WEE1 inhibitors and their production and use

Abstract

The present invention relates to a WEE1 inhibitor and its preparation and use, the structure of which is shown in Formula 1. The present invention relates to a compound of Formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, and its use in the manufacture of a medicament for treating a disease associated with WEE1 activity. TIFF2025525290000185.tif57170

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit WEE1 kinase activity and the use of these compounds in the manufacture of medicaments for treating WEE1-mediated diseases. [Background technology]

[0002] WEE1 tyrosine kinase is a G2 checkpoint kinase in the cell cycle. The cell cycle is tightly controlled, and if the cell's DNA is not damaged, the G1, S, and G2 checkpoints ensure the cell transitions to mitosis and completes the cell cycle smoothly (Clinical Cancer Research, 2011, 17(13):4200-4207). The cell cycle is regulated by cyclin-dependent kinases (CDKs), which include 14 serine / threonine protein kinases. CDK activity is controlled by phosphorylation and binding to different cyclins. The transition from G2 to mitosis is positively regulated by the phosphorylation of CDK1 (also known as CDC2) and its associated cyclin B. Before cell division, CDK1 is inactive and is phosphorylated at tyrosine 15 by WEE1 and at threonine 14 by the myelin transcription factor 1 (MYT1). WEE1 is a negative regulator of the cell cycle, blocking the entry of cyclin B and activated CDK1 complexes into the nucleus, thereby negatively controlling the transition from G2 to mitosis. WEE1 expression and activity are elevated during S and G2 phases and decreased during M phase, where it is highly phosphorylated. When cells are in G2 and DNA damage is absent, polo-like kinase 1 (PLK1) phosphorylates WEE1, leading to its degradation by the ubiquitin ligase complex. PLK1 also phosphorylates and activates the protein phosphatase cell division cycle 25 homolog (CDC25), which then dephosphorylates and activates CDK1. Active CDK1 can bind to cyclin B and promote cell mitosis (Molecular & Cellular Biology, 2012, 32(20):4226).

[0003] If a cell's DNA is damaged, the G1, S, and G2 phase checkpoints delay the cell's transition to mitosis, allowing time for the damaged DNA to be repaired and ensuring genomic integrity before the cell begins to divide. P53, a key regulator of the G1 phase checkpoint, is mutated in many malignant tumor cells (Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(10):3753-3758). Tumor cells with defective p53 function are unable to arrest the cell cycle in the G1 phase even when DNA is damaged, making them more dependent on the G2 phase checkpoint. In response to DNA damage, the G2 phase checkpoint delays the cell's transition to mitosis by inhibiting CDK1 phosphorylation through two parallel but related pathways. Depending on the type of DNA damage, ataxia-telangiectasia mutated (ATM) or ataxia-telangiectasia related (ATR) protein kinase is activated (Oncotarget, 2016, 7(31): 49902-49916.). ATM is activated by ionizing radiation, radioactive materials, or agents that cause double-stranded DNA breaks. ATM phosphorylates and activates checkpoint kinase 2 (CHK2), which then phosphorylates cell division cycle 25C phosphatase (CDC25C) at Ser216. This causes CDC25C to be exported from the nucleus and segregated from the cytoplasm, inhibiting its phosphorylation activity. Inhibition of CDC25C activity inhibits the phosphorylation of the CDK1 / CDK2-bound cyclin B complex, rendering CDK1 inactive and preventing cell progression into mitosis (Molecular Cancer, 2014, 13(1):72.). ATR is generally activated by genotoxic stimuli that cause single-strand DNA breaks. ATR is the primary kinase that phosphorylates and activates CHK1. CHK2 is activated only by ATM, whereas CHK1 is activated by either ATM or ATR. CHK1 also phosphorylates WEE1 and CDC25C, activating WEE1 kinase activity and inhibiting CDC25C phosphatase activity. WEE1 phosphorylates CDK1-bound cyclin B, arresting the cell cycle in G2 phase to allow time for DNA repair (Drug News & Perspectives, 2010, 23(7):425.).

[0004] WEE1 is overexpressed in many malignant tumors, including liver cancer, breast cancer, malignant neuroma, melanoma, and adult and pediatric brain tumors. Some tumor cells exhibit abnormalities in the G1 checkpoint. Inhibition of WEE1 activity leads to a malfunction of the G2 checkpoint, resulting in cells with unrepaired DNA damage continuing to divide and ultimately dying (Molecular Cancer Therapeutics, 2013, 12(12):2675-2684). Inhibition of WEE1 activity, whether by a pyrimidine derivative (PD0166285) or small interfering RNA knockdown, renders ovarian, colon, uterine, osteosarcoma, malignant neuroma, and lung cancer cells more sensitive to DNA damage induced by radiation or topoisomerase inhibition. Therefore, WEE1 inhibitors, both alone and in combination, are expected to be widely used (Cancer Biology & Therapy, 2010, 9(7):523-525). Patent Documents 1 to 11, etc., describe small molecule compounds with WEE1 kinase inhibitory activity. The most promising compound at present is AZD1775, which has already undergone phase II clinical trials and has been confirmed to have excellent cancer therapeutic effects. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 126122 [Patent Document 2] International Publication No. 2008 / 133866 [Patent Document 3] International Publication No. 2013 / 012681 [Patent Document 4] International Publication No. 2013 / 126656 [Patent Document 5] International Publication No. 2014 / 167347 [Patent Document 6] International Publication No. 2015 / 092431 [Patent Document 7] International Publication No. 2018 / 011569 [Patent Document 8] International Publication No. 2018 / 011570 [Patent Document 9] International Publication No. 2018 / 090939 [Patent Document 10] International Publication No. 2018 / 133829 [Patent Document 11] International Publication No. 2018 / 171633 Summary of the Invention

[0006] An object of the present invention is to provide a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. TIFF2025525290000002.tif57170[Among them, R 1 But -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 0~2 Alkylene groups -CN, -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 alkylene group-(3- to 10-membered heterocycloalkyl group), R 2 is selected from the group consisting of formula 2, TIFF2025525290000003.tif108170X is selected from the group consisting of O, NH, or CH2; X1 is selected from the group consisting of CH or N; R 21 , R 22 , R 29 are independently hydrogen, deuterium, halogen, cyano group, nitro group, -OH, -C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl group, -C 0~2 Alkylene groups -OH, -O(C 1~6 alkyl group), -O(halogen-substituted C 1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -C 0~2 Alkylene group -N(C 1~6 alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 alkylene group-(3- to 10-membered heterocycloalkyl group), R 23 , R 24 form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring together with the atom directly linked thereto, R 25 , R 26 form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring together with the atom directly linked thereto, R 27 , R 28 form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring together with the atom directly linked thereto, R 3 However, hydrogen, deuterium, halogen, cyano group, nitro group, -C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl group, -C 0~2 Alkylene groups -OH, -O(C 1~6 alkyl group), -O(halogen-substituted C 1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -C 0~2 Alkylene group -N(C 1~6 alkyl group)(C1~6 alkyl groups), R 4 is selected from the group consisting of 3- to 12-membered heterocycloalkyl groups; and said heterocycloalkyl groups further comprise one, two, three, or four independent R 41 may be substituted with R 41 However, hydrogen, halogen, cyano group, nitro group, -OH, -C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl group, -C 0~2 Alkylene groups -OH, -O(C 1~6 alkyl group), -O(halogen-substituted C 1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -C 0~2 Alkylene group -N(C 1~6 alkyl group)(C 1~6 alkyl group), -C(O)C 1~6 alkyl group, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring further comprise one, two, three, or four independent R 31 may be substituted with Alternatively, R 3 , R 4 together with the atom directly linked thereto form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring, and the carbocyclic ring or heterocycloalkyl group further has one, two, three or four independent R 31 may be substituted with, 31 However, hydrogen, halogen, cyano group, nitro group, -OH, -C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl group, -C 0~2 Alkylene groups -OH, -O(C 1~6 alkyl group), -O(halogen-substituted C 1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -C 0~2 Alkylene group -N(C 1~6 alkyl group)(C 1~6alkyl groups).

