme: [ka] Reacting a compound of formula VII with R2R1OH to form a compound of formula II, and reacting a compound of formula VIII with R2R1OH to form a compound of formula III, or [ka] with YR1R2 to produce a compound of formula II and a compound of formula III, where Y is a leaving group, M is H or an alkali metal, and the remaining substituents are as defined in the scheme above.

[0048] In the above preparation method, Y is F, Cl, Br, I, - OTs , -ONO2, -OLCMS or -OTf, and a base is added during the reaction.

[0049] The base here may be an organic base (including organic amines) or an inorganic base (MOH, where M is an alkali metal or alkaline earth metal): alkali metal or alkaline earth metal carbonates, bicarbonates, sulfites, and bisulfites, alkali metal or alkaline earth metal hydroxides and hydrides, or other dehydrogenating reagents: alkali metal alkylates (RM, where R is an alkyl group and M is an alkali metal), and alkali metal alcoholates (MOR, where R is a hydrocarbyl group and M is an alkali metal).

[0050] In the medicaments or formulations described herein, the prepared medicament comprises a particular dosage range of the compound or a salt or solvate thereof, and / or the prepared medicament is in a particular dosage form and is administered using a particular mode of administration.

[0051] In the use described herein, the prepared medicament may also contain pharmaceutically acceptable adjuvants or excipients.The medicament may be in any dosage form suitable for clinical administration, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated tablets, granules, dry powders, oral solutions, injection needles, lyophilized powders for injection, or infusion solutions.According to specific dosage forms and administration modes, the pharmaceutically acceptable adjuvants or excipients in the medicament may include one or more of diluents, solubilizers, disintegrants, suspensions, lubricants, adhesives, fillers, flavorings, sweeteners, antioxidants, surfactants, preservatives, packaging agents, and pigments.

[0052] Preferably, the patient is a mammal, more preferably a human. DETAILED DESCRIPTION OF THE INVENTION

[0053] The present invention will be further described in detail below with reference to examples. Those skilled in the art will understand that these examples are only used to illustrate the present invention and do not limit the scope of the present invention in any way.

[0054] Unless otherwise specified, all experimental methods in the following examples are conventional methods. All raw materials such as medicines and reagents used in the following examples are commercially available products unless otherwise specified.

[0055] "Patient" and "subject" are used interchangeably to refer to a mammal in need of treatment for cancer. Generally, a patient is a human. Generally, a patient is a human who has been diagnosed with cancer. In certain embodiments, a "patient" or "subject" may refer to a non-human mammal used in screening, characterizing, and evaluating drugs and treatments, such as a non-human primate, dog, cat, rabbit, pig, mouse, or rat.

[0056] A "prodrug" refers to a compound that is metabolized or otherwise converted into a biologically active or more active compound (or drug) with respect to at least one property after administration. A prodrug is chemically modified to render it less active or inactive relative to the drug, such that the corresponding drug is produced by metabolism or other biological processes after the prodrug is administered. A prodrug may have altered metabolic stability or transport properties, fewer side effects or lower toxicity, or an improved flavor relative to an active drug (see, e.g., Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may be synthesized using reactants other than the corresponding drug.

[0057] "Solid tumor" refers to solid tumors including, but not limited to, metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcomas).

[0058] A "therapeutically effective amount" of a drug refers to an amount of drug that, when administered to a cancer patient, will produce the intended therapeutic effect (e.g., reduction, remission, alleviation, or elimination of one or more symptoms of cancer in the patient). The therapeutic effect does not necessarily occur in a single administration, but may occur only after a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0059] "Treating" a patient's condition refers to taking steps to achieve beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, relief or amelioration of one or more symptoms of cancer; reduction in the extent of disease; delay or slowing of disease progression; relief, palliation, or stabilization of the disease state; or other beneficial results. Treatment of cancer may in some cases result in a partial response or stable disease.

[0060] "Tumor cell" refers to a tumor cell of an appropriate species (eg, a mammal such as a mouse, dog, cat, horse, or human).

[0061] It should be noted that the above description of the embodiments of the present invention does not limit the present invention. Those skilled in the art can make various modifications and changes according to the present invention, and any modifications and changes within the spirit of the present invention are intended to be included in the scope of the claims attached to the present invention.

[0062] 1. Test data on H460 cancer cell inhibition In vitro human tumor cell line cytotoxicity assay In vitro proliferation data for the H460 non-small cell lung cancer human tumor cell line is reported in the compound table below.

[0063] I C 50 Values ​​are reported in nanomolar and are obtained by 2 hours of compound exposure at various concentrations followed by a wash step, addition of fresh medium and proliferation and cell viability staining compared to a medium-only treated control.

[0064] Specifically, exponentially growing cells were plated at 4 × 10 cells per well in a 96-well plate. 3Cells were seeded at a density of 0.1 μg / well and incubated at 37°C, 5% CO2, 95% air, and 100% relative humidity for 24 hours before adding test compounds. Compounds were solubilized in 100% DMSO at 200x the desired final test concentration. At the time of drug addition, compounds were further diluted in complete medium to 4x the desired final concentration. A 50 μL aliquot of compound at the specified concentration was added to microtiter wells already containing 150 μL of medium to obtain the reported final drug concentration. After drug addition, the plates were incubated for an additional 2 hours at 37°C, 5% CO2, 95% air, and 100% relative humidity, then the drug was washed off, fresh medium was added, and the plates were incubated for 70 hours at 37°C, 5% CO2, 95% air, and 100% relative humidity. At the end of this incubation, viable cells were quantified using the AlamarBlue assay. 50% (IC 50 The drug concentrations that resulted in growth inhibition of the β-glucanase 1 (β-glucanase 1) were calculated using computer software. The results are listed in Tables 1A-H below.

[0065] Similarly, to further verify that the compounds are activated by human AKR1C3 (aldosterone reductase family 1 member C3), the effects of some compounds on the proliferation of H460 cancer cells were tested in the presence of a specific AKR1C3 enzyme inhibitor (3 micromolar concentration). The inhibitor-added compound solution was added to the cell culture 2 hours before treatment with the compound. The inhibitor used was compound 36, i.e., [ka] It was.

[0066] [Table 1A] [Table 1B] [Table 1C] [Table 1D] [Table 1E] [Table 1F] [Table 1G] [Table 1H]

[0067] The above experiments demonstrated that human AKR1C3 promotes the activation of the above compounds, and at the same time demonstrated that this series of compounds has the activity of inhibiting the proliferation of cancer cells.

[0068] 2. Example of compound synthesis THF is tetrahydrofuran, DCM is dichloromethane, EA or EtOAC is ethyl acetate, TEA is triethylamine, HPLC is high-performance liquid chromatography, MTBE is methyl tert-butyl ether, DMAP is 4-dimethylaminopyridine, DBAD is di-tert-butylazodicarboxylic acid, TFA is trifluoroacetic acid, LCMS is liquid chromatography-mass spectrometry, EtOH is ethanol, t-BuOH is tert-butanol, DMF is dimethylformamide, PE is petroleum ether, eq. is equivalent, i.e., molar ratio, TBAF is tetrabutylammonium fluoride, and DIPEA is N,N-diisopropylethylamine. In the synthetic process, all chemical reagents and pharmaceuticals for which the source is not indicated were analytically or chemically pure and purchased from commercial reagent companies.

[0069] Other English abbreviations mentioned herein are to be understood within the field of organic chemistry.

[0070] Synthesis of Compound No. 1 [ka] 1-D (5 g, 38.4 mmol) was dissolved in TFA (40 mL), and urotropine (5.6 g, 38.4 mmol, 1 equivalent, commercially available) was added and refluxed overnight. After the reaction was completed, the temperature was lowered to room temperature. The solvent was removed by concentration. The residue was dissolved in DCM (70 mL), washed with NaHCO3 solution, and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous phase was extracted with DCM (50 mL × 2), and the combined organic phases were dried over Na2SO4 and concentrated to give 1-E (2.5 g, 41.3% yield) as a white solid. 1 H-NMR (300M, CDCl): δ ppm 9.82 (s, 1H), 7.49 (d, J = 6.6 Hz, 2H). LCMS: calculated 158.1, found 157.0 ([M-H] - ).

[0071] Under nitrogen protection, [ka] 1-E (1 g, 3.16 mmol) and 1-E (1 g, 6.32 mmol) were dissolved in ultra-dry THF (15 mL). Triphenylphosphine (1.66 g, 6.32 mmL, 2 equiv.) was added. A THF solution (6 mL) of DBAD (1.46 g, 6.32 mmol, 2 equiv.) was added dropwise at 0 °C. The reaction was carried out at room temperature overnight. 8 mL of water was added dropwise at 0 °C. After extraction with DCM (20 mL × 3), the mixture was dried and concentrated. The samples were mixed and passed through a column (200-300 mesh silica gel, petroleum ether:EA = 3:1) to give 1-E (680 mg, 47% yield, 80% content) as a pale yellow solid.

[0072] Under nitrogen protection, 1-F (510 mg, 1.11 mmol) was dissolved in THF (5 mL). The temperature was lowered to 0 °C. Sodium borohydride (84 mg, 2.22 mmol, 2 equiv.) was added batchwise, and the temperature was maintained at 0 °C. The reaction was allowed to proceed for 1 h. After the reaction was completed, saturated aqueous ammonium chloride solution (3 mL) was added dropwise. After extraction with EA (10 mL × 3), the mixture was washed with brine, dried, concentrated, and subjected to column separation (100-200 mesh silica gel, DCM:methanol = 50:1) to obtain product 1-B (300 mg, yield = 58.9%) as a pale yellow solid. 1 H-NMR (300M, CDCl3): δppm8.01 (d, J=8.4Hz, 1H), 7.43 (d, J=8.7Hz, 2H), 7.34~ 7.37 (m, 1H), 6.86 (d, J=8.4Hz, 1H), 5.14 (s, 2H), 4.60 (s, 2H), 3.09 (brs, 6H). LCMS: Calculated value 458.4, Actual value 459.0 ([M+H] + ).

[0073] Under nitrogen protection, 1-B (300 mg, 0.65 mmol) was dissolved in THF (5 mL). Triphenylphosphine (375 mg, 1.43 mmol, 2.2 equiv.) and bromoisophosphoramide nitrogen mustard intermediate (Br-IPM, 442 mg, 1.43 mmol, 2.2 equiv., commercially available) were added. The temperature was lowered to 0 °C. DBAD (329 mg, 1.43 mmol, 2.2 equiv.) in THF (3 mL) was added dropwise and reacted at room temperature for 3 h. 3 mL of water was added dropwise. Extraction with DCM (10 mL × 3) was followed by drying, concentration, and column separation (200-300 mesh silica gel, DCM:methanol = 30:1) afforded the product (400 mg, 82% yield) as a reddish-brown solid. 1H-NMR (300M, CDCl3): δppm7.99(d, J=8.4Hz, 1H), 7.48~7.46(m, 2H), 7.33~7.31(m, 1H), 7.12(s, 1H), 7.00(d, J=8.1Hz) , 2H), 6.93(d, J=8.4Hz, 2H), 5.16(s, 2H), 4.93(d, J=8.4Hz, 2H), 3.45~3.43(m, 4H), 3.37~3.32(m, 4H), 3.07(brs, 6H). LCMS: Calculated value 750.3, Actual value 750.8 ([M+1] + ).

[0074] Under nitrogen protection, 1-C (400 mg, 0.533 mmol) was dissolved in ultra-dry THF (4 mL). Silver oxide (1.46 g, 6.29 mmol, 11.8 equiv.) was added, and diisopropylethylamine (345 mg, 2.67 mmol, 5 equiv.) was added dropwise. The temperature was raised to reflux, and the reaction was monitored by LCMS. The reaction was complete in 2.5 h. Suction filtration through Celite, followed by several washes with THF, and concentration at low temperature gave compound No. 1 (19 mg, 6.07% yield) as a white solid. 1 H-NMR (400M, CDCl3): δppm7.99 (d, J=7.2Hz, 1H), 7.45 (d, J=7.8Hz, 2H), 7.32 (d, J=8.4Hz, 1H), 7.16 (d, J=1.6Hz, 1H), 7. 04~7.06(m, 2H), 6.95(d, J=8.4Hz, 2H), 5.15(s, 2H), 5.05(d, J=8.0Hz, 2H), 3.11(s, 3H), 3.03(s, 3H), 2.23~2.13(m, 8H). LCMS: Calculated value 588.0, Actual value 589.0 ([M+H] + ).

[0075] Synthesis of Compound No. 2 [ka] 2-A1 (10.0 g, 50.99 mmol), triethyl orthoformate (9.8 g, 66.07 mmol, 1.32 equiv.), and 12 N HCl (0.15 mL) were added to EtOH (30 mL) and refluxed overnight. After the reaction was completed, the solvent was spin-dried to give 2-A2 (11.2 g, crude product).

[0076] Before the reaction was completed, 2-A2 (11.2 g, crude product, 51.0 mmol) and KOH (2.3 g, 204.0 mmol, 4 equiv.) were refluxed in t-BuOH (150 mL) for 4 h. The temperature was lowered to room temperature, water (100 mL) was added, and extraction with EtOAc (100 mL × 3) was performed. The aqueous phase was adjusted to pH 3–4 with 12 N HCl and stirred overnight. It was then extracted with EtOAc (100 mL × 3), dried over Na2SO4, spin-dried, and slurried in petroleum ether (PE) (20 mL) to give 2-A3 (4.4 g, 44.4% yield) as an off-white solid. 1 H-NMR (400M, CDCl3): δ ppm 10.21 (s, 1H), 6.46 (s, 1H). LCMS: calculated 194.0, found 192.8 ([MH]-).

[0077] Under nitrogen protection, 2-B1 (500 mg, 1.5 mmol), i.e. [ka] 2-A3 (1.45 g, 7.5 mmol, 5 equiv.) and DIEA (965 mg, 7.5 mmol, 5 equiv.) were added to DMF (5 mL) and heated to 50 °C overnight. The conversion of the reaction reached approximately 50% and did not increase after that. After cooling to room temperature, HO (20 mL) was added and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (15 mL × 3) and water (15 mL × 5). The organic phase was dried over NaSO, spun to remove the solvent, and passed through a 200-300 silica gel column (PE: EtOAc = 3:1) to give 2-A4 (290 mg, yield = 33.9%) as a pale yellow solid. 1H-NMR (400M, CDCl3): δppm10.15(s, 1H), 7.94(d, J=8.4Hz, 1H), 7.41(d, J=8.4Hz, 2H ), 7.23(d, J=8.4Hz, 1H), 7.04~6.99(m, 3H), 5.31(s, 2H), 3.06(s, 3H), 2.96(s, 3H). LCMS: Calculated value 492.1, Actual value 493.1 ([M+H] + ).

[0078] Under nitrogen protection, 2-A4 (270 mg, 0.548 mmol) was dissolved in THF (3 mL) before the temperature was lowered to 0 °C. Then, NaBH (42 mg, 1.1 mmol, 2 equiv.) was added to the system in a batchwise manner, and the reaction was completed in 30 min. HO (5 mL) was added dropwise, and extraction with DCM (10 mL × 3) was performed. The organic phase was washed with water (10 mL × 3), dried over anhydrous NaSO, spun dry, and passed through a column (PE: EtOAc = 1:1) to give 2-A5 (95 mg, yield = 35.0%) as a yellow solid. 1 H-NMR (400M, CDCl3): δppm8.01 (d, J=8.4Hz, 1H), 7.45 (d, J=8.4Hz, 2H), 7.33~7.30 (m, 1H) , 7.00(d, J=8.4Hz, 2H), 6.94(s, 1H), 5.20(s, 2H), 4.74(s, 2H), 3.10(s, 3H), 3.05(s, 3H). LCMS: Calculated value 495.1, Actual value 495.1 ([M+H] + ).

[0079] Under nitrogen protection, POCl3 (100 mg, 0.405 mmol, 2 equiv.) was dissolved in DCM (2 mL), and the temperature was then reduced to -40 oThe temperature was then lowered to -40 °C. Then, 2-A5 (100 mg, 0.202 mmol, 1 eq) and TEA (51 mg, 0.506 mmol, 2.5 eq) were added to the system, and the reaction was maintained at -40 °C for 6 h until completion. 2-Bromoethylamine hydrobromide (338 mg, 1.618 mmol, 8 eq) was added to the system, followed by dropwise addition of TEA (164 mg, 1.618 mmol, 8 eq). After completion, the temperature was maintained at -40 °C, and the reaction was completed in 30 min. After the temperature was raised to room temperature, NH4Cl solution (15 mL) was added dropwise, and the mixture was extracted with DCM (10 mL x 3). The organic phase was washed with water (10 mL x 3) and dried over anhydrous Na2SO4. After spin drying, the residue was passed through a 200-300 silica gel column (EtOAc) to obtain a yellow solid, AST-2-A6 (50 mg, content 70%, yield 31.4%).

[0080] Under nitrogen protection, 2-A6 (30 mg, 0.038 mmol, 1 equiv.), AgO (44 mg, 0.191 mmol, 5 equiv.), and DIEA (26 mg, 0.191 mmol, 5 equiv.) were added to THF (1 mL) and heated to reflux at 65 °C. The reaction was completed in 2 h. After cooling to room temperature, the system was suction filtered through silica gel and washed with THF. The mother liquor was spin-dried, then separated by neutral preparative liquid chromatography, extracted with DCM, spin-dried, and lyophilized to give compound No. 2 (6 mg, yield = 25.2%) as a brown solid. 1 H-NMR (400M, MeOD): δ8.34 (d, J=8.4Hz, 1H), 7.50 (d, J=8.8Hz, 2H), 7.45~7.43 (m, 1H), 7.30 (s, 1H), 7. 08(d, J=8.8Hz, 2H), 5.38(s, 2H), 5.25(d, J=7.6Hz, 2H), 3.10(s, 3H), 3.05(s, 3H), 2.20~2.15(m, 8H). LCMS: Calculated value 624.1, Actual value 625.2 ([M+H] + ).

[0081] Synthesis of Compound No. 3 [ka] Under nitrogen protection, 3-B1 (500 mg, 1.49 mmol, [ka] ), 3-A0 (1.45 g, 7.470 mmol, 5 equiv.), and DIEA (965 mg, 7.470 mmol, 5 equiv.) were added to DMF (10 mL) and heated at 50 °C overnight. The conversion of the reaction reached approximately 50% and did not increase after that. After cooling to room temperature, HO (20 mL) was added and extracted with EtOAc (20 mL × 3). The organic phase was washed with water (15 mL × 5) and saturated brine (15 mL × 3). The organic phase was dried, spun dry, and passed through a 200-300 silica gel column (PE:EtOAc = 3:1) to give 3-A1 (295 mg, yield = 40.1%) as a pale yellow solid. 1 H-NMR (400 M, CDCl): δ ppm 10.22 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.46-7.42 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.10-7.08 (m, 3H), 5.37 (s, 2H), 3.11 (s, 3H), 2.99 (s, 3H). LCMS: calculated 492.1, found 493.1 ([M+H] + ).

[0082] Under nitrogen protection, 3-A1 (290 mg, 0.589 mmol) was dissolved in THF (3 mL) before the temperature was lowered to 0 °C. Then, NaBH (45 mg, 1.178 mmol, 2 equiv.) was added to the system in a batchwise manner, and the reaction was completed in 30 min. HO (5 mL) was added dropwise to the system, and extraction was performed with DCM (10 mL × 3). The organic phase was washed with water (10 mL × 3), dried, spun, and passed through a column (PE: EtOAc = 1:1) to give 3-A2 (m = 100 mg, yield = 35.0%) as a yellow solid. 1H-NMR (400M, CDCl3): δppm7.99(d, J=8.4Hz, 1H), 7.44(t, J=8.4Hz, 1H), 7.31(d, J=7.6Hz, 1H), 7.22(d, J=7 .6Hz, 1H), 7.13(dd, d, J=8.0, 1.6Hz, 1H), 7.05(s, 1H), 6.91(s, 1H), 5.24(s, 2H), 4.73(s, 2H), 3.02(m, 6H). LCMS: Calculated value 494.1, Actual value 495.1 ([M+H] + ).

[0083] Under nitrogen protection, POCl3 (61 mg, 0.202 mmol) was dissolved in DCM (2 mL) and cooled to -40 °C. Then, 3-A2 (50 mg, 0.101 mmol) and TEA (26 mg, 0.253 mmol, 2.5 equiv.) were added to the system, and the reaction was maintained at -40 °C for 6 h until completion. 1-Bromoethylamine hydrobromide (169 mg, 0.81 mmol) was added to the system, followed by the dropwise addition of TEA (82 mg, 0.809 mmol, 8 equiv.). After completion, the temperature was maintained at -40 °C for 30 min before the reaction was completed. After the temperature was raised to room temperature, aqueous NH4Cl (10 mL) was added dropwise, and the mixture was extracted with DCM (8 mL × 3). The organic phase was washed with water (5 mL × 3), and the organic phase was dried, spun dry, and passed through a 200-300 silica gel column (EtOAc) to give a yellow solid, 3-A3 (62 mg, 80.0%, content 70%), which was used in the next step.

[0084] Under nitrogen protection, 3-A3 (60 mg, 0.08 mmol, 1 equiv.), AgO (88 mg, 0.382 mmol, commercially available), and DIEA (49 mg, 0.38 mmol) were added to THF (2 mL) and heated to reflux at 65 °C. The reaction was completed in 2 h. After cooling to room temperature, the system was suction filtered through silica gel and washed with THF. The mother liquor was spin-dried, purified, extracted with DCM, spin-dried, and lyophilized to give compound No. 3 (10 mg, 12% yield) as a brown solid. 1H-NMR (400M, MeOD): δ8.03 (d, J=8.4Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.43 (d, J=8.0Hz, 1H), 7.28~7.25 (m, 2H), 7.13~7.10(m, 2H), 5.37(s, 2H), 5.25(d, J=7.6Hz, 2H), 3.09(s, 3H), 3.00(s, 3H), 2.21~2.16(m, 8H). LCMS: Calculated value 624.1, Actual value 625.1 ([M+H] + ).

[0085] Synthesis of Compound No. 4 [ka] Under nitrogen protection, 4-A1 (3.7 g, 18.45 mmol) and p-trifluoromethylphenol (2 g, 12.3 mmol, commercially available) were dissolved in ACN (30 mL). KCO (3.4 g, 24.6 mmol) was added, and the mixture was heated to 80 °C and stirred overnight. After the reaction was completed, the system was suction filtered through Celite and concentrated to give crude product 4-A2 (5.6 g, 97.2%) as a yellow solid, which was used directly in the next step. 1 H-NMR (400M, CDCl3): δppm8.03~7.95 (m, 2H), 7.76 (d, J=1.6Hz, 1H), 7.66 (d, J=8.8Hz, 2H), 7.11 (d, J=8.8Hz, 2H), 3.94 (s, 3H). LCMS: Calculated value 341.1, Actual value 342.1 ([M+H] + ).

[0086] Under nitrogen protection, 4-A2 (1.6 g, 4.7 mmol) was dissolved in THF (30 mL). NaBH (1.4 g, 37.6 mmol) was added batchwise, heated to 60 °C, and stirred overnight. After the reaction was completed, the temperature was lowered to 5 °C, and saturated aqueous NH Cl (15 mL) was added dropwise. After extraction with DCM (20 mL), the mixture was washed with water (4 × 5 mL), dried, and concentrated to give crude product 4-A3 (1.6 g) as a yellow oily liquid, which was used directly in the next step. 1H-NMR (400M, CDCl3): δppm8.02 (d, J=8.4Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.31 ~7.28(m, 1H), 7.15(s, 1H), 7.08(d, J=8.4Hz, 2H), 4.77(s, 2H), 1.86(s, 1H). LCMS: Calculated value 313.1, Actual value 314.0342.1 ([M+H] + ).

[0087] Under nitrogen protection, the crude product 4-A3 (600 mg, 1.92 mmol) obtained in the above step was dissolved in ultra-dry DCM (10 mL). The temperature was lowered to 0 °C, and SOCl (457 mg, 3.84 mmol) was slowly added dropwise. After 1 h, an additional 1 equivalent of TEA (194 mg, 1.92 mmol) was added, and the reaction was completed in 30 min. The temperature was lowered, and saturated NaHCO solution (10 mL) was added dropwise. After extraction with DCM (15 mL × 2), the mixture was washed with water (5 mL × 3), dried, and concentrated to give crude product 4-A4 (580 mg) as a pale yellow liquid, which was used directly in the next step.

[0088] Under nitrogen protection, 4-A4 (580 mg, 1.75 mmol) and [ka] After dissolving 4-A5 (692 mg, 4.375 mmol) in DMF (10 mL), DIEA (1.4 g, 10.5 mmol) was added and the reaction was carried out overnight at 40 °C. After the reaction was completed, the product was extracted with EA (15 mL × 2), washed with water (5 mL × 6), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 10:1-5:1) to obtain product 4-A5 (300 mg, 55.0%) as a yellow oily liquid. 1 H-NMR (400M, CDCl3): δppm9.84~9.85 (m, 1H), 8.04 (d, J=8.4Hz, 1H), 7.64 (d, J=8.8Hz, 2H), 7 .46(d, J=8.2Hz, 2H), 7.38(d, J=8.4Hz, 1H), 7.21(s, 1H), 7.09(d, J=8.4Hz, 2H), 5.32(s, 2H).

[0089] Under nitrogen protection, 4-A5 (300 mg, 0.66 mmol) was dissolved in THF (6 mL). The temperature was lowered to 0 °C. NaBH (50 mg, 1.32 mmol, commercially available) was added in a batchwise manner. The reaction was completed in 30 min. Saturated aqueous NH Cl (5 mL) was added dropwise at 0 °C. After extraction with DCM (15 mL × 2), the mixture was washed with water (5 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, heptane:EA = 10:1-5:1) to obtain product 4-A6 (190 mg, 90.6%) as a pale yellow solid. 1 H-NMR (400M, CDCl3): δppm8.02 (d, J=8.4Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7.36~7.38 (m, 1 H), 7.23(s, 1H), 7.07(d, J=8.4Hz, 2H), 6.90(d, J=8.8Hz, 2H), 5.17(s, 2H), 4.63(s, 2H).

[0090] Under nitrogen protection, POCl3 (130 mg, 0.84 mmol, commercially available) was dissolved in ultra-dry DCM (5 mL). The temperature was lowered to -30 °C. A solution of 4-A6 (190 mg, 0.42 mmol) in DCM (5 mL) was added dropwise, followed by TEA (106 mg, 1.05 mmol). The temperature was maintained at -30 °C for 6 h until the starting material was completely consumed. 2-Bromoethylamine hydrobromide (688 mg, 3.36 mmol) was added at -30 °C, followed by TEA (340 mg, 3.36 mmol). After the reaction was complete, the temperature was lowered to 0 °C, and saturated aqueous NH4Cl (10 mL) was added. Extraction with DCM (15 mL × 2) was followed by washing with water (5 mL × 4), drying, concentration, and column separation (200-300 mesh silica gel, heptane:EA = 1:2 to EA) to obtain the product as a yellow solid (120 mg, yield = 57.6%). 1H-NMR (400M, CDCl3): δppm8.03(d, J=8.4Hz, 1H), 7.64(d, J=8.8Hz, 2H), 7.37(d, J=8.0Hz, 1H), 7.24(s, 1H), 7.08(d, J =8.4Hz, 2H), 6.95(d, J=8.4Hz, 2H), 5.18(s, 2H), 4.94(d, J=8.4Hz, 2H), 3.14~3.46(m, 4H), 3.33(m, 4H), 3.14(m, 2H). LCMS: Calculated value 747.0, Actual value 748.0 ([M+H] + ).

[0091] Under nitrogen protection, 4-A7 (120 mg, 0.16 mmol) was dissolved in THF (10 mL), and AgO (222 mg, 0.96 mmol, commercially available) and N,N-diisopropylethylamine (124 mg, 0.96 mmol, commercially available) were added. The temperature was raised to 65 °C and the reaction was completed in 2 h. The reaction was then suction filtered through Celite. The solid was washed with DCM (20 mL), and the mother liquor was concentrated and purified by high-performance liquid chromatography to give the pure product (14.3 mg, 28.4%) as a yellow waxy solid. 1 H-NMR (400M, CDCl3): δppm8.02(d, J=8.4Hz, 1H), 7.64(d, J=8.8Hz, 2H), 7.37(d, J=8.4Hz, 1H), 7.24(s, 1 H), 7.08(d, J=8.8Hz, 2H), 6.96(d, J=8.4Hz, 2H), 5.18(s, 2H), 5.06(d, J=8.4Hz, 2H), 2.13~2.23(m, 8H). LCMS: Calculated value 585.1, Actual value 586.1 ([M+H] + ).

[0092] Synthesis of Compound No. 5 [ka] Under nitrogen protection, 5-A1 (5.8 g, 28.9 mmol) and 2-chloro-5-hydroxypyridine (2.5 g, 19.3 mmol) were dissolved in acetonitrile (50 mL). After potassium carbonate (5.3 g, 38.6 mmol) was added, the temperature was raised to 80 °C and stirred overnight. After the reaction was completed, the mixture was filtered through Celite with suction. The mother liquor was concentrated, slurried with n-heptane, and filtered with suction to give the pure product 5-A2 (5.7 g, 95.7%) as a pale yellow solid. 1 H-NMR (400M, CDCl3): ppm8.20 (s, 1H), 7.94~8.03 (m, 2H), 7.69 (s, 1H), 7.37 (s, 2H), 3.93 (s, 3H). LCMS: Calculated value 308.0, Actual value 309.0 ([M+H] + ).

[0093] Under nitrogen protection, 5-A2 (2 g, 6.5 mmol) was dissolved in THF (30 mL), and then NaBH4 (1.97 g, 52 mmol) was added batchwise. The temperature was raised to 60 °C and stirred overnight. After the reaction was completed, the temperature was lowered, and saturated aqueous NH4Cl (15 mL) was added dropwise. After extraction with DCM (20 mL), the mixture was washed with water (4 × 5 mL), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 5:1 to 1:1) to obtain the product 5-A3 (m = 800 mg, yield = 44.4%) as a pale yellow solid. 1 H-NMR (400M, CDCl3): ppm8.16(s, 1H), 8.02(d, J=8.4Hz, 1H), 7.34(s, 2H), 7.29(d, J=8.4Hz, 1H), 7.12(s, 1H), 4.77(s, 2H), 1.84(s, 1H). LCMS: Calculated value 280.0, Actual value 281.0 ([M+H] + ).

[0094] Under nitrogen protection, 5-A3 (800 mg, 2.85 mmol) was dissolved in ultra-dry DCM (10 mL). The temperature was lowered to 0 °C, and SOCl (1.19 g, 9.98 mmol) was added dropwise slowly. The reaction was completed in 4 h. The temperature was lowered, and saturated NaHCO solution (10 mL) was added dropwise. Extraction was performed with DCM (15 mL × 3). The organic phase was washed with aqueous NaHCO (5 mL × 2), dried, and concentrated to give product 5-A4 (440 mg, pale yellow liquid, 51.6%), which was used directly in the next step.

[0095] Under nitrogen protection, 5-A4 (440 mg, 1.47 mmol) and [ka] After dissolving the 5-amino-3-methyl-2-propanol (581 mg, 3.675 mmol) in DMF (10 mL), DIEA (1.14 g, 8.82 mmol) was added. The reaction was carried out overnight. After completion of the reaction, the mixture was extracted with EA (15 mL × 2), washed with water (5 mL × 6), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 10:1 to 5:1) to obtain product 5-A5 (m = 340 mg, yield = 55.0%) as a yellow oily liquid. 1 H-NMR (400M, CDCl3): ppm9.85(t, J=1.6Hz, 1H), 8.16(d, J=1.2Hz, 1H), 8.03(d, J =8.4Hz, 1H), 7.46(d, J=8.0Hz, 2H), 7.34~7.38(m, 3H), 7.18(s, 1H), 5.32(s, 2H). LCMS: Calculated value 420.0, Actual value 421.0 ([M+H] + ).

[0096] Under nitrogen protection, 5-A5 (340 mg, 0.81 mmol) was dissolved in THF (6 mL). The temperature was lowered to 0 °C, and sodium borohydride (61 mg, 1.62 mmol) was added in batches. The reaction was completed in 30 min. Saturated aqueous NH4Cl (5 mL) was added dropwise at 0 °C. After extraction with DCM (10 mL × 2), the mixture was washed with water (5 mL × 3), dried, and concentrated to give product 5-A6 (310 mg, pale yellow solid, 90.6%), which was used directly in the next step.1 H-NMR (400M, DMSO-d6): ppm8.03(d, J=8.4Hz, 1H), 7.55(d, J=2.8Hz, 1H), 7.46~7.34( m, 2H), 7.01(d, J=1.2Hz, 1H), 6.90~6.87(m, 2H), 5.17(s, 2H), 4.61(d, J=6.4Hz, 2H). LCMS: Calculated value 422.0, Actual value 423.0 ([M+H] + ).

[0097] Under nitrogen protection, phosphorus oxychloride (224 mg, 1.46 mmol) was added dropwise to ultra-dry DCM (5 mL). The temperature was lowered to -30 °C. A solution of 5-A6 (310 mg, 0.73 mmol) in DCM (5 mL) was added dropwise, followed by triethylamine (185 mg, 1.825 mmol). The temperature was maintained at -30 °C for 5 h until the starting material was completely consumed. 2-Bromoethylamine hydrobromide (1.2 g, 5.84 mmol) was added at -30 °C, followed by triethylamine (591 mg, 5.84 mmol). After the reaction was completed, the mixture was extracted with DCM (15 mL × 2), washed with water (5 mL × 4), dried, concentrated, and column-separated (200-300 mesh silica gel) to obtain the product 5-A4 (300 mg, yield = 57.6%) as a pale yellow oil. 1 H-NMR (400M, CDCl3): ppm8.10(s, 1H), 8.00(d, J=8.4Hz, 1H), 7.34~7.35(m, 3H), 7.18(s, 1H), 6.93(d, J=8.4Hz, 2H), 5.29(s, 2H), 5.17(s, 2H), 4.92(d, J=8.4Hz, 2H), 3.42~3.48(m, 4H), 3.29~3.36(m, 4H), 3.20~3.22(m, 2H). LCMS: Calculated value 713.9, Actual value 714.9 ([M+H] + ).

[0098] Under nitrogen protection, 5-A7 (300 mg, 0.42 mmol) was dissolved in THF (10 mL), and silver oxide (584 mg, 2.52 mmol, commercially available) and N,N-diisopropylethylamine (326 mg, 2.52 mmol) were added. The temperature was raised to 60 °C, and the reaction was completed in 2.5 h. The mixture was then filtered through Celite with suction. The solid was washed with DCM (20 mL), and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give pure compound No. 5 (66 mg, 28.4%) as a pale yellow solid. 1 H-NMR (400M, CDCl3): ppm8.16 (d, J=2.4Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.31~7.37 (m, 3H), 7.20(s, 1H), 6.96(d, J=8.4Hz, 2H), 5.17(s, 2H), 5.06(d, J=8.0Hz, 2H), 2.24~2.14(m, 8H). LCMS: Calculated value 552.1, Actual value 553.1 ([M+H] + ).

[0099] Synthesis of Compound No. 6 [ka] Under nitrogen protection, 6-A1 (1.5 g, 9.15 mmol, commercially available) and [ka] (1 g, 6.10 mmol) was dissolved in acetonitrile (20 mL). The temperature was raised to 80 °C, and the reaction was completed in 5 h. The temperature was lowered to room temperature, and the mixture was suction filtered through Celite. The filter cake was washed with EA. The mother liquor was concentrated and purified using a silica gel column (200-300 mesh silica gel, heptane:EA = 2:1-1:1) to obtain product 6-A2 (1.2 g, yield = 63.2%) as a pale yellow oily liquid. 1H-NMR (400M, CDCl3): δppm9.96(s, 1H), 8.04(d, J=8.2Hz, 1H), 7.73(dd, J=8.2, 1.5Hz, 1H), 7.51(d, J=1 .4Hz, 1H), 7.49~7.43(m, 1H), 7.35~7.27(m, 1H), 7.14(dd, J=7.9, 1.3Hz, 2H), 3.09(s, 3H), 2.99(s, 3H). LCMS: Calculated value 314.1, Actual value 315.1 ([M+H] + ).

[0100] Under nitrogen protection, 6-A2 (550 mg, 1.75 mmol) was dissolved in THF (10 mL) and (trifluoromethyl)-trimethylsilane (373 mg, 2.62 mmol) was added. The temperature was lowered to 0 °C, and tetrabutylammonium fluoride (0.04 mL, 0.04 mmol, 1 min THF) was added dropwise. After 2 h, 3 N hydrochloric acid (0.5 mL) was added dropwise. After extraction with DCM (10 mL × 2), the mixture was washed with NaHCO3 solution (5 mL × 3), washed with water, washed with brine, dried, and concentrated to give 600 mg of crude product 6-A3 as a pale yellow oily liquid, which was used directly in the next step.

[0101] Under nitrogen protection, phosphorus oxychloride (376 mg, 2.45 mmol) was added to ultra-dry DCM (15 mL). The temperature was lowered to -30 °C. A DCM solution (5 mL) of 6-A3 (470 mg, 1.22 mmol, crude) was added dropwise, followed by triethylamine (312 mg, 3.03 mmol). The temperature was maintained at -30 °C for 4 h until the starting material was completely converted. 2-Bromoethylamine hydrobromide (2.0 g, 9.78 mmol) was added at -30 °C, followed by triethylamine (940 mg, 9.78 mmol). The temperature was maintained at -30 °C. The reaction was completed in 1 h. Saturated aqueous ammonium chloride solution (8 mL) was added dropwise at 0 °C. Extraction with dichloromethane (15 mL × 2) was performed, followed by washing with water, drying, concentration, and column separation (200–300 mesh silica gel, PE:EA = 1:2-EA) to obtain product 6-A4 (440 mg, yield = 53.4%) as a yellow oily liquid. 1H-NMR: δppm7.98(d, J=8.3Hz, 1H), 7.49~7.46(m, 1H), 7.29~7.21(m, 4H), 7. 07(s, 1H), 5.71~5.67(m, 1H), 3.46~3.12(m, 10H), 3.07(s, 3H), 2.99(s, 3H). MS: Calculated value 676.0, MS: Actual value 677.0 ([M+1] + ).

[0102] Under nitrogen protection, 6-A4 (440 mg, 0.65 mmol) was dissolved in THF (25 mL), and silver oxide (910 mg, 3.92 mmol) was added, followed by DIEA (510 mg, 3.92 mmol). The temperature was raised to 65 °C. The reaction was completed in 2 h. The temperature was then lowered to room temperature. The mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give pure compound No. 6 (90.0 mg, 27%) as a white solid. 1 H-NMR (400M, CDCl3): δppm8.00 (d, J=8.4Hz, 1H), 7.52~7.32 (m, 2H), 7.26~7.23 (m, 2H), 7.0 8~7.06(m, 2H), 5.72(dq, J=12.2, 6.1Hz, 1H), 3.09(s, 3H), 2.97(s, 3H), 2.32~1.89(m, 8H). LCMS: calculated value 514.1, measured value 515.1 [(M+H)+].