[0007] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R 1 is selected from the group consisting of Formula 3. TIFF2025525290000004.tif31170

[0008] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R 21 , R 22 , R 29 are each independently selected from the group consisting of hydrogen, deuterium, cyano, methyl, ethyl, -OH, trifluoromethyl, cyclopropyl, -CH2OH, and -NH2.

[0009] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R 23 , R 24 together with the atom directly connected thereto form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; R 25 , R 26 together with the atom directly connected thereto form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; R 27 , R 28 together with the atom directly connected to them form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group.

[0010] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R 2 is selected from the group consisting of Formula 4. TIFF2025525290000005.tif255169TIFF2025525290000006.tif73169

[0011] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R3 is selected from the group consisting of hydrogen, fluorine, a methyl group, —CH2OH, and a methoxy group.

[0012] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R 4 is selected from the group consisting of a 6-membered nitrogen-containing heterocycle, a 7-membered nitrogen-containing bridged ring, an 8-membered nitrogen-containing bridged ring, a 9-membered nitrogen-containing heterospirocycle, and an 11-membered nitrogen-containing heterospirocycle. Furthermore, R 4 is selected from the group consisting of Formula 5. TIFF2025525290000007.tif65170Furthermore, R 4 is selected from the group consisting of Formula 6. TIFF2025525290000008.tif113170

[0013] Preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, are R 3 , R 4 together with the atoms directly connected to them form a six-membered nitrogen-containing heterocycle.

[0014] More preferably, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof are R 3 , R 4 together with the atoms directly connected to them form formula 7. TIFF2025525290000009.tif35170Furthermore, R 31 is selected from methyl groups.

[0015] Preferably, in the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to the present invention, the compound represented by formula 1 is the following compound: [Table 1] TIFF2025525290000011.tif221170TIFF2025525290000012.tif221170TIFF2025525290000013.tif221170TIFF20255252900000 14.tif234170TIFF2025525290000015.tif234170TIFF2025525290000016.tif203170TIFF2025525290000017.tif221170TIFF202 5525290000018.tif221170TIFF2025525290000019.tif234170TIFF2025525290000020.tif228170TIFF2025525290000021.tif22 8170TIFF2025525290000022.tif221170TIFF2025525290000023.tif221170TIFF2025525290000024.tif221170TIFF20255252900 00025.tif221170TIFF2025525290000026.tif240170TIFF2025525290000027.tif240170TIFF2025525290000028.tif221170TIF F2025525290000029.tif240170TIFF2025525290000030.tif240170TIFF2025525290000031.tif240170TIFF2025525290000032.t if246170TIFF2025525290000033.tif240170TIFF2025525290000034.tif246170TIFF2025525290000035.tif240170TIFF2025525 290000036.tif240170TIFF2025525290000037.tif245165TIFF2025525290000038.tif221170TIFF2025525290000039.tif172170

[0016] More preferably, the compound of the present invention, its stereoisomer, or pharmaceutically acceptable salt thereof, is a compound according to formula 1 selected from the group consisting of formula 8: TIFF2025525290000040.tif64170

[0017] The present invention further provides use of any of the above-described compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a WEE1-mediated disease. The WEE1-mediated disease is one or more of diseases associated with inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes. The present invention further provides a pharmaceutical composition, which is a formulation comprising any of the above-described compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof as a pharmaceutically active ingredient, together with pharmaceutically acceptable additives.

[0018] The terms used in the present invention will be interpreted and explained below. "Cancer" or "malignancy" refers to any of a number of diseases characterized by the uncontrolled abnormal growth of cells, the ability of affected cells to spread locally or via the bloodstream and lymphatic system to other sites in the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cells" refer to cells at early, intermediate, or late stages that undergo multistage tumor progression. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, compounds of Formula I are used to treat cancers selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer. Autoimmune diseases are caused by the body's immune response to substances or tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Grave's disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barré syndrome, multiple sclerosis, and autoimmune retinopathy. Some embodiments of the present invention relate to the treatment of autoimmune diseases such as psoriasis and multiple sclerosis. Inflammatory diseases include many conditions characterized by pathological inflammation of tissues. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammation, reperfusion injury, rheumatoid arthritis, nodular disease, vasculitis, mite-induced airway inflammation, and interstitial cystitis. There is clear overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is commonly involved in inflammatory diseases, as seen in allergic reactions and some muscle disorders, and many immune system disorders cause abnormal inflammation. IL-17A-mediated diseases also include autoimmune inflammatory diseases.

[0019] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, Ohio) naming systems. Unless otherwise specified, the initial definition of a group or term used in the present invention applies to the group or term throughout the present specification. Terms not specifically defined in the present specification should be given the meaning that a person skilled in the art can give them based on the disclosure and context. "Substituted" means that a hydrogen atom in a molecule is replaced with another, different atom or molecule. The minimum and maximum carbon atom content in the hydrocarbon group is indicated by a prefix, e.g., the prefix C a~b The alkyl group refers to an alkyl group containing "a" to "b" carbon atoms. 1~4 "Alkyl group" means an alkyl group containing 1 to 4 carbon atoms. "Alkyl group" means a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1~6By alkyl group is meant an alkyl group having 1 to 6 member atoms, e.g., 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more of the substituents defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. The alkyl group may be part of another group, e.g., a C1-C6 alkoxy group. The terms "cycloalkyl group" and "cycloalkane" refer to saturated or partially saturated cyclic groups containing carbon atoms, no ring-forming heteroatoms, and a single ring or multiple rings (including fused and unfused rings). For polycyclic ring systems containing aromatic and non-aromatic rings without ring-forming heteroatoms, the term "cycloalkyl group" applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthylene-5-yl). The term "cycloalkyl group" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups containing polycyclic bicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, and bicyclooctyl. For example, see Formula 9: TIFF2025525290000041.tif26170

[0020] The term "alkenyl group" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, in some embodiments 2 to 6 carbon atoms, or 2 to 4 carbon atoms, and at least one vinyl unsaturation site (>C=C<). For example, a Ca-Cb alkenyl group refers to an alkenyl group having a to b carbon atoms, including, for example, vinyl, propenyl, isopropenyl, and 1,3-butadiene groups. The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl group" also includes hydrocarbon groups having one triple bond and one double bond. For example, a (C2-C6)alkynyl group includes ethynyl, propynyl, and the like. "Halogen" is fluorine, chlorine, bromine or iodine. The term "haloalkyl group" means that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms. For example, C 1~4 Haloalkyl group refers to an alkyl group containing from 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms. The terms "heterocycle," "heterocycloalkyl group," and "heterocycloalkane" refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom, where a heteroatom is a nitrogen atom, an oxygen atom, or a sulfur atom. The term "heteroaryl ring" refers to an aromatic unsaturated ring containing at least one heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom. "Stereoisomer" includes enantiomers and diastereomers.

[0021] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist as different stereoisomers. All stereoisomers of the compounds of the present invention include, but are not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist as optically active compounds, possessing the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L, or R, S are used to denote the absolute chiral configuration of the molecule. These stereoisomers have the same chemical structure but different stereochemistry. Specific stereoisomers may also be enantiomers, and mixtures of isomers are typically referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and there may be no stereoselectivity or stereoorientation during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, lacking optical activity. The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and / or formed salt is usually chemically or physically compatible with the other ingredients that make up a drug dosage form and is physiologically compatible with the receptor.

[0022] The pharmaceutical composition of the present invention may be in any reusable pharmaceutical dosage form, such as oral, injectable, or topical. Oral dosage forms include, but are not limited to, tablets, capsules, oral solutions, granules, pills, and suspensions. Injectables are selected from aqueous solutions and powders, and topical preparations are selected from patches and pastes. Each formulation can be prepared according to conventional pharmaceutical techniques using the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt as the active pharmaceutical ingredient, and optionally adding a pharmaceutically acceptable carrier. The active pharmaceutical ingredient per unit dose is 0.1 mg to 1000 mg, for example, 0.1 mg to 1000 mg per tablet, preferably 5 to 500 mg. The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds or their stereoisomers with a certain amount of acid or base (e.g., equimolar amounts). These salts can be obtained by forming a precipitate in a solution and collecting it by filtration, recovering it after evaporating the solvent, or reacting it in an aqueous medium and lyophilizing it. The salts referred to in the present invention may be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds. In some embodiments, one or more compounds of the present invention can be used in combination with each other. Compounds of the present invention can also be used in combination with other active agents to prepare drugs or drug compositions for regulating cellular function or treating disease. When a group of compounds is used, these compounds can be administered to a subject simultaneously, separately, or sequentially.

[0023] The method for producing the compound of the present invention will be explained below. The specific steps are shown in Scheme 10. <Process 1> TIFF2025525290000042.tif46170 R in Equation B and Equation C P represents a protecting group for a hydrogen atom or an imino group, and R P The protecting group for the imino group in Formula B, Formula C and Formula D is preferably a benzyl group, a p-methoxybenzyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or the like. 1 The groups refer to the definitions above and are the same as those defined above. In the above step 1, a compound represented by formula A is reacted with a hydrazine derivative represented by formula B in the presence of a base to obtain a compound represented by formula C. The reaction can generally be carried out in the presence of an organic base such as triethylamine, diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine, etc., or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc. For example, the reaction can be carried out in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, benzene, toluene, xylene, dimethylformamide, etc., or a mixed solvent. Thereafter, a deprotection reaction is carried out to form a compound represented by formula D by ring formation of the compound. The amount of the base used is preferably equimolar to excess molar amount, more preferably 1 to 5 molar amount, and most preferably 1 to 3 molar amount, relative to 1 mole of the compound of formula A. When the base is liquid, it may be used as both a solvent and a base. The reaction temperature is generally -78°C to 200°C, preferably 20 to 100°C. The reaction time is generally 5 minutes to 7 days, preferably 8 to 96 hours. In the above step 1, the compound of formula C undergoes deprotection and ring formation to obtain the compound of formula D, wherein the deprotection reagent is selected from the group consisting of trifluoroacetic acid, hydrochloric acid solution, etc., and the solvent is selected from methanol, dichloromethane, or 1,4-dioxane, etc., preferably TFA / CHCl2 to remove the protecting group; when Boc is used as the protecting group, the deprotection reaction can be carried out under standard conditions, such as dichloromethane / trifluoroacetic acid system or saturated hydrogen chloride dioxane solution; wherein the ring formation reaction is carried out under basic conditions, such as a concentrated sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, or sodium bicarbonate solution, etc., preferably sodium hydroxide solution. The reaction temperature for deprotection and ring formation is generally -78°C-200°C, preferably 20-100°C, and the reaction time is generally 5 minutes to 7 days, preferably 8 hours to 96 hours.

[0024] <Process 2> The compound represented by formula G can be produced by the method of step 2-1 or step 2-2, and the production method of step 2-1 or step 2-2 is as follows. <<Process 2-1>> TIFF2025525290000043.tif48170 Substituent R of compounds described in formulas E and G 1 and R 2 The groups are defined as above. In this reaction, the compound of formula E is reacted with the compound of formula D by a C-N coupling reaction to obtain the compound of formula G. The reaction solvent is 1,4-dioxane, tetrahydrofuran, diethyl ether, benzene, toluene, xylene, etc., or a mixed solvent, and the reaction temperature is 0-200°C, preferably 20-150°C. <<Process 2-2>> TIFF2025525290000044.tif40170 Substituent R of compounds described in formula F and formula G 1 and R 2 The groups refer to the definitions above and are the same as those defined above, and the halogen atoms are F, Cl, Br, and I. The compound represented by formula F and the compound represented by formula D undergo a C-N coupling reaction to obtain the compound represented by formula G, and the reaction solvent is 1,4-dioxane, tetrahydrofuran, diethyl ether, benzene, toluene, xylene, etc. or a mixed solvent, and the reaction temperature is 0-200°C, preferably 20-150°C. In this step, the C-N coupling reaction is a coupling method for forming a C-N bond that is well known in the art, such as the Ullmann reaction or the Buchwald reaction, preferably the Ullmann reaction, more preferably under the reaction conditions of cuprous iodide / potassium carbonate / N,N-diisopropylethylamine DMEDA / 1,4-dioxane (the coupling reaction conditions are CuI, DMEDA, K2CO3, 1,4-dioxane), or more preferably CuI / K2CO3 / N,N'-dimethyl-1,2-cyclohexylenediamine, anisole / NaI / microwave, or more preferably CuI / K2CO3 / anisole / NaI / microwave. In the above steps 2-1 and 2-2, compound R 2 B(OH)2 and R 2 The -halogen atom can be prepared using readily available starting materials by conventional synthetic methods in the field of organic chemistry.

[0025] <Process 3> TIFF2025525290000045.tif47170 Substituent R of compounds described in formula H and formula G 1 , R 2 , R 3 , R 4 The groups are defined as above. The compound of formula G is first reacted with an oxidizing agent to form a sulfoxide, which is a more active intermediate, and then undergoes a substitution reaction with the compound of formula H to obtain the compound of formula I. The reaction solvent is selected from the group consisting of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, benzene, toluene, xylene, dimethylformamide, etc., or a mixture thereof; the oxidizing agent in the oxidation reaction is preferably metachloroperbenzoic acid (m-CPBA); the conditions for the substitution reaction are those known in the art, for example, basic or acidic conditions, the basic conditions are preferably diisopropylethylamine (DIPEA), and the acidic conditions are preferably trifluoroacetic acid; the reaction temperature is -20-200°C, preferably 20-150°C, and most preferably room temperature. In the above step 3, the substituted aniline compound of formula H can be prepared by conventional synthetic methods in the field of organic chemistry using readily available starting materials.