[0103] Synthesis of Compound No. 7 [ka] Under nitrogen protection, 7-A1 (1.5 g, 9.15 mmol, commercially available) and p-trifluoromethylphenol (990 mg, 6.10 mmol) were dissolved in acetonitrile (20 mL). Potassium carbonate (1.7 g, 12.2 mmol, commercially available) was added. The temperature was raised to 80 °C, and the reaction was completed in 2.5 h. The temperature was then lowered to room temperature, and the mixture was suction filtered through Celite. The filter cake was washed with EA. The mother liquor was concentrated and subjected to column separation (200-300 mesh silica gel, heptane:EA = 5:1 to 1:1) to obtain the product 7-A2 (1.1 g, yield = 38.6%) as a pale yellow solid.1 H-NMR (400M, CDCl3): δppm10.01(s, 1H), 8.09(d, J=8.2Hz, 1H), 7.79(dd, J=8.2, 1.6Hz, 1H), 7.68(d, J=8.6Hz, 2H), 7.57(d, J=1.5Hz, 1H), 7.15(d, J=8.6Hz, 2H).

[0104] Under nitrogen protection, 7-A2 (400 mg, 1.29 mmol) was dissolved in THF (10 mL) and (trifluoromethyl)-trimethylsilane (274 mg, 1.93 mmol) was added. The temperature was lowered to 0 °C, and tetrabutylammonium fluoride (0.04 mL, 0.04 mmol, 1 mol / L THF solution) was added dropwise. After 2 h, 3 N hydrochloric acid (0.5 mL) was added dropwise. After extraction with DCM (10 mL × 2), the mixture was washed with NaHCO3 solution (5 mL × 3), water, brine, dried, and concentrated to give 450 mg of crude product 7-A3 as a pale yellow oil. 1 H-NMR (400M, CDCl3): δppm8.04(d, J=7.8Hz, 1H), 7.64(d, J=7.9Hz, 2H), 7.45( d, J=7.7Hz, 1H), 7.30(s, 1H), 7.09(d, J=8.0Hz, 2H), 5.09(s, 1H), 3.26(s, 1H). LCMS: Calculated value 381.2, Actual value 382.0 ([M+1] + ).

[0105] Under nitrogen protection, phosphorus oxychloride (362 mg, 2.36 mmol) was added to ultra-dry DCM (15 mL). The temperature was lowered to -30 °C. A DCM solution (5 mL) of 7-A3 (450 mg, 1.18 mmol, crude) was added dropwise, followed by triethylamine (300 mg, 2.95 mmol). The temperature was maintained at -30 °C for 4 h until complete conversion of the starting material. 2-Bromoethylamine hydrobromide (1.9 g, 9.44 mmol) was added at -30 °C, followed by triethylamine (960 mg, 9.44 mmol). The temperature was maintained at -30 °C. The reaction was completed in 1 h. Saturated aqueous ammonium chloride solution (6 mL) was added dropwise at 0 °C. After extraction with DCM (15 mL × 2), the mixture was washed with water, dried, concentrated, and subjected to column separation (200–300 mesh silica gel, heptane:EA = 1:1–0:1) to obtain product 7-A4 (440 mg, 55.4%) as a yellow oily liquid. 1 H-NMR (400MHz, CDCl3): δppm8.05 (d, J=8.4Hz, 1H), 7.65 (d, J=8.6Hz, 2H), 7.44 (d, J=8 .5Hz, 1H), 7.23(s, 1H), 7.10(d, J=8.5Hz, 2H), 5.72~5.64(m, 1H), 3.40~3.10(m, 10H). LCMS: Calculated value 672.9, Actual value 673.9 ([M+1] + ).

[0106] Under nitrogen protection, 7-A4 (400 mg, 0.59 mmol) was dissolved in THF (25 mL), and silver oxide (826 mg, 3.57 mmol) was added, followed by DIEA (461 mg, 3.57 mmol). The temperature was raised to 65 °C. The reaction was completed in 2 h. The temperature was then lowered to room temperature. The mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give pure compound No. 7 (68 mg, yield = 22.5%) as a white solid. 1H-NMR (400M, CDCl3): δppm8.05 (d, J=8.5Hz, 1H), 7.65 (d, J=8.6Hz, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.27(s, 1H), 7.09(d, J=8.5Hz, 2H), 5.75(d, J=4.4Hz, 1H), 2.33~1.98(m, 8H). LCMS: Calculated value 511.1, Actual value 512.0 ([M+H] + ).

[0107] Synthesis of Compound No. 8 [ka] 8-A1 (5.5 g, 27.6 mmol) and p-trifluoromethylphenol (3.0 g, 18.5 mmol, commercially available) were dissolved in acetonitrile (30 mL). K2CO3 (5.1 g, 37.0 mmol, commercially available) was added. The temperature was raised to 80 °C and stirred overnight before the reaction was completed. The temperature was allowed to cool to room temperature, and the mixture was suction filtered through Celite. The filter cake was washed with EA (10 mL × 3). The mother liquor was concentrated, and the crude product 8-A2 (4.6 g, 72.9%) was obtained as a yellow solid by crystallization from methyl tert-butyl ether. This crude product was used directly in the next reaction.

[0108] 8-A2 (2.5 g, 7.33 mmol) was dissolved in THF, and sodium borohydride (2.2 g, 58.7 mmol, commercially available) was added in batches and stirred at room temperature for 30 min. The temperature was raised to 65 °C, and the reaction progress was monitored by stirring. The reaction was completed in 2 h. The system was cooled to 0 °C, and HO (20 mL) was added dropwise and stirred for 20 min. After extraction with DCM (50 mL × 3), the mixture was washed with water, dried over anhydrous NaSO, and concentrated to give crude product 8-A3 (1.5 g, 65.4%) as a pale yellow solid.

[0109] Under nitrogen protection, 8-A3 (1.5 g, 4.79 mmol) was dissolved in DCM (20 mL). The temperature was lowered to 0 °C, and SOCl (1.1 g, 9.58 mmol) and TEA (485 mg, 4.79 mmol) were added dropwise and stirred. The reaction progress was monitored. The reaction was completed in 1 h. At 0 °C, saturated aqueous NaHCO (5 mL) was added dropwise. After extraction with DCM (20 mL × 3), the mixture was washed with aqueous NaHCO, dried over anhydrous NaSO, and concentrated to give crude product 8-A5 (1.3 g, 81.8%) as a reddish-brown liquid, which was used directly in the next step.

[0110] 8-A4 (220 mg, 0.66 mmol) and 2,3,5,6-tetrafluoro-4-hydroxybenzaldehyde (513 mg, 2.65 mmol) were dissolved in DMF (5 mL). DIEA (430 mg, 3.32 mmol) was added dropwise and stirred. The temperature was raised to 45 °C. The reaction progress was monitored. The reaction was completed in 3 h. H2O (10 mL) was added, and the temperature was allowed to cool to room temperature. Extraction with EA (8 mL × 3), drying over anhydrous Na2SO4, and concentration gave the crude product 8-A5 (70 mg) as a pale yellow liquid, which was used directly in the next step.

[0111] 8-A5 (70 mg, 0.14 mmol) was dissolved in THF (5 mL). The temperature was lowered to 0 °C. NaBH (11 mg, 0.37 mmol) was added in batches. The reaction progress was monitored. The reaction was completed in 0.5 h. At 0 °C, HO (3 mL) was added dropwise and stirred for 20 min. After extraction with DCM (10 mL × 3), the mixture was washed with water, dried over anhydrous NaSO, and concentrated to give 50 mg of crude product 8-A6 as a pale yellow liquid, which was used directly in the next step.

[0112] POCl3 (31 mg, 0.20 mmol, commercially available) was dissolved in DCM (3 mL). The temperature was lowered to -30 °C. A DCM solution (1 mL) of 8-A6 (50 mg, 0.10 mmol) was added dropwise, followed by a DCM solution (1 mL) of triethylamine (26 mg, 0.26 mmol). The reaction was carried out while maintaining the temperature at -30 °C. The progress of the reaction was monitored. The starting material disappeared within 2 hours. The temperature was lowered to -40 °C. 2-Bromoethylamine hydrobromide (167 mg, 0.82 mmol) and TEA (83 mg, 0.82 mmol) were added. The temperature was maintained at -40 °C. The reaction was complete in 30 minutes. After the temperature was raised to 5 °C, HO (5 mL) was added, and the mixture was extracted with DCM (5 mL × 3), washed with water (3 mL × 2), dried over anhydrous NaSO, concentrated, and subjected to column chromatography (200-300 mesh silica gel, n-heptane:EA = 1:1) to obtain product 8-A7 (50 mg, 62.7%) as a pale yellow liquid.

[0113] 8-A7 (50 mg, 0.064 mmol) was dissolved in THF (5 mL), and AgO (74 mg, 0.32 mmol, commercially available) and DIEA (41 mg, 0.32 mmol) were added. The temperature was raised to 65 °C. The reaction progress was monitored. The reaction was complete in 1 h. The temperature was lowered to room temperature, and the mixture was suction filtered through Celite. The solid was washed with THF (2 mL × 3). The mother liquor was concentrated, and the product (2.2 mg, 5.5%) was isolated as a white wax by high-performance liquid chromatography. 1 H-NMR (400M, CDCl3) δ8.04 (d, J=8.4Hz, 1H), 7.65 (d, J=8.6Hz, 2H), 7.36 (dd, J=8.4, 1.6Hz, 1H), 7. 20(d, J=1.5Hz, 1H), 7.09(d, J=8.5Hz, 2H), 5.28(s, 2H), 5.23(d, J=6.1Hz, 2H), 2.26~2.15(m, 8H). LCMS: Calculated value 621.1, Calculated value 622.1 ([M+H] + ).

[0114] Synthesis of Compound No. 9 [ka] Under nitrogen protection, 9-A1 (500 mg, 2.97 mmol) and 4-fluoro-4'-hydroxybiphenyl (723 mg, 3.84 mmol, commercially available pharmaceutical product) were dissolved in acetonitrile (10 mL). Potassium carbonate (820 mg, 5.94 mmol, commercially available) was added. The temperature was raised to 85 °C and stirred for 2 h. The reaction was then terminated. The temperature was then lowered to room temperature and suction filtered. The mother liquor was concentrated and isolated by column chromatography (200-300 mesh silica gel, heptane:EA = 20:1) to give the product (420 mg, yield = 42.0%) as a pale yellow solid. 1 H-NMR (400M, CDCl3): δppm9.98 (s, 1H), 8.05 (d, J=8.0Hz, 1H), 7.70 (dd, J1=8. 0Hz, J2=1.6Hz, 1H), 7.56~7.60(m, 2H), 7.52~7.56(m, 3H), 7.12~7.17(m, 4H).

[0115] Under nitrogen protection, 9-A2 (400 mg, 1.19 mmol) was dissolved in anhydrous THF (8 mL), and then (trifluoromethyl)-trimethylsilane (254 mg, 1.79 mmol) was added dropwise. The temperature was lowered to 0 °C, and TBAF (0.03 mL, 1 min THF) was added dropwise. The temperature was maintained at 0 °C for 1.5 h until the reaction was complete. 2 mL of 3 N hydrochloric acid was added dropwise. The temperature was allowed to rise to room temperature naturally. Stirring was continued for 1 h, and 5 mL of water was added. The mixture was extracted with DCM (10 m × 3), washed with water (5 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 10:1) to obtain the product 9-A3 (380 mg, yield = 78.4%) as a pale yellow solid. 1 H-NMR (400M, CDCl): δ ppm 8.00 (d, J = 8.4 Hz, 1H), 7.51-7.57 (m, 4H), 7.35 (d, J = 8.4 Hz), 7.24 (s, 1H), 7.10-7.16 (m, 4H), 5.04-5.06 (m, 1H). LCMS: calculated 407.0, found 430.0 ([M+Na] + ).

[0116] Under nitrogen protection, phosphorus oxychloride (285 mg, 1.866 mmol) was added dropwise to anhydrous DCM (10 mL). The temperature was lowered to -40 °C. A DCM solution (4 mL) of 9-A3 (380 mg, 0.933 mmol) was added dropwise, followed by triethylamine (236 mg, 2.333 mmol). The temperature was maintained at -40 °C to -35 °C for 2 h. As monitored by LC-LCMS, 9-A3 disappeared and was converted to the intermediate. 2-Bromoethylamine hydrobromide (1.53 g, 7.464 mmol) was added at -40 °C, followed by the dropwise addition of triethylamine (755 mg, 7.464 mmol) in DCM (2 mL). The temperature was maintained at -40 °C for 1 h, resulting in complete conversion of the intermediate. The temperature was allowed to rise to 0°C, and saturated aqueous ammonium chloride solution (5 mL) was added dropwise. After extraction with DCM (10 mL × 3), the mixture was washed with purified water (3 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1) to obtain the product as an off-white solid (m = 350 mg, yield = 53.7%). 1 H-NMR (400M, CDCl3): δppm8.01(d, J=8.4Hz, 1H), 7.52~7.58(m, 4H), 7.34( d, J=8.4Hz, 1H), 7.11~7.18(m, 5H), 5.61~5.68(m, 1H), 3.13~3.81(m, 10H). LCMS: Calculated value 699.0, Actual value 700.0 ([M+H] + ).

[0117] Under nitrogen protection, 9-A4 (350 mg, 0.5 mmol) was dissolved in THF (10 mL), and then silver oxide (700 mg, 3.0 mmol) and DIPEA (390 mg, 3.0 mmol) were added. The temperature was raised to 65 °C and stirred for 3 h. After the reaction was completed, the temperature was lowered to room temperature. The mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated and purified by preparative chromatography to give the pure product (m = 31.4 mg, white solid, yield = 11.7%). 1H-NMR (400M, CD3OD): δppm8.08 (d, J=8.4Hz, 1H), 7.63~7.69 (m, 4H), 7.50 (d, J=8 .4Hz, 1H), 7.31(s, 1H), 7.16~7.20(m, 4H), 5.99~6.04(m, 1H), 2.03~2.24(m, 8H). LCMS: Calculated value 537.0, Actual value 538.0 ([M+H] + ).

[0118] Synthesis of Compound No. 11 [ka] Under nitrogen protection, 11-A1 (500 mg, 2.97 mmol) and p-trifluoromethoxyphenol (684 mg, 3.84 mmol, commercially available pharmaceutical product) were dissolved in acetonitrile (10 mL). Potassium carbonate (820 mg, 5.94 mmol, commercially available) was added. The temperature was raised to 85 °C and stirred for 2 h before the reaction was terminated. The temperature was then lowered to room temperature and suction filtered. The mother liquor was concentrated and isolated by column chromatography (200-300 mesh silica gel, n-heptane:EA = 30:1) to give product 11-A2 (520 mg total, pale yellow solid, yield = 53.5%). 1 H-NMR (400M, CDCl3): δppm9.99(s, 1H), 8.06(d, J=8.4Hz, 1H), 7.73(dd, J1=8.4Hz , J2=1.6Hz, 1H), 7.50(d, J2=1.2Hz, 1H), 7.29(d, J=8.4Hz, 1H), 7.10~7.14(m, 2H).

[0119] Under nitrogen protection, 11-A2 (500 mg, 1.528 mmol) was dissolved in anhydrous THF (8 mL), and (trifluoromethyl)-trimethylsilane (370 mg, 2.598 mmol) was added dropwise. The temperature was lowered to 0 °C, and TBAF (0.03 mL, 1 min THF) was added dropwise. The temperature was maintained at 0 °C for 1.5 h until the reaction was complete. 2 mL of 3 N hydrochloric acid was added dropwise. The temperature was allowed to rise to room temperature. After stirring for 1 h, 5 mL of water was added. The mixture was extracted with DCM (10 mL × 3), washed with water (5 mL × 3), dried, concentrated, and column-separated (200-300 mesh silica gel, n-heptane:EA = 20:1 to 10:1) to obtain the product (400 mg, yield = 65.9%) as a yellow oil. 1 H-NMR (400M, CDCl3): δppm8.00 (d, J=8.4Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 7.25 (d, J= 8.8Hz, 2H), 7.21(s, 1H), 7.06(d, J=8.8Hz, 2H), 5.04~5.09(m, 1H), 3.05(brs, 1H).

[0120] Under nitrogen protection, phosphorus oxychloride (310 mg, 2.014 mmol) was added dropwise to anhydrous DCM (10 mL). The temperature was lowered to -40 °C. A DCM solution (4 mL) of 11-A3 (400 mg, 1.007 mmol) was added dropwise, followed by triethylamine (255 mg, 2.518 mmol). The temperature was maintained at -40 °C to -35 °C for 2 h. LC-LCMS monitoring showed that 11-A3 had disappeared and was converted to the intermediate. 2-Bromoethylamine hydrobromide (1.65 g, 8.056 mmol) was added at -40 °C, followed by the dropwise addition of a DCM solution (2 mL) of triethylamine (815 mg, 8.056 mmol). The temperature was maintained at -40 °C for 1 h, resulting in complete conversion of the intermediate. The temperature was allowed to rise to 0 °C, and saturated aqueous ammonium chloride solution (5 mL) was added dropwise. After extraction with DCM (10 mL × 3), the mixture was washed with purified water (3 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1 to 100% EA) to obtain product 11-A4 (m = 160 mg, yield = 23.1%) as a yellow oily liquid. 1H-NMR (400M, CDCl3): δppm8.02 (d, J=8.4Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 7.27 (d, J=8.8Hz, 2H), 7.14 (s, 1H), 7.08 (d, J=8.8Hz, 2H), 5.63~5.68(m, 1H), 3.46~3.49(m, 2H), 3.34~3.42(m, 2H), 3.26~3.32(m, 2H), 3.02~3.25(m, 4H). LCMS: Calculated value 688.9, Actual value 689.8 ([M+H] + ).

[0121] Under nitrogen protection, 11-A4 (160 mg, 0.230 mmol) was dissolved in THF (10 mL), followed by the addition of silver oxide (323 mg, 1.393 mmol) and DIPEA (180 mg, 1.393 mmol). The temperature was raised to 65 °C and stirred for 3 h. After the reaction was completed, the temperature was lowered to room temperature. The mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated to give pure compound No. 11 (m = 26.3 mg, yield = 21.7%) as a yellow wax. 1 H-NMR (400M, CDCl3): δppm8.01(d, J=8.4Hz1H), 7.39(d, J=8.4Hz, 1H), 7.26(d, J= 8.8Hz, 2H), 7.18(s, 1H), 7.05~7.08(m, 2H), 5.60~5.74(m, 1H), 2.00~2.26(m, 8H). LCMS: Calculated value 527.1, Actual value 528.0 ([M+H] + ).

[0122] Synthesis of Compound No. 12 [ka] 12-A1 (1.0 g, 5.9 mmol) and 4-fluoro-3(trifluoromethyl)phenol (2.1 g, 11.8 mmol, 2 equiv., commercially available) were dissolved in acetonitrile (20 mL). Under nitrogen, K2CO3 (1.6 g, 11.8 mmol, 2 equiv.) was added to the system. The temperature was raised to 80 °C. After monitoring for 1 h, the starting material disappeared, and the reaction was terminated. The workup was as follows: After cooling to room temperature, the system was suction filtered through Celite and washed with DCM. After spin-drying the mother liquor, the sample was mixed with 300-400 silica gel (10 times) and passed through a flash column (n-heptane:EA = 94%:6%) to obtain 12-A2 (1.15 g, 59.2%) as a pale yellow oily liquid. 1 H-NMR (400M, CDCl3): δppm10.00 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.76 (dd, J1=8.4Hz, J2=1. 6Hz, 1H), 7.46(d, J=1.6Hz, 1H), 7.33~7.34(m, 1H), 7.27~7.28(m, 1H), 7.26~7.53(m, 1H).