[0026] <Step 4> If the compound of formula 1 prepared in step 3 above contains a chiral center, those skilled in the art can obtain pure enantiomers by chromatography or other resolution means, referring to known separation techniques. For example, two enantiomers containing one chiral center can be obtained by SFC resolution. If the compound of formula 1 prepared in step 3 above does not contain a chiral center, the resolution step in step 4 above is not necessary. Obviously, according to the above content of the present invention, many other forms of modifications, substitutions or alterations can be made based on the common technical knowledge and common practices of those skilled in the art without departing from the above basic technical idea of the present invention. The above content of the present invention will be described in more detail below with reference to specific embodiments in the form of examples. However, it should be understood that the scope of the above content of the present invention should not be limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] The structure of the compound is confirmed by magnetic resonance (NMR) and mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The values are given in ppm. NMR measurements were performed on Bruker Avance III 400 and Bruker Avance 300 magnetic resonance spectrometers using deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CDOD) as solvents, with tetramethylsilane (TMS) as the internal standard. LC-MS measurements were performed using a Shimadzu chromatography mass spectrometer (Shimadzu LC-MS 2020 (ESI)). HPLC measurements were performed using a Shimadzu high-performance liquid chromatograph (Shimadzu LC-20A). MPLC (medium-pressure preparative chromatography) was performed using a Gilsong X-281 reversed-phase preparative chromatograph. Thin-layer chromatography was performed using Yantai Yellow Sea HSGF254 or Qingdao GF254 silicon gel plates (China). Thin-layer chromatography was performed using 0.4 mm to 0.5 mm silicon gel plates. Column chromatography generally used Yantai Yellow Sea Silica Gel 200 to 300 mesh silica gel (China). The known starting materials of the present invention may be synthesized by methods known in the art or may be purchased from companies such as Anergy Chemical, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, and Bai Lingwei Science and Technology. Unless otherwise specified in the examples, reactions were carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, solutions were aqueous solutions. Unless otherwise specified in the examples, reactions were at room temperature. Unless otherwise specified in the examples, M is in moles / liter. THF: tetrahydrofuran; DIPEA: N,N-diisopropylethylamine; DCM: dichloromethane; TFA: trifluoroacetic acid; m-CPBA: metachloroperbenzoic acid; DMF: dimethylformamide; PTSA: paratoluenesulfonamide; DMSO: dimethyl sulfoxide; NBS: N-bromosuccinimide; AIBN: azodiisobutalonitrile; DMP: dimethyl phthalate; TBAHS: tetrabutylammonium hydrogen sulfate; BMS: 4-benzoyl-4''-methyl-diphenyl sulfide; Unless otherwise specified in the examples, the HPLC measurement conditions were as follows. <Method A> Column specifications: Bostongreen C18 150mm*4.6mm 5um; Mobile phase: A: 0.05% TFA Water, B: 0.05% TFA Acetonitrile; Gradient: B from 5% to 95% in 10.0min and hold 95% for 5.0min; Flow rate: 1.5mL / min; Column temperature: 40℃. <Method B> Column specifications: Bostongreen ODS 150mm*4.6mm 5um; Mobile phase: A: 0.01M NH4HCO3 Water, B: Acetonitrile; Gradient: B from 5% to 95% in 10.0min and hold 95% for 5.0min; Flow rate: 1.5mL / min; Column temperature: 40℃. Unless otherwise specified, the terms of division of SFC are as follows: Column specifications: 3 μm, 150 mm * 3 mm, mobile phase: A: CO2, mobile phase B: ethanol; flow rate: 1 mL / min, column temperature: 40 °C.

[0028] "Intermediate Example 1: Synthesis of Intermediate IM-1" TIFF2025525290000046.tif50170<Step 1: Synthesis of Compound IM-1-3> In a dry one-neck flask, the substrate IM-1-2 (8.15 g, 35 mmol) and THF (50 mL) were added and dissolved by stirring. Then, IM-1-1 (6.3 g, 37 mol) and DIPEA (15 mL, 75 mol) were added and the mixture was heated to 110°C. The reaction was monitored by LC-MS. After the reaction was completed, the system was allowed to return to room temperature, and the precipitated solid was filtered and dried in an oven to obtain the crude product IM-1-3 (9.87 g, 76.6% yield). LCMS (ESI) + ) m / z: 369.2 [M+H] + . <Step 2: Synthesis of Compound IM-1> Substrate IM-1-3 (9.16 g, 27.5 mmol) and DCM (18 mL) were added to a dry one-neck flask and stirred to dissolve. Then, TFA (18 mL) was slowly added and the mixture was heated to 75°C. The reaction was monitored by LC-MS. After completion of the reaction, the organic solvent was concentrated under reduced pressure, and the mixture was dissolved in ethanol. 6M NaOH solution was added and the mixture was stirred at room temperature. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure. A solid precipitated. The solid was filtered, washed three times with water, washed three times with cold ethanol, and dried under air at room temperature to obtain crude product IM-1 (5 g, 81.7% yield). LCMS (ESI) + ) m / z: 223.1 [M+H] + .

[0029] Example 1: Synthesis of Compound 1 TIFF2025525290000047.tif75170<Step 1: Synthesis of Compound 1-3> Substrate 1-1 (1 g, 4.72 mmol) and THF (10 mL) were added to a dry one-neck flask and dissolved by stirring. Then, n-BuLi (2.5 M, 4.15 mL) was slowly added dropwise at -40 °C under nitrogen protection. The reaction was continued for 1 hour with stirring at -40 °C. Then, 1-2 (2.66 g, 14.15 mmol) was added dropwise. After the addition was complete, the mixture was returned to room temperature and reacted for 12 hours. The reaction was monitored by LC-MS. After the reaction was complete, 4 N HCl (5 mL) was added, and the solvent was evaporated. The mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, and evaporated to give product 1-3 (1.2 g, crude). LCMS (ESI) + ) m / z: 238 / 240 [M+H] + .

[0030] <Step 2: Synthesis of Compound 1-4> Substrate 1-3 (700 mg, 2.94 mmol) and DMF (3 mL) were added to a dry one-neck flask and dissolved by stirring. Then, iodoethane (458.57 mg, 2.94 mmol) and cesium carbonate (1.05 g, 3.23 mmol) were added and the reaction was stirred at 75 °C for 8 hours, and the reaction was monitored by LC-MS. After completion of the reaction, water and EA were added and extracted three times. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse phase column chromatography to give product 1-4 (285 mg, 1.07 mmol, 36.42% yield), LCMS (ESI) + ) m / z: 266 [M+H] + . <Step 3: Synthesis of Compound 1-5> Substrate 1-4 (155 mg, 582.41 μmol), B(pin)2 (325.38 mg, 1.28 mmol), Pd(dppf)Cl2 (42.73 mg, 58.24 μmol), and potassium carbonate (241.47 mg, 1.75 mmol) were added to a dry one-neck flask, dissolved in 1,4-dioxane (5 mL), and the mixture was heated to 110 °C under nitrogen protection and stirred for 12 h. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was evaporated, and the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 1-5 (80 mg, 255.43 μmol, 43.86% yield). LCMS (ESI) + ) m / z: 314 [M+H] + . <Step 4: Synthesis of Compound 1-6> In a dry one-neck flask, substrate 1-5 (57 mg, 181.99 μmol) was added and dissolved in ACN (5 mL). HCl (6 M, 1 mL) was added and heated to 60 °C. The reaction was stirred for 6 h and monitored by LC-MS. After completion of the reaction, the solvent was evaporated, and the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 1-6 (24 mg, 103.87 μmol, 57.07% yield). LCMS (ESI) + ) m / z: 232 [M+H] + .

[0031] <Step 5: Synthesis of Compound 1-7> In a dry one-neck flask, substrate 1-6 (24 mg, 103.87 μmol) was added and dissolved in DCM (3 mL). IM-1 (26.93 mg, 121.18 μmol), copper acetate (4.52 mg, 24.86 μmol), and pyridine (9.59 mg, 121.18 μmol, 9.76 μL) were added and the reaction was stirred at room temperature for 72 hours and monitored by LC-MS. After completion of the reaction, the solvent was evaporated and the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 1-7 (19 mg, 46.63 μmol, 38.48% yield). LCMS (ESI) + ) m / z: 408 [M+H] + . <Step 6: Synthesis of Compound 1> In a dry one-neck flask, substrate 1-7 (19 mg, 46.63 μmol) was dissolved in THF (1.5 mL). m-CPBA (14.48 mg, 83.93 μmol) was added and the mixture was stirred at room temperature for 0.5 h. DIPEA (30.13 mg, 233.14 μmol, 40.61 μL) and 1-8 (10.70 mg, 55.95 μmol) were then added. The mixture was stirred at room temperature for 12 h and monitored by LC-MS. After completion of the reaction, the solvent was evaporated and the mixture was purified by reverse-phase column chromatography to give product 1 (3.1 mg, 5.63 μmol, 12.07% yield). 1 H NMR(600MHz,DMSO-d6)δ10.03(s,1H),8.81(s,1H),7.52(s,2H),7.21(s,2H),7.1 1-7.09(m,1H),6.83(d,J=6.0Hz,2H),5.70-5.67(m,1H),5.09(d,J=10.2Hz,1H), 4.97(d,J=17.4Hz,1H),4.28(s,2H),3.82-3.78(m,2H),3.06(s,4H),2.47(s,4H) ,2.23(s,3H),1.69(d,J=3.6Hz,2H),1.58(d,J=3.0Hz,2H),1.15(t,J=6.6Hz,3H). LCMS(ESI + ) m / z: 551.2 [M+H] + ,HPLC Method B: RT =5.65min,purity:100%.

[0032] Example 2: Synthesis of Compound 2 TIFF2025525290000048.tif64170<Step 1: Synthesis of Compound 2-2> Substrate 2-1 (870 mg, 4.42 mmol) and DMF (8 mL) were added to a dry one-neck flask and dissolved by stirring. Then, iodoethane (1.38 g, 8.83 mmol) and potassium carbonate (1.22 g, 8.83 mmol) were added and the reaction was stirred at 75 °C for 4 hours, and the reaction was monitored by LC-MS. After completion of the reaction, water and EA were added and extracted three times. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse phase column chromatography to give product 2-2 (600 mg, 2.67 mmol, 60.37% yield), LCMS (ESI) + ) m / z: 225 [M+H] + . <Step 2: Synthesis of Compound 2-3> Substrate 2-2 (600 mg, 2.67 mmol) and 1,4-dioxane (10 mL) were added to a dry one-neck flask and stirred to dissolve. Tribromopyridine (3.41 g, 10.66 mmol) was then added and the reaction was stirred at room temperature for 16 hours, and monitored by LC-MS. After completion of the reaction, the solvent was evaporated, and the mixture was extracted three times with water and DCM. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 2-3 (230 mg, 576.62 μmol, 21.63% yield). LCMS (ESI) + ) m / z: 399 [M+H] + .

[0033] <Step 3: Synthesis of Compound 2-4> Substrate 2-3 (230 mg, 576.62 μmol) and THF (1.5 mL) were added to a dry one-neck flask and stirred to dissolve. Then, saturated ammonium chloride solution (1.5 mL) and zinc powder (753.99 mg, 11.53 mmol) were added. The reaction was stirred at room temperature for 10 minutes and monitored by LC-MS. After completion of the reaction, the mixture was filtered, the solvent was evaporated, and the product was purified by reverse-phase column chromatography to give product 2-4 (44 mg, 182.51 μmol, 31.65% yield). LCMS (ESI) + ) m / z: 241 [M+H] + . <Step 4: Synthesis of Compound 2-5> Substrate 2-4 (20 mg, 82.96 μmol) and DMF (1 mL) were added to a dry one-neck flask and dissolved by stirring. NaH (11.95 mg, 497.75 μmol) was then added and the reaction was continued for 0.5 hours with stirring at 0 °C. 1,3-diiodopropane (73.64 mg, 248.88 μmol) was then added and the reaction was continued for 0.5 hours with stirring at room temperature. The reaction was monitored by LC-MS. Upon completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 2-5 (10 mg, 35.57 μmol, 42.87% yield). LCMS (ESI) + ) m / z: 281 [M+H] + . <Step 5: Synthesis of Compound 2-6> Substrate 2-5 (10 mg, 35.57 μmol) and 1,4-dioxane (1 mL) were added to a dry one-neck flask and dissolved with stirring. IM-1 (10 mg, 44.99 μmol), CuI (15.58 mg, 81.80 μmol), KCO (7.91 mg, 57.26 μmol), and DMEDA (14.42 mg, 163.60 μmol) were then added. The mixture was heated to 110 °C under nitrogen protection and stirred for 3 h. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 2-6 (5 mg, 11.83 μmol, 28.93% yield). LCMS (ESI) + ) m / z: 423 [M+H] + . <Step 6: Synthesis of Compound 2> In a dry one-neck flask, substrate 2-6 (5.0 mg, 11.86 μmol) was dissolved in THF (1 mL). m-CPBA (3.68 mg, 21.35 μmol) was added and the mixture was stirred at room temperature for 0.5 h. DIPEA (7.67 mg, 59.31 μmol, 10.33 μL) and 1-8 (2.72 mg, 14.23 μmol) were then added. The mixture was stirred at room temperature for 8 h and monitored by LC-MS. After completion of the reaction, the solvent was evaporated and the mixture was purified by reverse-phase column chromatography to give product 2 (2.1 mg, 3.71 μmol, 31.30% yield). 1 H NMR(600MHz,CDCL3)δ 8.77(s,1H),7.77(d,J=7.8Hz,1H),7.44(d,J=4.8Hz,2H),7.36(d,J=7.8Hz,1H),6.8 6(d,J=9.0Hz,2H),5.67-5.62(m,1H),5.00(d,J=9.6Hz,1H),4.92(d,J=16.8Hz,1H),4 .65(d,J=5.4Hz,2H),3.75(q,J=14.4Hz,2H),3.40(s,4H),2.93-2.87(m,2H),2.64-2 .61(m,4H),2.37-2.28(m,4H),2.23-2.18(m,1H),1.57(s,2H),1.21(t,J=7.2Hz,3H). LCMS(ESI+ ) m / z: 566.2 [M+H] + ,HPLC Method B: R T =6.03min,purity:85.9%.