[0123] Under nitrogen protection, 12-A2 (620 mg, 1.9 mmol) and TMSCF3 (539 mg, 3.8 mmol, 2 equiv.) were dissolved in THF (6 mL). The temperature was lowered to 0 °C. TBAF (0.04 mL, 0.04 mmol, 1 min THF, commercially available) was added dropwise to the system. After maintaining the temperature at 0 °C for 30 min, 12-A2 completely disappeared. 3 N HCl (3 mL) was added dropwise to the system, which became clear. After stirring at 0 °C for 1 h, all the raw material was converted to the product. The workup was as follows: Extraction was performed with DCM (5 mL × 3). The organic phase was washed with water (5 mL × 3), dried, and spun dry. The sample was mixed with 300-400 silica gel (7 times) (n-heptane:EA = 95:5) to give 12-A3 (600 mg, 79.1%) as a pale yellow oil. 1H-NMR (400M, CDCl3): δppm8.02 (d, J=8.4Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.29 (dd, J1=6.4Hz, J2=2.8Hz, 1H), 7.24~7.18(m, 3H), 5.08(dd, J1=12.4Hz, J2=6.0Hz, 1H).

[0124] Under nitrogen protection, POCl3 (384 mg, 2.5 mmol, 2 equiv.) was dissolved in DCM (5 mL). The temperature was then lowered to -40 °C. Next, 12-A3 (500 mg, 1.3 mmol) was dissolved in DCM (2 mL), and TEA (317 mg, 3.1 mmol, 2.5 equiv.) was added dropwise to the system. After maintaining the temperature at -40 °C for 2 h, 12-A3 was completely converted to the intermediate. Next, 2-bromoethylamine hydrobromide (2.1 g, 10.0 mmol, 8 equiv.) and TEA (1.0 g, 10.0 mmol) were added to the system and monitored. The reaction was completed in 30 min. The workup was as follows: At 0 °C, saturated aqueous ammonium chloride solution (10 mL) was added. Extraction was performed with DCM (20 mL × 3). The organic phase was washed with water and brine and spin-dried. Then, it was mixed with 200-300 silica gel (8 times) (n-heptane:EA=1:1) to obtain a pale yellow oily substance, 12-A4 (350 mg, 39.0%). 1 H-NMR (400M, CDCl): δ ppm 8.06 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.33-7.35 (m, 1H), 7.24-7.29 (m, 2), 7.17 (s, 1H), 5.70 (dd, J = 11.5, 6.0 Hz, 1H), 3.86-2.96 (m, 10H). LCMS: calculated 690.9, found 691.8 ([M+1] + ).

[0125] Under nitrogen protection, 12-A4 (350 mg, 0.5 mmol) was dissolved in THF (10 mL). Then, AgO (587 mg, 2.5 mmol) and DIEA (327 mg, 2.5 mmol, 5 equiv.) were added to the system. The temperature was raised to reflux and the reaction was monitored. The reaction was completed in 2 h, and the temperature was lowered to room temperature. The mixture was filtered through Celite with suction, washed with DCM, and the mother liquor was spin-dried. Neutral preparative chromatography afforded compound No. 12 (74 mg, 26.4%) as a pale yellow solid. 1 H-NMR (400M, CDCl3): δppm8.04 (d, J=8.4Hz, 1H), 7.43 (dd, J=8.4Hz, 1H), 7.28~7. 26(m, 1H), 7.23~7.22(m, 2H), 7.18(s, 1H), 5.76~5.71(m, 1H), 2.27~2.02(m, 8H). LCMS: Calculated value 529.1, actual value 530.0 ([M+1] + ).

[0126] Synthesis of Compound No. 13 [ka] Under nitrogen protection, 13-A1 (500 mg, 2.95 mmol) and 3-hydroxyquinoline (470 mg, 3.24 mmol, commercially available) were dissolved in acetonitrile (ACN) (5 mL). Potassium carbonate (830 mg, 6 mmol) was added. The temperature was raised to 80 °C and stirred for 4 h. After the reaction was complete, the mixture was filtered through Celite and concentrated. The samples were mixed and subjected to column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to obtain the product (560 mg, 64.5%) as a white solid, which was used directly in the next step. 1 H-NMR (300MHz, DMSO): δppm10.02(s, 1H), 8.92(d, J=2.6Hz, 1H), 8.34(d, J=8.2Hz, 1H), 8.09(d, J=8.6Hz, 2H), 7.94(t, J=8.2Hz, 2H), 7.82(s, 1H), 7.76(t, J=7.1Hz, 1H), 7.65(t, J=7.2Hz, 1H). LCMS: Calculated value 294.0, Actual value 295.0 ([M+1]+ ).

[0127] Under nitrogen protection, 13-A2 (460 mg, 1.56 mmol) and trifluoromethyltrimethylsilane (430 mg, 3 mmol) were dissolved in THF (5 mL). At 0 °C, a THF solution of tetrabutylammonium fluoride (0.1 mL, 0.1 mmol, 1 M) was added dropwise. The temperature was maintained for 6 h. 1 N hydrochloric acid (2 mL) was added and stirred for 10 min. THF was removed by concentration. Water (10 mL) was added to the crude product, which was then extracted with DCM (20 mL). The organic phase was separated and concentrated, and the samples were combined. The crude product was purified by column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to give the product (400 mg) as a pale yellow solid. 1 H-NMR (400MHz, DMSO): δppm8.87(d, J=2.8Hz, 1H), 8.23(d, J=8.5Hz, 1H), 8.08(d, J=8.4Hz, 1H), 8.00(d, J=2.7Hz, 1H), 7.96(d, J=7.4Hz, 1H), 7.76(ddd, J=8.4, 6.9, 1.4Hz, 1H), 7.69~7.62(m, 1H), 7.58(d, J=8.5Hz, 1H), 7.43(s, 1H), 7.19(d, J=5.9Hz, 1H), 5.43~5.31(m, 1H). LCMS: Calculated value 364.0, Actual value 365.0 ([M+1] + ).

[0128] Under nitrogen protection, POCl3 (168 mg, 1.1 mmol) was added dropwise to ultra-dry DCM (5 mL) and the temperature was lowered to -30 °C. A solution of 13-A3 (200 mg, 0.55 mmol) in DCM (5 mL) was added dropwise, followed by TEA (170 mg, 1.65 mmol). The temperature was maintained at -30 °C for 6 h until the starting material was completely consumed. 2-Bromoethylamine hydrobromide (897 mg, 4.4 mmol) was added at -30 °C, followed by TEA (440 mg, 4.4 mmol). After the reaction was completed, the temperature was lowered to 0 °C. Saturated aqueous NH4Cl (10 mL) was added. After extraction with DCM (15 mL × 2), the mixture was washed with water (5 mL × 4), dried, and concentrated to give 150 mg of crude product as a yellow solid, which was used directly in the next step.

[0129] Under nitrogen protection, 13-A4 (150 mg, 0.23 mmol) was dissolved in THF (10 mL), and AgO (170 mg, 1.38 mmol) and N,N-diisopropylethylamine (163 mg, 1.38 mmol) were added. The temperature was raised to 65 °C. The reaction was completed after 2 h and then filtered through Celite with suction. The solid was washed with DCM (20 mL), and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give pure compound No. 13 (41 mg, 36%) as a white solid. 1 H-NMR (400MHz, MeOD): δppm8.82 (d, J=2.8Hz, 1H), 8.22 (d, J=8.5Hz, 1H), 8.10 (d, J=8.6Hz, 1H), 7.94~7.87 (m, 2H), 7.77(ddd, J=8.4, 6.9, 1.4Hz, 1H), 7.69~7.62(m, 2H), 7.52(s, 1H), 6.13~6.02(m, 1H), 2.29~1.98(m, 8H). LCMS: Calculated value 494.1, Actual value 495.0 ([M+1] + ).

[0130] Synthesis of Compound No. 14 [ka] Under nitrogen protection, m-bromophenol (14-A0, 1.5 g, 8.57 mmol) and p-fluorophenylboronic acid (14-A1, 1.0 g, 7.15 mmol, commercially available) were added to a mixture of dioxane (30 mL) and HO (5 mL). The mixture was evacuated and refilled with nitrogen three times. After adding Pd(AcO) (80 mg, 0.36 mmol), PPh (94 mg, 0.36 mmol), and KCO (3.0 g, 21.44 mmol), the mixture was again evacuated and refilled with nitrogen three times and the temperature was raised to 100 °C. The reaction was monitored for 1 h before completion. Workup was performed as follows: the temperature was lowered to room temperature, and the mixture was filtered with suction and extracted with EtOAc (50 mL x 3). The organic phase was washed with water, washed with brine, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 12:1-9:1) to obtain the product 14-A2 (1.1 g, yield = 62.7%) as a white solid. 1 H-NMR (300MHz, MeOD): δppm7.59~7.54 (m, 2H), 7.23~7.10 (m, 3H), 7.04~6.99 (m, 2H), 6.76 (dd, J=8.1, 1.5Hz, 1H). LCMS: Calculated value 188.1, Actual value 189.1 ([M+H] + ).

[0131] 14-A2 (580 mg, 3.08 mmol) and 3-fluoro-4-nitrobenzaldehyde (434 mg, 2.57 mmol, commercially available) were dissolved in acetonitrile (10 mL). Under nitrogen, K2CO3 (887 mg, 6.42 mmol) was added. The temperature was raised to 80 °C. After monitoring for 2 hours, the reaction was terminated. After cooling to room temperature, the mixture was suction filtered through Celite and washed with DCM. The mother liquor was concentrated and column separated (flash reverse-phase column, acetonitrile:HO = 50%:50%) to give product 14-A3 (320 mg, 33.7%) as a yellow oil. 1H-NMR (400MHz, CDCl3): δppm9.98(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.71(d, J=1.6Hz , 1H), 7.69~7.43(m, 5H), 7.28~7.27(m, 1H), 7.15~7.11(m, 2H), 7.08~7.05(m, 1H).

[0132] Under nitrogen protection, 14-A3 (350 mg, 1.04 mmol) and TMSCF3 (296 mg, 2.08 mmol) were dissolved in THF (4 mL). The temperature was lowered to 0 °C. TBAF (0.01 mL, 0.01 mmol, 1 M in THF) was added dropwise to the system. After maintaining the temperature at 0 °C for 30 min, the reactant 14-A3 completely disappeared. 3 N HCl (2 mL) was added dropwise to the system, and the system became clear. After stirring at 0 °C for 1 h, all the raw materials were converted to the product, which was extracted with DCM (5 mL × 3). The organic phase was washed with water (5 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 12:1 to 10:1) to obtain the product (350 mg, yield = 82.8%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δppm8.00 (d, J=8.4Hz, 1H), 7.53~7.34 (m, 5H), 7.24~7.23 (m, 2H), 7.15~7.11 (m, 2H), 7.03~7.00 (m, 1H), 5.03~5.02 (m, 1H). LCMS: Calculated value 407.1, Actual value 408.0 ([M+H] + ).

[0133] Under nitrogen protection, POCl3 (188 mg, 1.23 mmol) was dissolved in DCM (5 mL). The temperature was then lowered to -40 °C, and 14-A4 (250 mg, 0.61 mmol) was dissolved in DCM (2 mL) and added dropwise to the system along with TEA (155 mg, 1.53 mmol). After maintaining the temperature at -40 °C for 3 h, 15-A3 was completely converted to the intermediate. Then, bromoethylamine hydrobromide (1.0 g, 4.91 mmol) and TEA (497 mg, 4.91 mmol) were added to the system and monitored. The reaction was completed in 30 min. At 0 °C, saturated NH4Cl (5 mL) was added. The mixture was extracted with DCM (20 mL × 3). The organic phase was washed with water, washed with brine, dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA=2:1-1:1) to give the product (200 mg, 46.6%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δppm8.01 (d, J=8.4Hz, 1H), 7.54~7.33 (m, 5H), 7.25 (d, J=2.0Hz, 1H), 7.18(s, 1H), 7.15~7.10(m, 2H), 7.03(d, J=1.2Hz, 1H), 5.70~5.60(m, 1H), 3.38~3.08(m, 8H). LCMS: Calculated value 699.0, Actual value 699.9 ([M+H] + ).

[0134] Under nitrogen protection, 15-A5 (150 mg, 0.22 mmol) was dissolved in THF (15 mL), followed by the addition of silver oxide (497 mg, 2.1 mmol) and DIPEA (277 mg, 2.1 mmol). The temperature was raised to 65 °C and stirred for 1.5 h. After the reaction was completed, the temperature was lowered to room temperature and the mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give the pure product (56 mg, 48.6%) as a white solid. 1H-NMR (400MHz, MeOD) δ8.08(d, J=8.4Hz, 1H), 7.67~7.59(m, 2H), 7.56~7.46(m, 3H), 7.31(d , J=2.2Hz, 2H), 7.22~7.13(m, 2H), 7.10~7.05(m, 1H), 6.05~5.95(m, 1H), 2.29~1.89(m, 8H). LCMS: Calculated value 537.1, Actual value 538.1 ([M+H] + ).

[0135] Synthesis of Compound No. 15 [ka] 15-A1 (500 mg, 2.96 mmol, commercially available) and 15-A0 (554 mg, 2.69 mmol) were dissolved in acetonitrile (10 mL). Under nitrogen, K2CO3 (743 mg, 5.38 mmol) was added. The temperature was raised to 80 °C and monitored for 1.5 h before the reaction was terminated. After cooling to room temperature, the mixture was filtered through Celite with suction and washed with DCM. The mother liquor was concentrated and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 15:1-10:1) to give the product (535 mg, yield = 56.0%) as a brown oil. 1 H-NMR (400MHz, CDCl3): δppm9.99(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.71(d, J=8.4Hz, 1H), 7 .56~7.55(m, 3H), 7.41(dd, J1=8.44.8Hz, 1H), 7.16(d, J=8.4Hz, 2H), 7.00~6.91(m, 2H).

[0136] Under nitrogen protection, 15-A2 (400 mg, 1.13 mmol) and TMSCF3 (320 mg, 2.25 mmol) were dissolved in THF (4 mL). The temperature was lowered to 0 °C, and TBAF (0.02 mL, 0.02 mmol, 1 min THF) was added dropwise to the system. After maintaining the temperature at 0 °C for 30 min, 15-A2 completely disappeared. 3N HCl (2 mL) was added dropwise to the system, and the system became clear. After stirring at 0 °C for 1 h, the system was extracted with DCM (5 mL × 3). The organic phase was washed with water (5 mL × 3), dried, and concentrated to give the crude product (405 mg, yield = 56.4%) as a yellow solid, which was used directly in the next step. LCMS: calculated 425.3, found 426.0 ([M+1] + ).

[0137] Under nitrogen protection, POCl3 (209 mg, 1.36 mmol, commercially available) was dissolved in DCM (5 mL). The temperature was then lowered to -40 °C, and 15-A3 (290 mg, 0.68 mmol) was dissolved in DCM (2 mL) and added dropwise to the system along with TEA (173 mg, 1.70 mmol). After maintaining the temperature at -40 °C for 2 h, 15-A3 was completely converted to the intermediate. Next, bromoethylamine hydrobromide (1.1 g, 5.46 mmol) and TEA (552 mg, 5.46 mmol) were added to the system, and the reaction was monitored and completed in 30 min. At 0 °C, saturated NH4Cl (5 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with water and then with brine. The organic phase was dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA=5:1-3:1) to obtain the product as a yellow solid (250 mg, yield=51.1%). 1 H-NMR (400MHz, CDCl3): δppm8.00(d, J=8.4Hz, 1H), 7.54(d, J=7.6Hz, 2H), 7.44~7.38(m, 1H), 7.35(d, J= 8.4Hz, 1H), 7.21(s, 1H), 7.13(d, J=8.8Hz, 1H), 7.00~6.95(m, 2H), 5.68~5.62(m, 1H), 3.42~3.11(m, 8H). LCMS: Calculated value 717.2, Actual value 717.9 ([M+H] + ).

[0138] Under nitrogen protection, 15-A4 (230 mg, 0.32 mmol) was dissolved in THF (15 mL), followed by the addition of silver oxide (372 mg, 1.60 mmol) and DIPEA (207 mg, 1.60 mmol). The temperature was raised to 65 °C and stirred for 1.5 h. After the reaction was completed, the temperature was lowered to room temperature and the mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give the pure product (102 mg, 57.5%) as a white solid. 1 H-NMR (400MHz, CDCl3): δppm8.01 (d, J=8.4Hz, 1H), 7.54 (d, J=1.6Hz, 2H), 7.51~7.36 (m, 2H) ), 7.24(s, 1H), 7.12~7.11(m, 2H), 6.97~6.93(m, 2H), 5.72~5.69(m, 1H), 2.26~2.01(m, 8H). LCMS: Calculated value 555.1, Actual value 556.1 ([M+H] + ).

[0139] Synthesis of Compound No. 16 [ka] Under nitrogen protection, 3-fluoro-4-bromophenol (5.0 g, 26.2 mmol, commercially available, 97%) and p-fluorophenylboronic acid (4.0 g, 28.8 mmol, commercially available, 97%) were dissolved in a mixture of dioxane and water (100 mL, dioxane:water = 9:1). Potassium carbonate (10.8 g, 78.6 mmol) was then added. The mixture was evacuated and refilled with gas three times. Palladium acetate (295 mg, 1.31 mmol, commercially available, 95%) and triphenylphosphine (345 mg, 1.31 mmol, commercially available, 97%) were added, followed by evacuation and refilling with gas three times. The temperature was raised to 100 °C and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature. The mixture was suction filtered through Celite and washed with EA. The mother liquor was concentrated and adjusted to pH 3 with 1 N hydrochloric acid. Extraction with EA (50 mL × 3), followed by washing with water (10 mL × 3), washing with brine, drying, concentration, and column separation (100–200 mesh silica gel, n-heptane:EA = 20:1) gave product 16-A0 (3.5 g, 64.8%) as a white solid. 1 H-NMR (300 M, DMSO-d 6) δ ppm 10.02 (s, 1H), 7.52-7.47 (m, 2H), 7.34-7.23 (m, 3H), 6.71-6.64 (m, 2H). LCMS: calculated 206.1, found 204.8 ([M-H] - ).

[0140] Under nitrogen protection, 16-A1 (930 mg, 5.50 mmol, commercially available, 97%) and 16-A0 (1.36 g, 6.60 mmol) were dissolved in acetonitrile (20 mL). Potassium carbonate (1.52 g, 11.0 mmol, commercially available, 99%) was added. The temperature was raised to 85 °C and stirred for 2 h before the reaction was terminated. The temperature was then cooled to room temperature and suction filtered. The mother liquor was concentrated and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 15:1) to give 16-A2 (1.10 g, 56.4%) as a pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δppm10.05(s, 1H), 8.30(d, J=8.3Hz, 1H), 7.92(dd, J=8.3, 1.5Hz, 1H), 7.78( d, J=1.5Hz, 1H), 7.69~7.55(m, 3H), 7.36~7.28(m, 2H), 7.27~7.21(m, 1H), 7.09(dd, J=8.5, 2.3Hz, 1H).

[0141] Under nitrogen protection, 16-A2 (700 mg, 1.970 mmol) was dissolved in anhydrous THF (10 mL), and then (trifluoromethyl)-trimethylsilane (476 mg, 3.35 mmol, commercially available, 98%) was added dropwise. The temperature was lowered to 0 °C, and TBAF (0.04 mL, 1 min THF) was added dropwise. The temperature was maintained at 0 °C for 1.5 h until the reaction was complete. 2 mL of 3N hydrochloric acid was added dropwise, and the temperature was allowed to rise to room temperature. The mixture was stirred for 1 h, and 5 mL of water was added. The mixture was extracted with DCM (10 mL × 3), washed with water (5 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 15:1 to 10:1) to obtain product 16-A3 (810 mg, 96.7%) as a yellow oil. 1 H-NMR (400MHz, DMSO-d6): δppm8.19(d, J=8.5Hz, 1H), 7.63~7.52(m, 4H), 7.44(s, 1H), 7.32(t, J=8.9Hz, 2H), 7.21(d, J=5.8Hz, 1H), 7.14(dd, J=11.7, 2.4Hz, 1H), 6.97(dd, J=8.5, 2.1Hz, 1H), 5.44~5.37(m, 1H).

[0142] Under nitrogen protection, phosphorus oxychloride (580 mg, 3.76 mmol, commercially available, 97%) was added dropwise to anhydrous DCM (10 mL). The temperature was lowered to -40 °C. A DCM solution (4 mL) of 16-A3 (800 mg, 1.88 mmol) was added dropwise, followed by triethylamine (476 mg, 4.70 mmol), and the temperature was maintained at -40 °C to -35 °C for 2 h. As monitored by LC-LCMS, 16-A3 disappeared and was converted to the intermediate. 2-Bromoethylamine hydrobromide (3.08 g, 15.04 mmol) was added at -40 °C, followed by the dropwise addition of triethylamine (1.52 g, 15.04 mmol) in DCM (2 mL). The temperature was maintained at -40 °C for 1 h, resulting in complete conversion of the intermediate. The temperature was allowed to rise to 0 °C, and saturated aqueous ammonium chloride solution (5 mL) was added dropwise. After extraction with DCM (10 mL × 3), the mixture was washed with purified water (3 mL × 3), dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1-100) to obtain product 16-A4 (600 mg in total, 44.4% yield) as a white solid. 1 H-NMR (400M, CDCl3): δppm8.04(d, J=8.4Hz, 1H), 7.55~7.47(m, 2H), 7.46~7.38(m, 2H), 7.27( s, 1H), 7.19~7.10(m, 2H), 6.95~6.83(m, 2H), 5.69(dd, J=11.4, 6.1Hz, 1H), 3.50~3.18(m, 8H). LCMS: Calculated value 716.9, Actual value 717.8 ([M+H] + ).

[0143] Under nitrogen protection, 16-A4 (600 mg, 0.837 mmol) was dissolved in THF (15 mL), followed by the addition of silver oxide (1.16 mg, 5.02 mmol) and DIPEA (649 mg, 5.02 mmol). The temperature was raised to 65 °C and stirred for 3 h. After the reaction was completed, the temperature was lowered to room temperature and the mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated. 1.5 mL of anhydrous ether was added to induce crystallization, followed by suction filtration to obtain pure compound No. 16 (159 mg, yield = 34.2%) as a white solid. 1H-NMR (400MHz, MeOD) δppm8.12(t, J=8.1Hz, 1H), 7.55(m, 4H), 7.45(s, 1H), 7.19(t , J=8.8Hz, 2H), 6.98(dd, J=7.8, 5.3Hz, 2H), 6.15~5.98(m, 1H), 2.39~1.93(m, 8H). LCMS: Calculated value 555.1, Actual value 556.1 ([M+H] + ).

[0144] Synthesis of Compound No. 17 [ka] Under nitrogen protection, 17-A1 (1.7 g, 11 mmol, commercially available), 17-A2 (2 g, 10 mmol), palladium acetate (21.5 mg, 0.1 mmol), triphenylphosphine (39 mg, 0.15 mmol), and potassium carbonate (2.8, 20 mmol) were dissolved in dioxane (20 mL) and water (2 mL). The temperature was raised to 80 °C and stirred overnight. After completion of the reaction, the mixture was filtered through Celite and concentrated. The samples were combined and subjected to column chromatography (100-200 mesh silica gel, n-heptane:EA = 5:1) to obtain the product 17-A3 (900 mg, 40%) as a white solid. 1 H-NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 7.55-7.08 (m, 3H), 6.79-6.50 (m, 3H). LCMS: calculated 224.0, found 222.6 [(M-H) - ].

[0145] Under nitrogen protection, 17-A3 (500 mg, 2.2 mmol) and 3-fluoro-4-nitrobenzaldehyde (370 mg, 2.2 mmol, commercially available) were dissolved in ACN (5 mL). Potassium carbonate (830 mg, 6 mmol) was added. The temperature was raised to 80 °C and stirred for 4 h. After the reaction was complete, the mixture was filtered through Celite and concentrated. The samples were mixed and subjected to column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to obtain 700 mg of crude product 17-A4 (80% pure white solid), which was used directly in the next step.1 H-NMR (300MHz, DMSO) δ10.03(s, 1H), 8.31(d, J=8.2Hz, 1H), 7.94(d, J=8.4Hz, 1H), 7.83(s , 1H), 7.59~7.50(m, 2H), 7.40(t, J=8.8Hz, 1H), 7.32~7.16(m, 2H), 7.10(d, J=8.6Hz, 1H).

[0146] Under nitrogen protection, 17-A4 (680 mg, 1.82 mmol) and trifluoromethyltrimethylsilane (510 mg, 3.6 mmol, commercially available) were dissolved in THF (8 mL). At 0 °C, a THF solution of tetrabutylammonium fluoride (0.1 mL, 0.1 mmol, 1 M, commercially available) was added dropwise, and the temperature was maintained for 6 h. 1N hydrochloric acid (2 mL) was added and stirred for 10 min. THF was removed by concentration. Water (10 mL) was added to the crude product, and it was extracted with DCM (20 mL). The organic phase was separated and concentrated, and the samples were mixed. The crude product was purified by column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to obtain product 17-A5 (400 mg, yield = 49.6%, purity = 90%) as a pale yellow solid. 1 H-NMR (300MHz, DMSO) δ8.19 (d, J=7.8Hz, 1H), 7.76 (t, J=8.5Hz, 1H), 7.57~7.51 (m, 2 H), 7.38(s, 1H), 7.28~7.19(m, 3H), 6.89(dd, J=8.8, 1.7Hz, 1H), 5.40~5.36(m, 1H).

[0147] Under nitrogen protection, POCl3 (168 mg, 1.1 mmol, commercially available) was added dropwise to ultra-dry DCM (5 mL). The temperature was lowered to -30 °C. A solution of 17-A5 (220 mg, 0.5 mmol) in DCM (5 mL) was added dropwise, followed by TEA (170 mg, 1.65 mmol). The temperature was maintained at -30 °C for 6 h until the starting material was completely consumed. 2-Bromoethylamine hydrobromide (897 mg, 4.4 mmol) was added at -30 °C, followed by TEA (440 mg, 4.4 mmol). After the reaction was completed, the temperature was lowered to 0 °C. A saturated aqueous solution of NH4Cl (10 mL) was added. After extraction with DCM (15 mL × 2), washing with water (5 mL × 4), drying, and concentration gave 250 mg of crude product 17-A6 as a yellow solid, which was used directly in the next step reaction. LCMS: calculated 732.9, found 733.9 ([M+H] + ).

[0148] Under nitrogen protection, 17-A6 (250 mg, 0.34 mmol) was dissolved in THF (10 mL), AgO (210 mg, 1.7 mmol, commercially available) and N,N-diisopropylethylamine (220 mg, 1.7 mmol) were added, and the temperature was raised to 65 °C. The reaction was completed after 2 h and then filtered through Celite with suction. The solid was washed with DCM (20 mL), and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give 22 mg of pure compound No. 17 (white solid, 11%). 1 H-NMR (400MHz, DMSO) δ8.26(d, J=8.5Hz, 1H), 7.67(d, J=8.5Hz, 1H), 7.59~7.48(m, 3H), 7.41(dt, J=10 .3, 2.5Hz, 1H), 7.24~7.19(m, 2H), 7.03(dd, J=8.5, 2.3Hz, 1H), 6.36~6.32(m, 1H), 2.20~1.91(m, 8H). LCMS: Calculated value 573.1, Actual value 574.1 ([M+H] + ).

[0149] Synthesis of Compound No. 18 [ka] Under nitrogen protection, 2-bromo-5-hydroxypyridine (3.0 g, 17.2 mmol, Xingtai All Fine) and p-fluorophenylboronic acid (18-A0, 2.7 g, 19.0 mmol, commercially available) were dissolved in a mixture of dioxane and water (60 mL, dioxane:water = 9:1). Potassium carbonate (4.7 g, 34.4 mmol) was then added. The mixture was evacuated and refilled with gas three times. Palladium acetate (193 mg, 0.86 mmol, commercially available) and triphenylphosphine (225 mg, 0.86 mmol, commercially available) were added, followed by evacuation and refilling with gas three times. The temperature was raised to 100 °C and stirred overnight. After completion of the reaction, the temperature was lowered to room temperature. The mixture was suction filtered through Celite, washed with EA, and the mother liquor was concentrated. 15 mL of water was added, and the mixture was extracted with EA (50 mL × 3), followed by washing with water (10 mL × 3), washing with brine, drying, concentrating, and column separation (200-300 mesh silica gel, n-heptane:EA = 15:1) gave the product as a white solid (1.2 g, 36.9%). 1 H-NMR (400 M, DMSO-d 6) :δppm10.03(s, 1H), 8.20(d, J=2.7Hz, 1H), 8.00(dd, J=8.8, 5.6Hz, 2H), 7.78(d, J=8.6Hz, 1H), 7.32~7.18(m, 3H). LCMS: Calculated value 189.1, Actual value 190.2 ([M+H] + ).

[0150] Under nitrogen protection, 18-A1 (600 mg, 3.55 mmol) and 18-A0 (806 mg, 4.26 mmol) were dissolved in acetonitrile (15 mL). Potassium carbonate (980 mg, 7.1 mmol, commercially available) was then added. The temperature was raised to 85 °C and stirred for 2 h before the reaction was terminated. The temperature was lowered to room temperature and suction filtered. The mother liquor was concentrated and column-separated (200-300 mesh silica gel, n-heptane:EA = 10:1) to obtain the product 18-A2 (760 mg, 63.3%) as a pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δppm10.03(s, 1H), 8.59(d, J=2.8Hz, 1H), 8.31(d, J=8.3Hz, 1H), 8.19~8. 11(m, 2H), 8.07(d, J=8.7Hz, 1H), 7.90(dd, J=8.3, 1.6Hz, 1H), 7.78~7.70(m, 2H), 7.37~7.26(m, 2H). LCMS: Calculated value 338.1, Actual value 339.0 ([M+H] + ).

[0151] Under nitrogen protection, 18-A2 (700 mg, 2.07 mmol) was dissolved in anhydrous THF (10 mL) and then (trifluoromethyl)-trimethylsilane (500 mg, 3.52 mmol) was added dropwise. The temperature was lowered to 0 °C, and TBAF (0.03 mL, 1 min THF) was added dropwise. The reaction was maintained at 0 °C for 1.5 h until completion, and 3 N hydrochloric acid (2 mL) was added dropwise. The temperature was allowed to rise to room temperature. After stirring for 1 h, 5 mL of water was added. The mixture was extracted with DCM (10 mL × 3), washed with water (5 mL × 3), dried, concentrated, and column-separated (200-300 mesh silica gel, n-heptane:EA = 15:1 to 10:1) to obtain the product (550 mg, 65.1%) as a yellow oil. 1 H-NMR (400MHz, DMSO-d6): δppm8.52 (d, J=2.9Hz, 1H), 8.19 (d, J=8.5Hz, 1H), 8.16~8.10 (m, 2H), 8.06 (d, J=8.8Hz, 1H), 7.64 (dd, J=8.8, 2.9Hz, 1H), 7.55(dd, J=8.7, 3.3Hz, 1H), 7.38(s, 1H), 7.36~7.28(m, 2H), 7.18(dd, J=5.8, 3.4Hz, 1H), 5.43~5.34(m, 1H). LCMS: Calculated value 408.1, Actual value 409.2 ([M+H] + ).

[0152] Under nitrogen protection, phosphorus oxychloride (414 mg, 2.70 mmol, commercially available) was added dropwise to anhydrous DCM (10 mL) and the temperature was lowered to -40 °C. A DCM solution (4 mL) of 18-A3 (550 mg, 1.35 mmol) was added dropwise, followed by triethylamine (342 mg, 3.36 mmol), and the temperature was maintained at -40 °C to -35 °C for 2 h. As monitored by LC-LCMS, 18-A3 disappeared and was converted to the intermediate. 2-Bromoethylamine hydrobromide (2.2 g, 10.8 mmol) was added at -40 °C, followed by the dropwise addition of a DCM solution (2 mL) of triethylamine (1.1 g, 10.8 mmol). The temperature was maintained at -40 °C for 1 h, and the intermediate was completely converted. The temperature was allowed to rise to 0 °C, and saturated aqueous ammonium chloride solution (5 mL) was added dropwise. After extraction with DCM (10 mL × 3), washing with purified water (3 mL × 3), drying, concentration, and column separation (200-300 mesh silica gel, n-heptane:EA = 1:1 ~ 100% EA) was performed to obtain the product (520 mg, 55.0%) as a white solid. 1 H-NMR (400M, CDCl3): δppm8.49 (d, J=2.7Hz, 1H), 8.06 (dd, J=8.4, 2.7Hz, 1H), 8.01~7.94 (m, 2H), 7.77 (d, J=8.7Hz, 1H), 7.54~ 7.48(m, 1H), 7.43(d, J=8.3Hz, 1H), 7.26~7.24(m, 1H), 7.18(t, J=8.7Hz, 2H), 5.69(dq, J=12.3, 6.2Hz, 1H), 3.49~3.16(m, 8H). LCMS: Calculated value 700.0, Actual value 700.9 ([M+H] + ).

[0153] Under nitrogen protection, 18-A4 (520 mg, 0.743 mmol) was dissolved in THF (15 mL), followed by the addition of silver oxide (1.03 g, 4.46 mmol, commercially available) and DIPEA (580 mg, 4.46 mmol). The temperature was raised to 65 °C and stirred for 3 h. After the reaction was completed, the temperature was lowered to room temperature and the mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 18 (106.7 mg, 26.7%) as a white solid. 1H-NMR (400MHz, MeOD): δppm8.43(d, J=2.9Hz, 1H), 8.16(d, J=8.5Hz, 1H), 8.07~7.97(m, 2H), 7.92(d, J =8.8Hz, 1H), 7.65~7.54(m, 2H), 7.46(s1H), 7.24~7.19(m, 2H), 6.13~6.03(m, 1H), 2.26~2.08(m, 8H). LCMS: Calculated value 538.1, Actual value 539.1 ([M+H] + ).

[0154] Synthesis of Compound No. 19 [ka] Under nitrogen protection, 19-A1 (500 mg, 2.65 mmol, commercially available), 19-A2 (460 mg, 2.65 mmol, commercially available), tetrakistriphenylphosphine palladium (373 mg, 0.3 mmol), and potassium fluoride (300 mg, 5.2 mmol) were dissolved in toluene (10 mL) and water (1 mL). The temperature was raised to 80 °C and stirred overnight. After the reaction was complete, the mixture was filtered through Celite and concentrated. The samples were mixed and subjected to column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to obtain the product 19-A3 (600 mg, 94.7%) as a white solid. 1 H-NMR (300MHz, DMSO) δ10.24(s, 1H), 8.26(d, J=2.4Hz, 1H), 8.19(d, J=8.1Hz, 2H), 7.91(d, J=8.7Hz, 1H), 7.78(d, J=8.1Hz, 2H), 7.29(dd, J=8.6, 2.7Hz, 1H). LCMS: Calculated value 239.0, Actual value 240.0 ([M+H] + ).

[0155] Under nitrogen protection, 19-A3 (870 mg, 2.9 mmol) and 3-fluoro-4-nitrobenzaldehyde (490 mg, 2.9 mmol, commercially available) were dissolved in ACN (8 mL). Potassium carbonate (830 mg, 6 mmol) was added. The temperature was raised to 80 °C and stirred for 4 h. After the reaction was complete, the mixture was suction filtered through Celite and concentrated. The samples were combined and subjected to column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to obtain the product 19-A4 (640 mg) as a white solid. 1 H-NMR (300MHz, CDCl3) δ10.03 (s, 1H), 8.57 (d, J=2.7Hz, 1H), 8.15~8.12 (m, 3H), 7.87~7.75 (m, 4H), 7.60~7.51 (m, 2H). LCMS: Calculated value 388.0, Actual value 389.1 ([M+H] + ).

[0156] Under nitrogen protection, 19-A4 (640 mg, 1.64 mmol) and trifluoromethyltrimethylsilane (430 mg, 3 mmol, commercially available) were dissolved in THF (5 mL). At 0 °C, a THF solution of tetrabutylammonium fluoride (0.1 mL, 0.1 mmol, 1 M, commercially available) was added dropwise. The temperature was maintained for 6 h. 1 N hydrochloric acid (2 mL) was added and stirred for 10 min. THF was removed by concentration. Water (10 mL) was added to the crude product, and extraction was performed with DCM (20 mL). The organic phase was separated and concentrated, and the samples were combined. The crude product was isolated by column chromatography (100-200 mesh silica gel, n-heptane:EA = 10:1) to give the product (640 mg, 85.2%) as a pale yellow solid. 1 H-NMR (300MHz, DMSO) δ8.59(d, J=2.7Hz, 1H), 8.30(d, J=7.5Hz, 2H), 8.19(t, J=9.2Hz, 2H), 7.86(d, J=8 .5Hz, 2H), 7.72~7.65(m, 1H), 7.59~7.56(m, 1H), 7.43(s, 1H), 7.20(d, J=5.8Hz, 1H), 5.39~5.37(m, 1H). LCMS: Calculated value 458.0, Actual value 459.0 ([M+H] + ).

[0157] Under nitrogen protection, POCl3 (200 mg, 1.3 mmol) was added dropwise to ultra-dry DCM (5 mL). The temperature was lowered to -30 °C. A solution of 19-A5 (300 mg, 0.65 mmol) in DCM (5 mL) was added dropwise, followed by TEA (270 mg, 2.6 mmol). The temperature was maintained at -30 °C for 6 h until the starting material was completely consumed. 2-Bromoethylamine hydrobromide (1.1 g, 5.2 mmol) was added at -30 °C, followed by TEA (530 mg, 5.2 mmol). After the reaction was completed, the temperature was lowered to 0 °C, and saturated aqueous NH4 salt (10 mL) was added. After extraction with DCM (15 mL × 2), washing with water (5 mL × 4), drying, and concentration gave 200 mg of crude product as a yellow solid, which was used directly in the next step reaction. 1 H-NMR (400MHz, CDCl3) δ8.46 (d, J=2.6Hz, 1H), 8.07~7.99 (m, 3H), 7.78~7.75 (m, 1H) ), 7.68(d, J=8.2Hz, 2H), 7.48~7.33(m, 3H), 5.65~5.61(m, 1H), 3.51~3.04(m, 10H). LCMS: Calculated value 747.9, Actual value 748.9 ([M+H] + ).

[0158] Under nitrogen protection, 19-A6 (150 mg, 0.23 mmol) was dissolved in THF (10 mL), and AgO (170 mg, 1.38 mmol, commercially available) and N,N-diisopropylethylamine (163 mg, 1.38 mmol) were added. The temperature was raised to 65 °C, and the reaction was completed in 2 h, followed by suction filtration through Celite. The solid was washed with DCM (20 mL), and the mother liquor was concentrated and purified by high-performance liquid preparative chromatography to give the pure product (41 mg, 36%) as a white solid. 1H-NMR (400MHz, DMSO) δ8.61(d, J=2.8Hz, 1H), 8.31(d, J=8.2Hz, 2H), 8.27(d, J=8.5Hz, 1H), 8.21(d, J=8.8Hz, 1H), 7.87( d, J=8.4Hz, 2H), 7.72(dd, J=8.8, 2.9Hz, 1H), 7.65(d, J=8.5Hz, 1H), 7.56(s, 1H), 6.32~6.28(m, 1H), 2.17~1.90(m, 8H). LCMS: Calculated value 588.1, Actual value 589.1 ([M+H] + ).