[0034] Example 3: Synthesis of Compound 3 TIFF2025525290000049.tif71170<Step 1: Synthesis of Compound 3-2> In a dry one-neck flask, the substrate NaH (166.08 mg, 4.15 mmol, 60% purity) and DMF (20 mL) were added and dissolved by stirring. Then, under nitrogen protection at 0 °C, a solution of 1,2-dibromoethane (780 mg, 4.15 mmol) and 3-1 (200 mg, 1.19 mmol) in DMF (10 mL) was added and reacted with stirring at 0 °C for 1 hour, then at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with saturated ammonium chloride solution and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give the following product 3-2 (35 mg, 180.76 μmol, 15.24% yield), LCMS (ESI) + ) m / z: 194.2 [M+H] + . <Step 2: Synthesis of Compound 3-3> Substrate 3-2 (33 mg, 170.43 μmol) and THF (5 mL) were added to a dry one-neck flask and dissolved by stirring. Methylmagnesium bromide (2 M, 340.86 μL) was added dropwise at 0°C under nitrogen protection. The reaction was stirred at 0°C for 1 hour and monitored by LC-MS. After completion of the reaction, saturated ammonium chloride solution and EA were added and extracted three times. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 3-3 (33 mg, 157.39 μmol, 92.35% yield). LCMS (ESI) + ) m / z: 210.1 [M+H] + .

[0035] <Step 3: Synthesis of Compound 3-4> Substrate 3-3 (33 mg, 157.39 μmol) and anisole (2 mL) were added to a dry one-neck flask and dissolved with stirring. IM-1 (34.98 mg, 157.39 μmol), CuI (59.95 mg, 314.78 μmol), KCO (54.38 mg, 393.47 μmol), N,N'-dimethyl-1,2-cyclohexylenediamine (89.55 mg, 629.56 μmol), and NaI (47.18 mg, 314.78 μmol) were then added. The reaction was heated at 130 °C in a microwave oven with stirring for 4 h and monitored by LC-MS. After the reaction was completed, the mixture was extracted three times with water and EA. The organic phases were combined and treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reversed-phase column chromatography to give the following product 3-4 (38 mg, 96.09 μmol, 61.05% yield). LCMS (ESI + ) m / z: 396.1 [M+H] + . <Step 4: Synthesis of Compound 3> In a dry one-neck flask, substrate 3-4 (38 mg, 96.09 μmol) was dissolved in THF (4 mL). m-CPBA (35.11 mg, 172.96 μmol, 85% purity) was added and reacted with stirring at room temperature for 1 hour. DIPEA (124.18 mg, 960.86 μmol, 167.36 μL) and 1-8 (22.05 mg, 115.30 μmol) were then added. The mixture was heated to 50 °C and stirred for 5 hours. LC-MS monitoring was performed. After completion of the reaction, the solvent was evaporated and the mixture was purified by reverse-phase column chromatography to give product 3 (22.6 mg, 40.24 μmol, 41.88% yield). 1H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.82(s,1H),7.92(s,1H),7.70(d,J=8.4Hz,1H),7.59(s,2H),6.92(d,J=8.4Hz,2 H),5.72-5.76(m,1H),5.02(s,1H),5.01(d,J=10.2Hz,1H),4.88(d,J=17.4Hz,1H),4.82-4.68(m ,1H),4.66-4.52(m,1H),3.09(t,J=4.8Hz,4H),2.93-2.86(m,2H),2.46(t,J=4.8Hz,4H),2.23( s,3H),1.22(s,3H),0.94-0.91(m,1H),0.70-0.67(m,1H),0.60-0.56(m,1H),0.48-0.45(m,1H). LCMS(ESI + ) m / z: 539.3 [M+H] + ,HPLC Method B: R T =6.92min,purity:95.9%. Compound 3 was resolved by SFC to give the following two compounds: 3a R T =2.51min; 3b R T =3.51 min (Unless otherwise specified, the chiral configuration of a compound here indicates only the distinction of molecular structure and does not mean the exact absolute configuration, and this also applies hereinafter). TIFF2025525290000050.tif641703aStructure identification: 1H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),8.83(s,1H),7.92(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.66-7.46(m,2H),6.9 2(d,J=8.8Hz,2H),5.74-5.67(m,1H),5.10-4.98(m,2H),4.90-4.86(m,1H),4.83-4.67(m,1H),4 .60(d,J=14.8Hz,1H),3.11(t,J=5.2Hz,4H),2.90(d,J=2.4Hz,2H),2.50-2.44(m,4H),2.26(s,3 H),1.22(s,3H),0.95-0.90(m,1H),0.71-0.66(m,1H),0.61-0.56(m,1H),0.48-0.45(m,Hz,1H). LCMS(ESI + )m / z: 539.3 [M+H] + ,HPLC Method B: R T =6.80min,purity:97.8%. 3b structure is defined as follows: 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),8.82(s,1H),7.92(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.59(s,2H),7.02-6. 83(m,2H),5.74-5.67(m,1H),5.06-4.97(m,2H),4.90-4.86(m,1H),4.80-4.66(m,1H),4.60(d, J=13.6Hz,1H),3.09(t,J=5.2Hz,4H),2.90(d,J=2.4Hz,2H),2.45(t,J=5.2Hz,4H),2.22(s,3H ),1.22(s,3H),0.95-0.90(m,1H),0.71-0.66(m,1H),0.61-0.56(m,1H),0.48-0.45(m,Hz,1H). LCMS(ESI + )m / z: 539.3 [M+H] + ,HPLC Method B: R T =6.80min,purity:98.1%.

[0036] "Example 4: Synthesis of Compound 4" TIFF2025525290000051.tif99170<Step 1: Synthesis of Compound 4-2> In a dry one-neck flask, the substrate NaH (1.40 g, 34.96 mmol, 60% purity) and DMF (150 mL) were added and dissolved by stirring. Then, under nitrogen protection at 0 °C, a solution of 1,2-dibromoethane (6.57 g, 34.96 mmol) and 4-1 (1.47 g, 9.99 mmol) in DMF (30 mL) was added and the reaction was stirred at 0 °C for 3 h, and monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with saturated ammonium chloride solution and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give the following product 4-2 (0.55 g, 3.18 mmol, 31.79% yield), LCMS (ESI) + ) m / z: 174.0 [M+H] + . <Step 2: Synthesis of Compound 4-3> Substrate 4-2 (470 mg, 2.71 mmol) and methanol (20 mL) were added to a dry one-neck flask and dissolved by stirring. Sodium borohydride (205.30 mg, 5.43 mmol) was then added at 0 °C. The reaction was stirred at 0 °C for 1 hour and monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with saturated sodium bicarbonate solution and DCM. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 4-3 (470 mg, 2.68 mmol, 98.95% yield). LCMS (ESI) + ) m / z: 176.2 [M+H] + .