[0159] Synthesis of Compound No. 20 [ka] Under nitrogen protection, 2-bromo-5-hydroxypyridine (1.5 g, 8.52 mmol, commercially available) and p-hydroxyphenylboronic acid (1.4 g, 10.23 mmol, commercially available) were added to a mixture of DME (33 mL) and HO (7 mL). The mixture was evacuated and filled with nitrogen three times. Pd(PPh) (300 mg, 0.26 mmol, commercially available) and NaCO (1.8 g, 17.05 mmol) were added, followed by evacuation and filling with nitrogen three times. The temperature was raised to 80 °C and the reaction was monitored for 2.5 h before completion. The temperature was lowered to room temperature and extracted with EtOAc (50 mL × 3). The organic phase was washed with water, washed with brine, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA=12:1-9:1) to obtain the product as a white solid (1.4 g, yield=86.8%). 1 H-NMR (300MHz, MeOD): δppm8.43 (d, J=2.7Hz, 1H), 7.81~7.77 (m, 3H), 7.64~7.58 (m, 1H), 6.87 (d, J=8.7Hz, 2H). LCMS: Calculated value 189.1, Actual value 190.1 ([M+H] + ).

[0160] Under nitrogen protection, 20-A3 (i.e., compound No. 46, 100 mg, 0.27 mmol) was dissolved in acetone (15 mL), followed by stirring at room temperature for 2 h with 20-A2 (102 mg, 0.54 mmol) and CsCO (309 mg, 0.95 mmol). After the reaction was complete, the mixture was filtered through Celite with suction. The solid was washed with acetone, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 20 (17 mg, 11.7%) as a brown solid. 1 H-NMR (400MHz, MeOD) δ8.52 (d, J=2.9Hz, 1H), 8.10 (d, J=8.5Hz, 1H), 8.06 (d, J=8.8Hz, 2H), 7.92 (dd, J=8.8, 4.3Hz, 1H), 7. 68(dt, J=8.6, 2.9Hz, 1H), 7.54(d, J=8.6Hz, 1H), 7.37(s, 1H), 7.19(d, J=8.8Hz, 2H), 6.06~5.99(m, 1H), 2.27~1.97(m, 8H). LCMS: Calculated value 538.1, Actual value 539.1 ([M+H] + ).

[0161] Synthesis of Compound No. 21 [ka] Under nitrogen protection, 21-A1 (2.0 g, 14.5 mmol) and thionyl chloride (8 mL) were stirred at room temperature for 1 h, and the thionyl chloride was removed by spinning. 10 mL of THF was added, the system was cooled to 0 °C, and a mixture of piperidine (1.85 g, 21.8 mmol) and TEA (2.2 g, 21.8 mmol) was added. After completion, the system temperature was allowed to rise to room temperature. After monitoring for 1 h, the reaction was terminated. The system was dissolved in EtOAc (50 mL) and washed with HO (30 mL × 5). The organic phase was dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1 to 0:1) to obtain the product (720 mg, yield = 24.3%) as a white solid. 1H-NMR (400MHz, DMSO-d6): δppm, 9.64 (s, 1H) 7.23 (t, J=8.0Hz, 1H), 6.79~6.82 (m, 1H), 6. 73(d, J=7.6Hz, 1H), 6.70(d, J=1.2Hz, 1H), 3.54(m, 2H), 3.26(m, 2H), 1.61~1.50(m, 6H). LCMS: Calculated value 205.1, Actual value 206.2 ([M+H] + ).

[0162] Under nitrogen protection, 21-A2 (60 mg, 0.25 mmol) was dissolved in acetone (10 mL), followed by the addition of 21-A3 (i.e., compound No. 46, 55.6 mg, 0.25 mmol) and CsCO (245 mg, 0.75 mmol) and stirring at room temperature for 2.5 h. After the reaction was complete, the mixture was filtered through Celite with suction. The solid was washed with acetone, and the mother liquor was concentrated. Pure compound No. 21 (25.0 mg, 16.9%) was obtained as an off-white solid by preparative high-performance liquid chromatography. 1 H-NMR (400MHz, CD3OD): δppm, 8.21 (d, J=8.0Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.53 (t, J=8.0Hz, 1H), 7.41 (s, 1H), 7.24 (d, J=8.0Hz, 1H), 7.20(dd, J=8.0, 2.4Hz, 1H), 7.05(s, 1H), 6.33~6.25(m, 1H), 3.55(m, 2H), 3.25(m, 2H), 2.15~1.93(m, 8H), 1.59~1.52(m, 6H). LCMS: Calculated value 554.2, Actual value 555.2 ([M+H] + ).

[0163] Synthesis of Compound No. 22 [ka] Under nitrogen protection, 22-A1 (0.2 g, 1.45 mmol) and T3P solution (propylphosphonic acid anhydride coupling reagent, CAS: 68957-94-8, 50% EA solution) were dissolved in 5 mL of DCM, 4,4-difluoropiperidine (0.25 g, 1.6 mmol) was added, and the mixture was stirred at room temperature. After 2 hours of monitoring, the reaction was terminated. The system was dissolved in DCM (20 mL) and washed with water (10 mL x 5). The organic phase was dried, concentrated, and column-separated (200-300 mesh silica gel, n-heptane:EA = 1:1) to obtain the product (190 mg, yield = 54.4%) as a white solid. 1 H-NMR (400MHz, CDCl3): δppm6.94~6.89(m, 2H), 6.87(d, J=8.0Hz, 1H), 6.36(s, 1H), 3.87(m, 2H), 3.56(m, 2H), 2.04~1.97(m, 4H). LCMS: Calculated value 241.1, Actual value 242.1 ([M+H] + ).

[0164] Under nitrogen protection, 22-A2 (60 mg, 0.25 mmol) was dissolved in acetone (10 mL), followed by stirring at room temperature for 2.5 h with 22-A3 (i.e., compound No. 46, 55.6 mg, 0.25 mmol) and CsCO (245 mg, 0.75 mmol). After the reaction was complete, the mixture was filtered through Celite with suction. The solid was washed with acetone, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 22 (25.0 mg, 16.9%) as a pale yellow solid. 1 H-NMR (400MHz, MeOD): δppm8.21(d, J=8.4Hz, 1H), 7.60~7.54(m, 2H), 7.40(s, 1H), 7.33(d, J=8 .0Hz, 1H), 7.25~7.21(m, 2H), 6.33~6.26(m, 1H), 3.68(m, 2H), 3.40(m, 2H) 2.15~1.93(m, 12H). LCMS: Calculated value 590.1, actual value 591.1 ([M+H] + ).

[0165] Synthesis of Compound No. 23 [ka] Under nitrogen protection, 23-A1 (2.0 g, 14.5 mmol) and thionyl chloride (8 mL) were stirred at room temperature for 1 h, and the thionyl chloride was removed by spinning. 10 mL of THF was added, the system was cooled to 0 °C, and a mixture of tetrahydropyrrole (1.5 g, 21.8 mmol) and TEA (2.2 g, 21.8 mmol) was added. After completion of the reaction, the system temperature was allowed to rise to room temperature. After monitoring for 1 h, the reaction was terminated. The system was dissolved in EtOAc (40 mL) and washed with HO (40 mL × 5). The organic phase was dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1 to EA) to obtain the crude product (850 mg, 30.7%, crude product content 80%) as a colorless oil.

[0166] Under nitrogen protection, 23-A2 (103 mg, 0.54 mmol) was dissolved in acetone (10 mL), and then 23-A3 (i.e., compound No. 46, 120 mg, 0.54 mmol) and CsCO (265 mg, 0.81 mmol) were added and stirred at room temperature for 2.5 h. After the reaction was completed, the mixture was filtered through Celite with suction. The solid was washed with acetone, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 23 (35.0 mg, 18.8%) as an off-white solid. 1 H-NMR (400MHz, MeOD): δppm8.20 (d, J=8.0Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.53 (t, J=8.0Hz, 1H) 7.39~7.38 (m, 2H), 7.24~7.21(m, 2H), 6.32~6.25(m, 1H), 3.43(t, J=6.8Hz, 2H) 3.36~3.34(m, 2H) 1.92~2.14(m, 8H) 1.84~1.77(m, 4H). LCMS: Measured value 540.1, Actual value 541.1 ([M+H] + ).

[0167] Synthesis of Compound No. 24 [ka] Under nitrogen protection, 24-A1 (500 mg, 3.6 mmol, commercially available) and T3P (4.6 g, 14.4 mmol, 50% EA solution) were dissolved in 10 mL of DCM, and 4,4-dimethylpiperidine hydrochloride (540 mg, 3.6 mmol, Shanghai Anmike) was added and stirred at room temperature. After monitoring for 2 hours, the reaction was terminated. The system was dissolved in DCM (20 mL) and washed with HO (10 mL × 5). The organic phase was dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1) to obtain the product (600 mg, yield = 71.4%) as a pale yellow solid. 1 H-NMR (400MHz, MeOD): δppm7.20 (t, J=8.0Hz, 1H), 6.82~6.81 (m, 1H), 6.80~6.75 (m, 1H), 6.73~6.72(m, 1H), 3.66(m, 2H), 3.34(s, 2H), 1.41(m, 2H), 1.30~1.29(m2H), 0.97(s, 6H). LCMS: Calculated value 233.1, Actual value 234.1 ([M+H] + ).

[0168] Under nitrogen protection, 24-A2 (103 mg, 0.54 mmol) was dissolved in acetone (10 mL), followed by stirring at room temperature for 2.5 h with 24-A3 (i.e., compound No. 46, 120 mg, 0.54 mmol) and CsCO (265 mg, 0.81 mmol). After the reaction was complete, the mixture was filtered through Celite with suction. The solid was washed with acetone, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 24 (35.0 mg, 18.8%) as an off-white solid. 1H-NMR (400MHz, DMSO): δppm8.21(d, J=8.4Hz, 1H), 7.59(d, J=8.4Hz, 1H), 7.53(t, J=8.0Hz, 1H), 7.40(s, 1H), 7.24(d, J=76Hz, 1H), 7.19(ddJ =76, 2.4Hz, 1H), 7.06~7.07(m, 1H), 6.32~6.27(m, 1H), 3.57(m, 2H), 3.26(m, 2H), 2.13~1.94(m, 8H), 1.23(m, 2H), 1.14(m, 2H), 0.94(s, 6H). LCMS: calculated 582.2, found 583.2 ([M+H] + ).

[0169] Synthesis of Compound No. 25 [ka] Under nitrogen protection, 25-A1 (500 mg, 2.19 mmol) and 4-(trifluoromethyl)piperidine (1.0 g, 6.57 mmol, commercially available) were added to DCM (10 mL), followed by dropwise addition of T3P (5.6 g, 8.77 mmol, 50% in EtOAc, commercially available). The system was then cooled to 5 °C, and DIEA (1.2 g, 8.77 mmol, commercially available) was added dropwise to the system. After completion, the temperature was allowed to rise to room temperature. After monitoring for 2 hours, the reaction was terminated. The solvent was concentrated, then dissolved in EtOAc (20 mL), and washed with HO (20 mL × 5). The organic phase was dried and concentrated to give the product (790 mg, yield = 98.9%) as a white solid. 1 H-NMR (400MHz, MeOD): δppm7.42(d, J=7.1Hz, 2H), 7.40~7.33(m, 3H), 7.32~7.26(m, 1H), 7.13~7.10(m, 1H), 6.98~6.95(m, 2H), 5.14(s, 2H), 4.70(m , 1H), 3.75~7.72(m, 1H), 3.08~3.08(m, 1H), 2.84(m, 1H), 2.54~2.46(m, 1 H), 1.98(m, 1H), 1.81~1.76(m, 1H), 1.55~1.53(m, 1H), 1.44~1.35(m, 1H). LCMS: calculated 363.1, found 364.1 ([M+H] + ).

[0170] Under nitrogen protection, 25-A2 (780 mg, 2.15 mmol) and Pd(OH)2 (90 mg, commercially available) were added to EtOH (10 mL). The mixture was evacuated and filled with nitrogen three times. After evacuating and filling with hydrogen three times, the temperature was raised to 35 °C overnight. The reaction was monitored the next day until completion. The mixture was suction filtered through Celite and washed with DCM. The mother liquor was concentrated to give 25-A3 (390 mg, yield = 66.6%) as a white solid. 1 H-NMR (400MHz, MeOD): δppm77.26(t, J=7.9Hz, 1H), 6.87(dd, J=8.1, 2.3Hz, 1H), 6.83(d, J=7.5Hz, 1H), 6.80~6.76(m , 1H), 4.70(m, 1H), 3.84(m, 1H), 3.13(m, 1H), 2.85(m, 1H), 2.57~2.47(m, 1H), 2.06~1.79(m, 2H), 1.50~1.46(m, 2H). LCMS: Calculated value 273.1, Actual value 274.2 ([M+H] + ).

[0171] Under nitrogen protection, 25-A4 (i.e., compound No. 46, 100 mg, 0.27 mmol) was dissolved in acetone (10 mL), followed by stirring at room temperature for 2 h with 25-A3 (148 mg, 0.54 mmol) and CsCO (309 mg, 0.95 mmol, commercially available). The reaction was then terminated. The workup was performed as follows: the mixture was filtered through Celite with suction, washed with acetone, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 25 (40.8 mg, 24.2%) as a yellow solid. 1H-NMR (400MHz, DMSO) δ8.20(d, J=8.5Hz, 1H), 7.59(d, J=8.6Hz, 1H), 7.54(t, J=7. 9Hz, 1H), 7.39(s, 1H), 7.28(d, J=7.6Hz, 1H), 7.22(dd, J=8.2, 2.0Hz, 1H), 7.13(s, 1H), 6.28(dq, J=12.9, 6.4Hz, 1H), 4.53(m, 1H), 3.60(m, 1H), 3.08(m, 1H), 2.78(m , 1H), 2.71~2.57(m, 1H), 2.13~1.92(m, 8H), 1.87~1.76(m, 2H), 1.39~1.37(m, 2H). LCMS: Calculated value 622.1, Actual value 623.1 ([M+H] + ).

[0172] Synthesis of Compound No. 26 [ka] Under nitrogen protection, 26-A1 (1.0 g, 4.38 mmol) and p-hydroxypiperidine (1.3 g, 13.12 mmol) were added to DCM (20 mL), followed by dropwise addition of T3P (11.2 g, 8.77 mmol, 50% in EtOAc). After cooling the system to 5 °C, DIEA (2.4 g, 17.54 mmol, commercially available) was added dropwise. After completion, the temperature was allowed to rise to room temperature. After 5 h of monitoring, the reaction was terminated. The workup was as follows: the system was concentrated, dissolved in EtOAc (40 mL), and washed with HO (40 mL × 5). The organic phase was dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1 to 0:1) to obtain 26-A2 (920 mg, yield = 67.4%) as a colorless oil. 1H-NMR (400MHz, MeOD): δppm7.43(d, J=8.0Hz, 2H), 7.38(t, J=7.6Hz, 3H), 7.32~7.28(m, 1H), 7.10(d, J=8.4Hz, 1H), 6.98(m, 1H), 5.95(d, J=8.0H) z, 1H), 5.13(s, 2H), 4.14(s, 1H), 3.89~3.85(m, 1H), 3.56(s, 1H), 3.17( s, 1H), 1.92(s, 1H), 1.74(s, 1H), 1.54(s, 1H), 1.40(s, 1H), 1.03(s, 1H). LCMS: calculated 311.2, found 312.2 ([M+H] + ).

[0173] Under nitrogen protection, 26-A2 (900 mg, 2.89 mmol) and PdOH catalyst (121 mg) were added to EtOH (10 mL). The mixture was evacuated and filled with nitrogen three times. After evacuating and filling with hydrogen three times, the temperature was raised to 35 °C overnight. The reaction was monitored the next day until completion. The workup was as follows: Under nitrogen protection, the mixture was suction filtered through Celite and washed with DCM. The mother liquor was concentrated to give product 26-A3 (460 mg, yield = 71.9%) as a colorless oily liquid. 1 H-NMR (400MHz, MeOD): δppm7.26(d, J=8.0Hz, 1H), 6.87(dd, J=8.4, 2.0Hz, 1H), 6.82(d, J=7.2Hz, 1H), 6.79(d, J=2 .0Hz, 1H), 4.16(m, 1H), 3.91~3.85(m, 1H), 3.62(m, 2H), 3.31~3.22(s, 1H), 1.80~1.64(m, 1H), 1.54~1.45(m, 2H). LCMS: Calculated value 221.1, Actual value 222.1 ([M+H] + ).

[0174] Under nitrogen protection, 26-A4 (i.e., compound No. 46, 100 mg, 0.27 mmol) and 26-A3 (120 mg, 0.54 mmol) were dissolved in acetone (10 mL), and then CsCO (265 mg, 0.81 mmol) was added. The mixture was stirred at room temperature for 2.5 hours, after which the reaction was terminated. The workup was carried out as follows: the mixture was filtered through Celite with suction, washed with acetone, and the mother liquor was concentrated. Pure compound No. 26 (29.0 mg, 18.8%) was obtained as an off-white solid by high-performance liquid preparative chromatography. 1 H-NMR (400MHz, DMSO) δ8.20(d, J=8.5Hz, 1H), 7.59(d, J=8.5Hz, 1H), 7.53(t, J=7.9Hz, 1 H), 7.40(s, 1H), 7.25(d, J=7.7Hz, 1H), 7.20(dd, J=7.9, 2.2Hz, 1H), 7.07(d, J=1.4Hz, 1H) ), 6.29(dq, J=13.0, 6.4Hz, 1H), 4.77(d, J=3.7Hz, 1H), 3.95(s, 1H), 3.72~3.71(m, 1H), 3 .44(m, 1H), 3.20~3.11(m, 2H), 2.23~1.90(m, 8H), 1.76~1.66(m, 2H), 1.52~1.18(m, 2H). LCMS: Calculated value 570.1, Actual value 571.2 ([M+H] + ).

[0175] Synthesis of Compound No. 27 [ka] Under nitrogen protection, 27-A2 (i.e., compound No. 46, 100 mg, 0.27 mmol) and 27-A1 (89 mg, 0.54 mmol) were dissolved in acetone (10 mL), and then Cs2CO3 (265 mg, 0.81 mmol) was added. The mixture was stirred at room temperature for 2 hours, after which the reaction was terminated. The workup was carried out as follows: the mixture was filtered through Celite with suction, washed with acetone, and the mother liquor was concentrated. High-performance liquid preparative chromatography afforded pure compound No. 27 (21.0 mg, 15.9%) as a yellow wax. 1H-NMR (400MHz, DMSO) δ8.22(d, J=8.5Hz, 1H), 7.61(d, J=8.6Hz, 1H), 7.50(d, J=8.6Hz, 2H), 7.42(s, 1 H), 7.14(d, J=8.6Hz, 2H), 6.31(dq, J=13.0, 6.4Hz, 1H), 2.97(s, 3H), 2.96(s, 3H), 2.22~1.90(m, 8H). LCMS: Calculated value 514.1, Actual value 515.1 ([M+H] + ).

[0176] Compound No. 28 [ka] Under nitrogen protection, p-hydroxybenzoic acid (28-A1, 2.0 g, 14.48 mmol, commercially available) was added to DCM (40 mL), followed by oxalyl chloride (5.5 g, 43.44 mmol) and DMF (53 mg, 0.72 mmol), and the mixture was stirred at room temperature. After monitoring for 2.5 hours, the raw material disappeared. The oxalyl chloride was removed by concentration. The system was dissolved in DCM (50 mL), and then piperidine (3.7 g, 43.44 mmol) and TEA (5.9 g, 57.92 mmol) were added dropwise to the system under nitrogen protection. The reaction was monitored for 30 minutes before completion. The workup was as follows: The reaction mixture was concentrated, then dissolved in 1N NaOH solution (50 mL), and then stirred for 5 minutes. The mixture was extracted with DCM (50 mL × 3), and the aqueous phase was acidified with 6N HCl to precipitate a white solid. The solid was filtered off under suction, and after drying, product 28-A2 (2.0 g, yield=67.3%) was obtained as a white solid. 1 H-NMR (400 MHz, MeOD): δ ppm 7.26 (dd, d1, J = 6.8, 2.0 Hz, 2H), 6.82 (dd, J = 6.4, 2.0 Hz, 2H), 3.64-3.48 (m, 4H), 1.72-1.60 (m, 6H). LCMS: calculated 205.1, found 206.1 ([M+H] + ).

[0177] Under nitrogen protection, 28-A3 (i.e., compound No. 46, 150 mg, 0.41 mmol) and 28-A2 (167 mg, 0.81 mmol) were dissolved in acetone (10 mL). CsCO (463 mg, 1.42 mmol) was then added to the system. After stirring at room temperature for 2 hours, the reaction was terminated. The workup was performed as follows: the mixture was filtered through Celite with suction, washed with acetone, and the mother liquor was concentrated. Pure compound No. 28 (57 mg, 25.3%) was obtained as a yellow solid by high-performance liquid preparative chromatography. 1 H-NMR (400MHz, DMSO) δ8.22(d, J=8.5Hz, 1H), 7.61(d, J=8.5Hz, 1H), 7.47~7.43(m, 3H), 7.13(t, J= 5.6Hz, 2H), 6.30(dt, J=12.9, 6.5Hz, 1H), 3.84~3.34(m, 4H), 2.25~1.86(m, 8H), 1.70~1.38(m, 6H). LCMS: Calculated value 554.2, Actual value 555.1 ([M+H] + ).

[0178] Synthesis of Compound No. 29 [ka] Under nitrogen protection, 29-A1 (500 mg, 2.19 mmol) and 4-(trifluoromethyl)piperidine (1.0 g, 6.57 mmol, commercially available) were added to DCM (10 mL), and then T3P (5.6 g, 4.38 mmol, 50% EtOAc solution, commercially available) was added dropwise to the system. After cooling the system to 5 °C, DIEA (1.2 g, 8.77 mmol) was added dropwise to the system. After completion, the temperature was allowed to rise to room temperature. The reaction was run overnight before completion, and the workup was as follows: The system was concentrated, dissolved in EtOAc (20 mL), and washed with HO (20 mL × 5). The organic phase was dried and concentrated to give 29-A2 (790 mg, yield = 98.9%) as a white solid. 1H-NMR (400MHz, MeOD): δppm7.44~7.31(m, 7H), 7.09~7.06(m, 2H), 5.14(s, 2H), 4.66( m, 1H), 3.97(m, 1H), 3.04(m, 2H), 2.55~2.47(m, 1H), 1.92(m, 2H), 1.54~1.51(m, 2H). LCMS: Calculated value 363.1, Actual value 364.2 ([M+H] + ).

[0179] Under nitrogen protection, 29-A2 (790 mg, 2.20 mmol) and PdOH (100 mg) were added to EtOH (10 mL). The mixture was evacuated and filled with nitrogen three times. After evacuating and filling with hydrogen three times, the temperature was raised to 35 °C overnight. The reaction was monitored the next day until completion. After suction filtration through Celite and washing with DCM, the mother liquor was concentrated to give 29-A3 (450 mg, yield = 75.2%) as a white solid. 1 H-NMR (400MHz, MeOD): δppm7.29(d, J=8.4Hz, 2H), 6.84(d, J=8.4Hz, 2H), 4.59(s, 1H), 4.06(s, 1H), 3.00(m, 2H), 2.55~2.47(m, 1H), 1.92(sm2H), 1.54~1.50(m, 2H). LCMS: Calculated value 273.1, Actual value 274.0 ([M+H] + ).

[0180] Under nitrogen protection, 29-A4 (i.e., compound No. 46, 100 mg, 0.27 mmol) and 29-A3 (118 mg, 0.54 mmol) were dissolved in acetone (10 mL), and then Cs2CO3 (265 mg, 0.81 mmol) was added. The mixture was stirred at room temperature for 3 hours, after which the reaction was terminated. The workup was carried out as follows: the mixture was filtered through Celite with suction, washed with acetone, and the mother liquor was concentrated. Pure compound No. 29 (55.0 mg, 32.6%) was obtained as a pale yellow solid by high-performance liquid preparative chromatography. 1H-NMR (400MHz, DMSO) δ8.22(d, J=8.5Hz, 1H), 7.62(d, J=8.5Hz, 1H), 7.51(d, J=8.6Hz, 2H), 7.44(s, 1H), 7.14(d, J=8.6Hz, 2H), 6.31(dq, J= 12.8, 6.2Hz, 1H), 4.54(s, 1H), 3.71(s, 1H), 2.86(s, 2H), 2.67~2.63(m, 1H), 2.20~1.93(m, 8H), 1.84(m, 2H), 1.43(qd, J=12.6, 4.2Hz, 2H). LCMS: calculated 622.1, found 623.2 ([M+H] + ).

[0181] Synthesis of Compound No. 30 [ka] Under nitrogen protection, 30-A1 (1.5 g, 4.95 mmol, commercially available) and p-fluoroiodobenzene (1.0 g, 4.50 mmol, commercially available) were added to DMF (90 mL). After evacuating and filling with nitrogen three times, dppfPdCl2, i.e., 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (330 mg, 0.45 mmol, commercially available) and K2CO3 (1.9 g, 13.51 mmol) were added to the system. After completion, the system was evacuated and filled with nitrogen three times again. The system temperature was raised to 110 °C overnight. The next day, the reaction was monitored until completion. After cooling to room temperature, the system was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The organic phase was washed with water, washed with brine, dried, concentrated, and column separated (200-300 mesh silica gel, n-heptane:EA = 15:1-10:1) to give product 30-A2 (920 mg, yield = 73.6%) as a pale green liquid. 1 H-NMR (400MHz, CDCl3): δppm7.34~7.31 (m, 2H), 7.03~6.99 (t, J=8.8Hz, 2H), 5. 97(m, 1H), 4.06(d, J=2.4Hz, 2H), 3.64~3.61(m, 2H), 2.49(m, 2H), 1.49(s, 9H). LCMS: Calculated value 277.1, Actual value 222.1 ([M-56+H]+ ).

[0182] 30-A2 (800 g, 2.88 mmol) was dissolved in MTBE (methyl tert-butyl ether, 2 mL), and then dioxane hydrochloride solution (4 M, 2 mL, 7.21 mmol) was added dropwise to the system. The temperature was maintained at room temperature overnight. The reaction was monitored the next day until completion. Suction filtration was performed, and the solid was washed with MTBE to give product 30-A3 (460 mg, 74.70%) as an off-white solid. 1 H-NMR (400MHz, DMSO): δppm9.18(s, 2H), 7.52(d, J=8.8, 5.6Hz, 2H), 7.23~7.19(m, 2H), 6.16(s, 1H), 3.72(s, 2H), 3.29(m, 2H), 2.66(m, 2H). LCMS: Calculated value 213.1, actual value 178.1 ([M-HCl+H] + ).

[0183] Under nitrogen protection, [ka] (350 mg, 1.53 mmol) and 30-A3 (407 mg, 2.30 mmol) were added to DCM (10 mL), and then T3P (3.90 g, 6.12 mmol, 50% in EtOAc) was added dropwise to the system. After cooling the system to 5 °C, DIEA (791 mg, 6.12 mmol) was added dropwise to the system. After completion, the temperature was allowed to rise to room temperature. After monitoring for 2 h, the reaction was terminated. The system was concentrated, dissolved in EtOAc (10 mL), and washed with HO (10 mL × 5). The organic phase was dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA = 1:1 to 0:1) to obtain product 30-A4 (460 mg, yield = 77.9%) as a pale green oil. 1H-NMR (400MHz, MeOD): δppm7.45~7.43 (m, 6H), 7.39~7.36 (m, 2H), 7.32 (d, J=7.2Hz, 1H), 7.10~7 .03(m, 4H), 6.13~5.97(m, 1H), 5.15(s, 2H), 4.29~4.22(m, 2H), 3.93~3.69(m, 2H), 2.60(m, 2H).

[0184] Under nitrogen protection, 30-A4 (450 mg, 1.16 mmol) and Pd(OH) (81 mg, commercially available) were added to EtOH (10 mL). The mixture was evacuated and filled with nitrogen three times. After evacuating and filling with hydrogen three times, the temperature was raised to 35 °C overnight. The reaction was monitored the next day until completion. The mixture was filtered through Celite with suction and washed with DCM. The mother liquor was concentrated to give the product 30-A5 (310 mg, yield = 89.2%) as a colorless oil. 1 H-NMR (400MHz, MeOD): δppm7.33~7.31(m, 2H), 7.29~7.25(m, 2H), 7.04~6.99(m, 2H), 6.87~ 6.84(m, 2H), 4.72(m, 2H), 4.00(m, 1H), 3.19~2.96(m, 2H), 1.86(m, 2H), 1.68~1.66(m, 2H). LCMS: Calculated value 299.1, actual value 300.1 ([M+H] + ).

[0185] Under nitrogen protection, 30-A6 (i.e., compound No. 46, 100 mg, 0.27 mmol) was dissolved in acetone (10 mL), and then 30-A5 (97 mg, 0.33 mmol) and CsCO (265 mg, 0.81 mmol) were added and stirred at room temperature for 3 h. After the reaction was completed, the mixture was filtered through Celite with suction, the solid was washed with acetone, and the mother liquor was concentrated. Pure compound No. 30 (29.0 mg, 16.5%) was obtained as a pale yellow solid by high-performance liquid preparative chromatography. 1H-NMR (400MHz, DMSO-d6): δppm8.22 (d, J=8.5Hz, 1H), 7.61 (d, J=8.5Hz, 1H), 7.53 (d, J=8.6Hz, 2H), 7.44 (s, 1H), 7.34~7 .31(m, 2H), 7.16~7.11(m, 4H), 6.38~6.26(m, 1H), 4.62(m, 1H), 3.72(m, 1H), 3.24~3.10(m, 2H), 2.83(m, 1H), 2.17~1.91 (m, 8H), 1.86~1.59(m, 4H). LCMS: Calculated value 648.2, Actual value 649.2 ([M+H] + ).

[0186] Synthesis of Compound No. 33 [ka] Under nitrogen protection, [ka] (1 g, 3.16 mmol) and 33-A (886 mg, 6.33 mmol, 1.2 equiv., commercially available) were dissolved in THF (15 mL). Triphenylphosphine (1.66 g, 6.33 mmL, 2 equiv., commercially available) was added, and the temperature was lowered to 0 °C. A THF solution (8 mL) of di-tert-butyl azodicarboxylate (1.46 g, 6.33 mmol, 2 equiv., commercially available) was added dropwise. The reaction was carried out at room temperature and completed in 4 h. 10 mL of water was added, and the mixture was extracted with DCM (25 mL × 3), dried, and concentrated. The samples were mixed and passed through a column (200-300 mesh silica gel, EA:n-heptane = 2:1) to give product 33-B (680 mg, yield = 49.3%) as a pale yellow solid. 1 H-NMR (300M, CDCl3): δppm9.87(s, 1H), 8.04(d, J=7.8Hz, 1H), 7.63(d, J=9.6Hz, 2H), 7.4 7(d, J=8.1Hz, 2H), 7.34(d, J=7.5Hz, 1H), 7.02~7.11(m, 4H), 5.19(s, 2H), 3.08(brs, 6H). LCMS: Calculated value 438.4, Actual value 439.0 ([M+H] + ).

[0187] 33-B (680 mg, 1.55 mmol) was dissolved in THF (10 mL), the temperature was lowered to 0 °C, and sodium borohydride (117 mg, 3.10 mmol, 2 equiv.) was added batchwise. The temperature was maintained at 0 °C, and the reaction was completed in 1 h. Saturated aqueous ammonium chloride (5 mL) was added dropwise, and the mixture was extracted with DCM (10 mL × 3), dried, concentrated, and purified by column chromatography (100-200 mesh silica gel, EA) to give product 33-C (410 mg, 60.3%) as a pale yellow solid. 1 H-NMR (300M, CDCl3): δppm8.02(d, J=8.1Hz, 1H), 7.43(d, J=7.8Hz, 2H), 7.31(d, J=6.0Hz, 1H), 7.12( d, J=12.3Hz, 1H), 6.99~7.03(m, 4H), 6.84(t, J=8.4Hz, 1H), 5.16(s, 2H), 4.62(s, 2H), 3.08(brs, 6H). LCMS: Calculated value 440.4, Actual value 441.0 ([M+H] + ).

[0188] Under nitrogen protection, 33-C (400 mg, 0.91 mmol) was dissolved in THF (5 mL). Triphenylphosphine (480 mg, 1.82 mmol) and Br-IPM (564 mg, 1.82 mmol, commercially available) were added. The temperature was lowered to 0 °C, and a THF solution (5 mL) of di-tert-butyl azodicarboxylate (420 mg, 1.82 mmol) was added dropwise at 0 °C. The reaction was carried out at room temperature for 3 h. Water (5 mL) was added at 0 °C, and the mixture was extracted with DCM (10 mL × 3), dried, concentrated, and subjected to column chromatography (200-300 mesh silica gel, DCM:methanol = 50:1) to give 33-D (300 mg, yield = 45.0%) as a pale yellow solid. 1H-NMR (400M, CDCl3): δppm8.01 (d, J=8.4Hz, 1H), 7.45 (d, J=8.8Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 7.26 (m, 1H), 7.16 (dd, J=11.5, 1.6Hz, 1H), 7.1 0(s, 1H), 7.02(d, J=8.4Hz, 2H), 6.89(t, J=8.4Hz, 1H), 5.13(s, 2H), 4. 95(d, J=8.4Hz, 2H), 3.45~3.41(m, 4H), 3.34~3.30(m, 4H), 3.08(s, 6H). LCMS: calculated 732.0, found 732.8 ([M+H] + ).

[0189] Under nitrogen protection, 33-D (200 mg, 0.27 mmol) was dissolved in THF (5 mL). Silver oxide (742 mg, 3.2 mmol, 11.8 equiv.) was added, followed by dropwise addition of diisopropylethylamine (176 mg, 1.365 mmol, 5 equiv.). The temperature was raised to reflux. The reaction was allowed to proceed for 2 h, after which the temperature was lowered to room temperature. The mixture was filtered through Celite under suction, washed several times with THF, and concentrated at low temperature to give compound No. 33 (5 mg, 3.2%) as a white solid. 1 H-NMR (400M, CDCl3): δppm7.99 (d, J=8.4Hz, 1H), 7.44 (d, J=8.8Hz, 2H), 7.31 (d, J=8.0Hz, 1H), 7.15 (dd, J=11.6, 2.0Hz, 1H), 7.11 (s, 1H), 7.03~7.07(m, 3H), 6.91(t, J=8.4Hz, 1H), 5.09(s, 2H), 5.05(d, J=8.0Hz, 2H), 3.09(s, 3H), 3.00(s, 3H), 2.18~2.08(m, 8H) (retention time: 7.359 minutes). LCMS: Calculated value 570.0, Actual value 571.0 ([M+H] + ).

[0190] Synthesis of Compound No. 34 [ka] 34-A (10.0 g, 71.4 mmol, commercially available) was added to acetic acid (30 mL), followed by the addition of sulfonyl chloride (14.4 g, 107 mmol, 1.5 equiv.), and the mixture was allowed to react at room temperature for 17 h. 300 mL of ice water was added. Extraction was performed with EA (300 mL × 2). The organic phase was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, and the solvent was spun off to obtain the crude product. The crude product was slurried with methyl tert-butyl ether and suction filtered to obtain 34-B (3.0 g, 25%) as a white solid. 1 H-NMR (400M, DMSO-d): δ ppm 9.98 (s, 1H), 7.80 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 11.6 Hz, 1H). LCMS: calculated 174.0, found 175.0 ([M+H] + ).

[0191] Under nitrogen protection, 34-B (375 mg, 2.15 mmol, 2 equiv) was added to THF (10 mL). [ka] (340 mg, 1.08 mmol) and triphenylphosphine (563 mg, 2.15 mmol, 2 equiv., commercially available) were added. DBAD (494.5 mg, 2.15 mmol, 2 equiv., commercially available) was added at 0 °C. The reaction was carried out at room temperature for 1 h. DCM (50 mL) was added for dilution. The organic phase was washed with water (10 mL × 2) and saturated brine (10 mL), dried, and spun dry. The samples were combined and passed through a flash column (300-400 mesh silica gel, EA and n-heptane, 33%-100%) to give the white product 34-C (400 mg, 78.7%). 1H-NMR (400M, DMSO-d6): δppm10.04(s, 1H), 8.18(d, J=8.4Hz, 1H), 7.87(d, J=7.2Hz, 1H), 7.49(d, J=8.4Hz, 2H ), 7.44(d, J=8.4Hz, 1H), 7.36(d, J=8.4Hz, 1H), 7.31(s, 1H), 7.15(d, J=8.4Hz, 2H), 5.44(s, 2H), 2.97(s, 6H). LCMS: Calculated value 472.1, Actual value 472.9 ([M+H] + ).

[0192] Under nitrogen protection, 34-C (200 mg, 0.42 mmol) was added to THF (10 mL), and sodium borohydride (32 mg, 0.84 mmol, 2 equiv., commercially available) was added at 0 °C. The temperature was allowed to rise, and the reaction was carried out for 0.5 h. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added dropwise. After extraction with DCM (20 mL × 3), the mixture was washed with water (10 mL), saturated brine (10 mL), dried, spin-dried, slurried in isopropanol, and suction-filtered to give 34-D (100 mg, 50%) as a white solid. 1 H-NMR (400M, DMSO-d6): δppm8.16 (d, J=8.4Hz, 1H), 7.49 (d, J=8.4Hz, 2H), 7.46 (d, J=8.0Hz, 1H), 7.43 (d, J=9.6 Hz, 1H), 7.30(s, 1H), 7.15~7.12(m, 3H), 5.32(s, 2H), 5.27(t, J=5.6Hz, 1H), 4.45(d, J=5.6Hz, 2H), 2.97(s, 6H). LCMS: Calculated value 474.1, Actual value 475.0 ([M+H] + ).

[0193] Under nitrogen protection, 34-D (100 mg, 0.21 mmol) was added to THF (10 mL). Triphenylphosphine (110 mg, 0.42 mmol, 2 equiv.) and Br-IPM (129 mg, 0.42 mmol, 2 equiv.) were added, followed by di-tert-butyl azodicarboxylate (97 mg, 0.42 mmol, 2 equiv.) at 0 °C. The reaction was carried out at room temperature for 4 h. Upon completion, DCM (50 mL) was added. The organic phase was washed with saturated brine (10 mL), dried, spun dry, and passed through a flash column (300-400 mesh silica gel, EA and n-heptane, 0-100%, then DCM:MeOH (20:1)) to give 34-E (70 mg, 43.7%) as a yellow oil. 1 H-NMR (400M, CDCl3): δppm7.96(d, J=8.4Hz, 1H), 7.40~7.38(m, 3H), 7.25(d, J=7.6Hz, 1H), 7.07(s, 1H), 6.99(d, J=8.8 Hz, 2H), 6.57(d, J=10.8Hz, 1H), 5.04(s, 2H), 4.92(d, J=8.0Hz, 2H), 3.36~3.39(m, 4H), 3.24~3.29(m, 4H), 3.01(s, 6H). LCMS: Calculated value 766.0, Actual value 766.8 ([M+H] + ).