[0037] <Step 3: Synthesis of Compound 4-4> Substrate 4-3 (470 mg, 2.68 mmol) and DCM (20 mL) were added to a dry one-neck flask and dissolved by stirring. DIPEA (1.39 g, 10.73 mmol, 1.87 mL) was then added at 0 °C. Acetyl chloride (421.10 mg, 5.36 mmol, 381.43 μL) was slowly added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour and monitored by LC-MS. After completion of the reaction, the solvent was evaporated and the product was purified by reverse phase column chromatography to give product 4-4 (540 mg, 2.49 mmol, 92.66% yield). LCMS (ESI) + ) m / z: 218.2 [M+H] + . <Step 4: Synthesis of Compound 4-6> Substrate 4-4 (540 mg, 2.49 mmol) and DCM (5 mL) were added to a dry one-neck flask and dissolved by stirring. Then, 4-5 (736.29 mg, 4.97 mmol) and HO (845.31 mg, 7.46 mmol, 761.54 μL, 30% purity) were added. The temperature was raised to 40 °C and the reaction was continued with stirring for 16 h. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with saturated sodium bicarbonate solution and DCM. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 4-6 (560 mg, 2.40 mmol, 96.59% yield). LCMS (ESI) + ) m / z: 234.0 [M+H] + . <Step 5: Synthesis of Compound 4-7> Substrate 4-6 (560 mg, 2.40 mmol) and DCM (20 mL) were added to a dry one-neck flask and dissolved under stirring. Triethylamine (1.28 g, 12.65 mmol, 1.76 mL) and POCl3 (775.65 mg, 5.06 mmol, 471.52 μL) were added dropwise at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 3 h and monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with saturated sodium bicarbonate solution and DCM. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, and evaporated to give crude product 4-7 (650 mg, crude). LCMS (ESI) +) m / z: 252.0 [M+H] + .

[0038] <Step 6: Synthesis of Compound 4-8: Substrate 4-7 (650 mg, 2.58 mmol) and methanol (20 mL) were added to a dry one-neck flask and stirred to dissolve. Potassium carbonate (1.78 g, 12.91 mmol) was then added and the reaction was stirred at room temperature for 2 hours and monitored by LC-MS. After completion of the reaction, the reaction was filtered, and the filtrate was evaporated and purified by reverse-phase column chromatography to give product 4-8 (197 mg, 939.56 μmol, 36.38% yield). LCMS (ESI) + ) m / z: 210.1 [M+H] + . <Step 7: Synthesis of Compound 4-9> According to the synthesis method of Step 3 in Example 3, except that 4-8 (40 mg, 190.77 μmol) was used instead of 3-3 in Step 3, the same synthesis method was used to obtain the following: compound 4-9 (39 mg, 98.62 μmol, 51.69% yield), LCMS (ESI + ) m / z: 396.0 [M+H] + . <Step 8: Synthesis of Compound 4> The same synthesis method as in Step 4 of Example 3 was used, except that 4-9 (39 mg, 98.62 μmol) was used instead of 3-4 in Step 4, to obtain compound 4 (24.4 mg, 45.30 μmol, 45.93% yield). 1H NMR(600MHz,DMSO-d6)δ 10.13(s,1H),8.81(s,1H),7.84(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.66-7.50(m,2H),6.92(d,J =8.4Hz,2H),5.70-5.64(m,1H),5.31(d,J=5.4Hz,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H) ,4.78-4.54(m,2H),3.75(d,J=5.4Hz,1H),3.10(t,J=4.8Hz,4H),2.88-2.79(m,2H),2.46(t,J=4.8Hz ,4H),2.28-2.19(m,4H),1.13-1.11(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.41-0.31(m,2H). LCMS(ESI + )m / z: 539.2 [M+H] + ,HPLC Method B: R T =6.98min,purity:98.9%. Compound 4をSFC splits the following compounds: 4a R T =3.12min; 4b R T =5.44min. TIFF2025525290000052.tif521704a has the same structure: 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.81(s,1H),7.84(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.59(s,2H),6.92(d,J= 9.2Hz,2H),5.74-5.61(m,1H),5.31(d,J=5.2Hz,1H),5.02-4.99(m,1H),4.91-4.87(m,1H),4.77- 4.57(m,2H),3.75(d,J=5.2Hz,1H),3.10(t,J=5.2Hz,4H),2.94-2.75(m,2H),2.46(t,J=5.2Hz,4H ),2.31-2.18(m,4H),1.13-1.10(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.41-0.31(m,2H). LCMS(ESI +) m / z: 539.2 [M+H] + ,HPLC Method B: R T =6.91min,purity:98.7%. 4b Structure Identification: 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.81(s,1H),7.84(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.59(s,2H),6.97-6.87 (m,2H),5.74-5.61(m,1H),5.31(d,J=5.6Hz,1H),5.02-4.99(m,1H),4.91-4.87(m,1H),4.76-4. 56(m,2H),3.75(d,J=5.2Hz,1H),3.10(t,J=4.8Hz,4H),2.97-2.76(m,2H),2.46(t,J=5.2Hz,4H) ,2.30-2.18(m,4H),1.13-1.10(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.41-0.31(m,2H). LCMS(ESI + ) m / z: 539.2 [M+H] + ,HPLC Method B: R T =6.92min,purity:98.0%.

[0039] Example 5: Synthesis of Compound 5 TIFF2025525290000053.tif83170<Step 1: Synthesis of Compound 5-1> Substrate 3-2 (40.21 mg, 207.64 μmol) and MeOH (1.2 mL) were added to a dry one-neck flask and dissolved by stirring. NaBD4 (9.56 mg, 228.40 μmol) was then slowly added at 0 °C. The reaction was stirred at 0 °C for 1 h and monitored by LC-MS. After completion of the reaction, water and EA were added and extracted three times. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse phase column chromatography to give product 5-1 (37 mg, 188.15 μmol, 90.62% yield), LCMS (ESI) + ) m / z: 196 [M+H] + . <Step 2: Synthesis of Compound 5-2> Substrate 5-1 (37 mg, 188.15 μmol) and anisole (2 mL) were added to a dry one-neck flask and dissolved by stirring. IM-1 (50.18 mg, 225.78 μmol), CuI (71.67 mg, 376.30 μmol), KCO (65.01 mg, 470.38 μmol), N,N'-dimethyl-1,2-cyclohexylenediamine (107.05 mg, 752.60 μmol), and NaI (56.40 mg, 376.30 μmol) were then added. The reaction was heated at 130 °C in a microwave oven with stirring for 5 h and monitored by LC-MS. After the reaction was completed, the mixture was extracted three times with water and EA. The organic phases were combined and treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reversed-phase column chromatography to give the following product 5-2 (13 mg, 34.08 μmol, 18.11% yield), LCMS (ESI + ) m / z: 383 [M+H] + .