[0194] 34-E (70 mg, 0.091 mmol) was added to THF (5 mL), and silver oxide (250 mg, 1.08 mmol, 11.8 equiv.) and DIEA (55 mg, 0.428 mmol, 4.7 equiv.) were added. The mixture was heated to 65 °C and reacted for 6 h. After the reaction was completed, the mixture was filtered under suction. The filter cake was washed with THF (10 mL × 2) and then filtered under suction again through a membrane filter. The filtrate was spin-dried to obtain the crude product. Preparative HPLC afforded 34 (5 mg, 9.1%) as a white solid. 1H-NMR (400M, CD3OD): δppm8.08 (d, J=8.4Hz, 1H), 7.54~7.47 (m, 4H), 7.37 (s, 1H), 7.12 (d, J=8.8Hz, 2H), 7. 06(d, J=11.2Hz, 1H), 5.29(s, 2H), 5.14(d, J=8.0Hz, 1H), 3.13(s, 3H), 3.07(s, 3H), 2.15~2.14(m, 8H) were obtained. LCMS: Calculated value 604.0, Actual value 605.0 ([M+H] + ).

[0195] For the synthesis of Compounds Nos. 35-44 / 47-49, please refer to the method described above. The properties, NMR, and mass spectrum data are as follows:

[0196] Compound No. 35 solid, 1 H-NMR (400MHz, CDCl3) δ7.99(d, J=8.4Hz, 1H), 7.47(d, J=8.6Hz, 2H), 7.32(d, J=8.3Hz, 1H), 7.17(s, 1H), 7.05(d, J=8.6Hz, 2H) ), 6.95(t, J=6.9Hz, 2H), 5.54~5.48(m, 1H), 5.14(s, 2H), 3.11(s, 3H), 3.03(s, 3H), 2.21~2.00(m, 8H), 1.57(d, J=6.5Hz, 3H). LCMS: Calculated value 602.2, Actual value 603.2 ([M+H] + ).

[0197] Compound No. 36 solid, 1 H-NMR (400MHz, CDCl3) δ8.01(d, J=8.4Hz, 1H), 7.71~7.62(m, 2H), 7.34(d, J=8.4Hz, 1H), 7.22(s, 1H), 7.04(d, J=8.8Hz, 2H), 6. 95(d, J=8.5Hz, 2H), 5.47~5.28(m, 1H), 5.17(s, 2H), 5.06(d, J=8.1Hz, 2H), 4.62~4.48(m, 2H), 4.38(m, 2H), 2.32~2.04(m, 8H). LCMS: Calculated value 518.1, Actual value 619.2 ([M+H] + ).

[0198] Compound No. 37 wax, 1 H-NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.46 - 7.38 (m, 1H), 7.31 (s, 1H), 7.09 - 7.01 (m, 2H), 6.97 (d, J = 8.6 Hz, 2H), 5.20 (s, 2H), 5.07 (d, J = 8.0 Hz, 2H), 2.31 - 2.06 (m, 8H). LCMS: calculated value 542.1, measured value 543.1 ([M + H] + )。

[0199] Compound No. 38 off-white solid, 1 H-NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 5.18 (s, 2H), 5.06 (d, J = 8.1 Hz, 2H), 4.59 - 4.53 (m, 4H), 2.38 - 2.02 (m, 8H). LCMS: calculated value 536.1, measured value 637.1 ([M + H][[ID=I7]] + )。

[0200] Compound No. 39 wax, 1 H-NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.25 - 7.20 (m, 2H), 7.02 - 6.90 (m, 2H), 5.20 (s, 2H), 5.06 (d, J = 8.0 Hz, 2H), 2.28 - 2.10 (m, 8H). LCMS: calculated value 542.1, measured value 543.1 ([M + H] + )。

[0201] Compound No. 40 off-white solid, 1H-NMR (400MHz, DMSO-d6): δppm8.90~8.89(s, 1H), 8.33(d, J=1.2Hz, 1H), 8.31(d, J=1.2Hz, 1H), 8.25(d, J=8. 4Hz, 1H), 8.13(d, J=10.0Hz), 7.63~7.55(m, 4H), 7.46(d, J=1.2Hz, 1H), 6.30~6.26(m, 1H) 2.11~1.92(m, 8H). LCMS: Calculated value 494.1, Actual value 495.1 ([M+H] + ).

[0202] Compound No. 41 Off-white solid, 1 H-NMR (400 MHz, MeOD): δ ppm 8.43 (d, J = 2.9 Hz, 1H), 7.24-7.19 (m, 2H), 6.13-6.03 (m, 1H), 2.26-2.08 (m, 8H). LCMS: calculated 576.1, found 577.2 ([M+H] + ).

[0203] Compound No. 42 Off-white solid, 1 H-NMR (400MHz, DMSO-d6): δppm8.20 (d, J=8.2Hz, 1H), 7.99~7.90 (m, 1H), 7.89 (s, 1H) 7.5 5(d, J=8.4Hz, 1H), 7.31~7.26(m, 1H), 6.28~6.24(m, 1H) 2.80(s, 3H), 2.10~1.91(m, 8H). LCMS: Calculated value 514.1, Actual value 515.0 ([M+H] + ).

[0204] Compound No. 43 Off-white solid, 1H-NMR (400 MHz, MeOD): δ ppm 8.05 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 8.8, 2.0 Hz, 1H), 7.17 (s, 1H), 5.99-5.94 (m, 1H), 2.20-2.02 (m, 8H). LCMS: calculated 497.1, found 498.1 ([M+H] + ).

[0205] Compound No. 44 Off-white solid, 1 H-NMR (400MHz, MeOD) δ8.07(d, J=8.4Hz, 1H), 7.75~7.67(m, 2H), 7.65~7.59(m, 2H), 7.49(d, J=8.5Hz, 1H), 7.44 (t, J=7.6Hz, 2H), 7.35(d, J=7.3Hz, 1H), 7.31(s, 1H), 7.20~7.14(m, 2H), 6.07~5.97(m, 1H), 2.26~2.03(m, 8H). LCMS: Calculated value 519.1, Actual value 520.1 ([M+H] + ).

[0206] Compound No. 47 Off-white solid, 1 H-NMR (400MHz, MeOD) δ8.03(d, J=8.4Hz, 1H), 7.43(d, J=8.4Hz, 1H), 7.34(d, J=8.5Hz, 2H), 7.19(s, 1H), 7.03(t, J=5.7Hz) , 2H), 6.07~5.94(m, 1H), 3.09~2.99(m, 1H), 2.24~2.02(m, 10H), 1.87~1.83(m, 2H), 1.77~1.68(m, 2H), 1.65~1.56(m, 2H). LCMS: Calculated value 511.1, Actual value 512.2 ([M+H] + ).

[0207] Compound No. 48 Off-white solid, 1H-NMR (400MHz, MeOD) δ8.03(d, J=8.4Hz, 1H), 7.43(d, J=8.6Hz, 1H), 7.31(d, J=8.5Hz, 2H), 7.19(s, 1H), 7.02(d, J= 8.5Hz, 2H), 6.00~5.96(m, 1H), 2.56(m, 1H), 2.23~2.03(m, 8H), 1.87(m, 4H), 1.78~1.75(m, 2H), 1.49~1.43(m, 5H). LCMS: Calculated value 525.2, Actual value 526.2 ([M+H] + ).

[0208] Compound No. 49 Yellow wax, 1 H-NMR (400MHz, MeOD) δ8.04(d, J=8.4Hz, 1H), 7.45(d, J=8.2Hz, 1H), 7.35(d, J=8.6Hz, 2H), 7.21(s, 1H), 7.04 (d, J=8.6Hz, 2H), 5.99 (dd, J=9.9, 6.2Hz, 1H), 2.74 (t, J=12.5Hz, 1H), 2.23~2.04 (m, 10H), 2.02~1.73 (m, 6H). LCMS: Calculated value 561.1, Actual value 562.2 ([M+H] + ).

[0209] Synthesis of Compound No. 46 [ka] Under nitrogen protection, A2 (2.0 g, 11.8 mmol, commercially available) and TMSCF3 (2.5 g, 17.7 mmol, commercially available) were dissolved in THF (20 mL). The temperature was lowered to 0 °C, and TBAF (2.6 mL, 0.26 mmol, 1 mol / L THF solution, commercially available) was added dropwise to the system. The temperature was maintained at 0 °C, and after 30 min, A2 completely disappeared. 3 N HCl (2 mL) was added dropwise to the system, and the system became clear. After stirring at 0 °C for 1 h, all the raw materials were converted to the product. Extraction was performed with DCM (10 mL × 3). The organic phase was washed with water (10 mL × 3), dried, concentrated, and column-separated (200-300 mesh silica gel, n-heptane:EA = 12:1 to 10:1) to obtain product A3 (1.5 g, yield = 53.2%) as a yellow oil.1 H-NMR (400MHz, CDCl3): δppm8.13~8.09(m, 1H), 7.60(d, J=11.6Hz, 1H), 7.43(d, J=8.4Hz, 1H), 5.12~5.18(m, 1H), 3.06(d, J=4.4Hz, 1H).

[0210] Under nitrogen protection, POCl3 (963 mg, 4.61 mmol, commercially available) was dissolved in DCM (10 mL). The temperature was then lowered to -40 °C. Next, A3 (1.5 g, 6.27 mmol) was dissolved in DCM (20 mL) and added dropwise to the system along with TEA (1.6 g, 15.70 mmol). The temperature was maintained at -40 °C for 2 h, after which 46-A3 was completely converted to the intermediate. Next, bromoethylamine hydrobromide (11.99 g, 50.16 mmol) and TEA (10.1 g, 0.1 mol) were added to the system and monitored. The reaction was complete in 30 min. Saturated NH4Cl (20 mL) was added at 0 °C, and the mixture was extracted with DCM (50 mL × 3). The organic phase was washed with water, washed with brine, dried, concentrated, and subjected to column separation (200-300 mesh silica gel, n-heptane:EA=5:1-1:1) to obtain product A4 (1.6 g, yield=65.3%) as a yellow oil. 1 H-NMR (400 MHz, CDCl): δ ppm 8.15–8.11 (m, 1H), 7.47 (d, J = 11.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.78–5.30 (m, 1H), 3.53–3.05 (m, 10H). LCMS: calculated 529.9, found 531.9 ([M+H] + ).

[0211] Under nitrogen protection, A4 (1.6 g, 3.0 mmol) was dissolved in THF (20 mL), followed by the addition of silver oxide (4.2 g, 18.0 mmol) and DIPEA (2.3 g, 18.0 mmol). The temperature was raised to 65 °C and stirred for 1.5 h. After the reaction was completed, the temperature was lowered to room temperature. The mixture was filtered through Celite with suction. The solid was washed with DCM, and the mother liquor was concentrated and subjected to column separation to obtain the crude product (520 mg, yield = 46.8%) (200-300 mesh silica gel, n-heptane:EA = 5:1 to 1:1). High-performance liquid preparative chromatography afforded the pure compound No. 46 (30 mg) as a white solid. 1 H-NMR (400 MHz, MeOD): δ ppm 8.24-8.20 (m, 1H), 7.70 (d, J = 11.6 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 6.14-6.10 (m, 1H), 2.28-2.14 (m, 8H). LCMS: calculated 369.1, found 370.1 ([M+H] + ).

[0212] The experimental evidence of the above specific compound examples demonstrates that all compounds provided by the present invention are either solid or wax (semi-solid), which overcomes the drawback that previous DNA alkylating agents disclosed in PCT / US2016 / 021581 (WO 2016 / 145092) (corresponding to Chinese Patent Application No. 2016800150788 (Chinese Patent Application Publication No. 107530556)) are oily, making formulations easier to prepare.

Claims

1. A compound of formula II or III 【Chemistry 1】 And, R 1 is C 6 -C 10 aryl or Z-substituted C6-C10 aryl, Z-substituted 4-15 membered heterocycle, 5-15 membered heteroaryl or Z-substituted 5-15 membered heteroaryl, or 7-15 membered fused ring, or Z-substituted 7-15 membered fused ring; R 2 is a hydrogen atom, a halogen atom, a cyano atom, C １ -C ６ alkyl or Z-substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or Z-substituted C 3 -C 8 cycloalkyl, C 6 -C 10 aryl or Z-substituted C 6 -C 10 aryl, Z-substituted 5-15 membered heteroaryl, Z-substituted alkoxy having 1 to 6 carbon atoms, —CONR ６ R ７ or R2 is the group R 1 together to form a 7- to 15-membered fused ring or a Z-substituted 7- to 15-membered fused ring; R 3 is hydrogen; R 4 and R 5 are each independently hydrogen; R 6 and R 7 are each independently C 1 -C 6 Alkyl, C 6 -C 10 aryl or R 6 and R 7 together with the atom to which they are attached form a 5- to 7-membered heterocyclyl or a Z-substituted 5- to 7-membered heterocyclyl; R 8 and R 10 are each independently hydrogen; R 9 is a substituted C substituted with at least one fluorine atom 6 -C 10 is aryl; The substituent Z is a halogen atom, cyano, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 3 -C 8 cycloalkyl, or aromatic ring; R 9 Substitution C in 6 -C 10 The substituent on the aryl is a halogen atom.

2. R 1 is phenyl or Z-substituted phenyl, Z-substituted 4-15 membered heterocycle, 6-membered nitrogen-containing heteroaryl or Z-substituted 6-membered nitrogen-containing heteroaryl, or 9-14 membered fused ring or Z-substituted 9-14 membered fused ring; R 2 is hydrogen, halogen atoms, cyano, C 1 -C 6 alkyl or Z-substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or Z-substituted C 3 -C 8 cycloalkyl, C 6 -C 10 Aryl or Z-substituted C 6 -C 10 aryl, Z-substituted 5-15 membered nitrogen-containing heteroaryl, fluorine-substituted C 1 -C 6 Alkoxy, -CONR ６ R ７ and R 6 and R 7 However, each independently, C １ -C ６ Alkyl or C 6 -C 10 aryl or R 6 and R 7 and together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic group or a Z-substituted 5- to 7-membered heterocyclic group.

3. In the above formula II and formula III, R 1 is phenyl or Z-substituted phenyl, Z-substituted 4-15 membered heterocycle, 6-membered nitrogen-containing heteroaryl or Z-substituted 6-membered nitrogen-containing heteroaryl, or 9-14 membered fused ring or Z-substituted 9-14 membered fused ring; R 2 is hydrogen, halogen atoms, cyano, C 1 -C 6 alkyl or Z-substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or Z-substituted C 3 -C 8 cycloalkyl, C 6 -C 10 Aryl or Z-substituted C 6 -C 10 aryl, Z-substituted 5-15 membered nitrogen-containing heteroaryl, fluorine-substituted C 1 -C 6 Alkoxy, -CONR ６ R ７ and R 6 and R 7 However, each independently, C １ -C 6 Alkyl or C 6 -C 10 aryl or R 6 and R 7 and together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic group or a Z-substituted 5- to 7-membered heterocyclic group.

4. In the above formula II and formula III, R 1 is phenyl, pyridine, quinoline, benzothiazole, benzimidazole, Z-substituted phenyl; R ２ But -CON(CH ３ ) ２ , -CF ３ , F, Cl, CN, Me, benzene, fluorobenzene, -OCF ３ , C5-C6 cycloalkyl, or F-substituted C5-C6 cycloalkyl, fluoropyridyl, -CONMePh, 【Chemistry 2A】 The compound of claim 1, wherein

5. R 9 2. The compound of claim 1, wherein is monofluoro, monofluoromonochloro, difluoro, or tetrafluoro substituted phenyl.

6. R 9 but, 【Transformation 3】 The compound of claim 1, wherein

7. The compound of claim 1 selected from the following compounds: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】

8. A compound having the structure of the following formula 35: 【Chemistry 5-4】

9. A pharmaceutical formulation containing a compound according to any one of claims 1 to 8.

10. 10. A pharmaceutical formulation according to claim 9 for use in treating tumors and cancer diseases in a patient, comprising: The tumors and cancers include lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, bone cell carcinoma, epithelial carcinoma, bile duct carcinoma, choroidal carcinoma, embryonal carcinoma, seminoma, Wilms' tumor, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemoblastoma, leukocyte cell carcin ... tumor, vocal cord neuroma, meningioma, neuroblastoma, optic neuroblastoma, retinoblastoma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, fibroadenoma, fibrochondroma, fibrocyst, fibromyxoma, fibroostoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, myxocyst, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxoadenoma, myxoblastoma, liposarcoma, lipoma, lipoadenoma, lipoblastoma, lipochondroma, lipofibroma, lipoangioma, myxolipoma, chondrosarcoma, chondroma, chondromyxofibroma, Chordoma, choriocarcinoma, chorioepithelioma, chorioma, osteosarcoma, osteoblastoma, osteochondrofibroma, osteochondrosarcoma, osteochondroma, bone cyst, osteodentoma, osteofibroma, osteofibrosarcoma, angiosarcoma, hemangioma, angiolipoma, hemangiochondroma, hemangioblastoma, angiokeratosis, hemangioglioma, hemangioendothelioma, angiofibroma, angiomyoma, angiolipoma, angiolymphangioma, angiolipoleiomyoma, angiomyolipoma, angiomyoneuroma, angiomyxoma, hemangioblastoma, lymphangiosarcoma, lymphogranuloma, lymphangioma, lymphoma, lymphoma Pharmaceutical preparations comprising lymphoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelioma, endodermal tumor, synovium, synovial sarcoma, mesothelioma, connective tissue tumor, Ewing's tumor, leiomyoma, leiomyosarcoma, leiomyoma asthma, leiomyofibrillar tumor, rhabdomyosarcoma, acute lymphocytic leukemia, acute myeloid leukemia, anemia of chronic disease, polycythemia, lymphoma, endometrial cancer, glioma, colorectal cancer, thyroid cancer, urothelial carcinoma or multiple myeloma.

11. 9. A method for preparing compounds according to any one of claims 1 to 8, characterized in that compounds V and VI are subjected to a condensation reaction to close the ring and obtain compounds of formula II and III above, comprising: 【Transformation 6】 where Y is a leaving group and R 1 , R ２ , R 3 , R 4 , R 5 , R ８ , R 9 and R １０ A method for preparing a compound, wherein

12. 12. The method of claim 11, wherein Y is Cl, Br, I, a tosylate group, or -ONO. 2 or a trifluoromethylsulfonic acid group, and an organic amine is used as an acid binder in a condensation reaction.

13. 13. The method according to claim 12, wherein Y is Br, and the condensation reaction uses N,N-diisopropylethylamine (DIPEA) as an acid binding agent and silver oxide (Ag) as a catalyst. ２ O). 【Request Item 14】 【Chemistry 7】 The compound of formula VII is reacted with R ２ R １ OH to form a compound of formula II above, and a compound of formula VIII is reacted with R ２ R １ OH to form a compound of formula III above, or 【Transformation 8】 The compound of formula IX is reacted with YR １ R ２ to form a compound of formula II, and reacting the compound of formula X with YR １ R ２ 9. A process for preparing a compound according to any one of claims 1 to 8, characterized in that it comprises reacting with where Y is a leaving group, M is H or an alkali metal, and R 1 , R ２ , R 3 , R 4 , R 5 , R ８ , R 9 and R １０ 10. A method for preparing a compound, wherein:

15. 15. The method of claim 14, wherein Y is F, Cl, Br, I, a tosylate group, or -ONO. ２ or a trifluoromethylsulfonic acid group.

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