[0040] <Step 3: Synthesis of Compound 5> The same synthesis method as in Step 4 of Example 3 was used, except that 5-2 (13 mg, 33.99 μmol) was used instead of 3-4 in Step 4, to obtain compound 5 (8.5 mg, 15.28 μmol, 44.96% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.82(s,1H),7.94(s,1H),7.68(d,J=7.8Hz,1H),7.59(s,2H),6.91(d,J=8 .4Hz,2H),5.69-5.67(m,1H),5.35(s,1H),5.02(d,J=10.2Hz,1H),4.90(d,J=16.8Hz,1H) ),4.63-4.49(m,2H),3.10-3.08(m,4H),3.07-3.04(m,1H),2.78(d,J=18.0Hz,1H),2.47 -2.45(m,4H),2.22(s,3H),1.01-0.98(m,1H),0.69(t,J=7.8Hz,2H),0.53-0.49(m,1H). LCMS(ESI + ) m / z: 526.4 [M+H] +,HPLC Method B: R T =6.47min,purity: 96.2%.

[0041] Example 6: Synthesis of Compound 6 TIFF2025525290000054.tif83170<Step 1: Synthesis of Compound 6-2> Substrate 6-1 (157 mg, 748.79 μmol) and DCM (10 mL) were added to a dry one-neck flask and dissolved by stirring. DMP (635.18 mg, 1.50 mmol) was then added and the reaction was stirred at 20 °C for 16 h, and monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with saturated sodium bicarbonate solution and DCM. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 6-2 (141 mg, 679.01 μmol, 90.68% yield), LCMS (ESI) + ) m / z: 208.2 [M+H] + . <Step 2: Synthesis of Compound 6-3> The following was obtained by the same synthesis method as in Step 2 of Example 3, except that 6-2 (141 mg, 679.01 μmol) was used instead of 3-2 in Step 2: Compound 6-3 (150 mg, crude), LCMS (ESI + ) m / z: 224.2 [M+H] + .

[0042] <Step 3: Synthesis of Compound 6-4> The same synthesis method as in Step 3 of Example 3 was used, except that 6-3 (95.39 mg, 429.15 μmol) was used instead of 3-3 in Step 3, to obtain the following compound 6-4 (75 mg, 183.15 μmol, 51.21% yield), LCMS (ESI + ) m / z: 410.4 [M+H] + . <Step 4: Synthesis of Compound 6> The same synthesis method as in Step 4 of Example 3 was used, except that 6-4 (45 mg, 109.89 μmol) was used instead of 3-4 in Step 4, to obtain compound 6 (28.5 mg, 51.56 μmol, 45.97% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.82(s,1H),7.79(s,1H),7.69(d,J=8.4Hz,1H),7.59(s,2H),6.93(d,J=8.4Hz,2H),5.70 -5.64(m,1H),5.04-4.95(m,1H),4.86(d,J=17.4Hz,1H),4.81(d,J=15.6Hz,1H),4.69(s,1H),4.69-4.63 (m,1H),3.10(t,J=4.8Hz,4H),2.90-2.86(m,1H),2.81-2.79(m,1H),2.47(s,4H),2.23(s,3H),2.01-1.9 6(m,1H),1.48-1.39(m,4H),0.86-0.85(m,1H),0.64-0.62(m,1H),0.34-0.31(m,1H),0.22-0.21(m,1H). LCMS(ESI + ) m / z: 553.2 [M+H] + ,HPLC Method B: R T =7.91min,purity:99.7%. Compound 6 was resolved by SFC to give the following two compounds: 6a R T =2.75min; 6b R T =4.41min TIFF2025525290000055.tif581706a Structure identification: 11H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.82 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 6.99 - 6.85 (m, 2H), 5.72 - 5.62 (m, 1H), 5.00 - 4.98 (m, 1H), 4.98 - 4.84 (m, 1H), 4.79 (s, 1H), 4.69 (d, J = 1.8 Hz, 1H), 4.68 - 4.66 (m, 1H), 3.10 (t, J = 4.8 Hz, 4H), 2.89 - 2.78 (m, 2H), 2.46 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.99 - 1.97 (m, 1H), 1.46 - 1.38 (m, 4H), 0.87 - 0.85 (m, 1H), 0.65 - 0.61 (m, 1H), 0.33 - 0.30 (m, 1H), 0.23 - 0.20 (m, 1H). LCMS (ESI + ) m / z: 553.2 [M+H] + , HPLC method B: R T = 7.91 min, purity: 97.9%. Identification of 6b structure: 1 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.82 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.67 - 7.49 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.72 - 5.62 (m, 1H), 5.03 - 4.94 (m, 1H), 4.88 - 4.84 (m, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 4.67 - 4.65 (m, 1H), 3.10 (t, J = 4.8 Hz, 4H), 2.93 - 2.77 (m, 2H), 2.46 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.99 - 1.97 (m, 1H), 1.47 - 1.36 (m, 4H), 0.87 - 0.84 (m, 1H), 0.65 - 0.62 (m, 1H), 0.33 - 0.30 (m, 1H), 0.22 - 0.20 (m, 1H). LCMS (ESI + ) m / z: 553.2 [M+H] + , HPLC method B: R T = 7.91 min, purity: 99.1%.

[0043] Example 7: Synthesis of Compound 7 TIFF2025525290000056.tif83170<Step 1: Synthesis of Compound 7-3> Substrate 7-1 (400 mg, 2.02 mmol) and DMSO (5 mL) were added to a dry one-neck flask and dissolved by stirring. Then, 7-2 (313.14 mg, 2.22 mmol) and potassium carbonate (836.50 mg, 6.05 mmol) were added and the reaction was stirred at 65 °C for 10 h. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 7-3 (633 mg, 1.98 mmol, 98.24% yield), LCMS (ESI) + ) m / z: 319 [M+H] + . <Step 2: Synthesis of Compound 7-4> Substrate 7-3 (633 mg, 1.98 mmol) and methanol (5 mL) were added to a dry one-neck flask and dissolved by stirring. Pd / C (60 mg, 494.03 μmol) was then added and the reaction was stirred in H2 at room temperature for 12 hours and monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to give crude product 7-4 (459 mg, crude). LCMS (ESI) + ) m / z: 290 [M+H] + .

[0044] <Step 3: Synthesis of Compound 7-5> Substrate 7-4 (150 mg, 518.36 μmol) and THF (5 mL) were added to a dry one-neck flask and dissolved by stirring. LiAlH (19.67 mg, 518.36 μmol) was then slowly added at 0 °C. The reaction was stirred at 65 °C for 4 hours and monitored by LC-MS. After completion of the reaction, water was added to quench the reaction at 0 °C. The reaction was treated with 10% sodium hydroxide solution, followed by the addition of more water. The reaction was filtered, and the filtrate was evaporated and purified by reverse phase column chromatography to give product 7-5 (70 mg, 0.34 mmol, 66.43% yield). LCMS (ESI)+ ) m / z: 204 [M+H] + . <Step 4: Synthesis of Compound 7> The same synthesis method as in Step 4 of Example 3 was used, except that 6-4 (15 mg, 36.63 μmol) was used instead of 3-4 in Step 4, and 7-5 (8.94 mg, 43.96 μmol) was used instead of 1-8, to obtain compound 7 (10.4 mg, 16.21 μmol, 44.25% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.76(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.66-7.47(m,2H),6.72(d,J=8.4Hz ,2H),5.72-5.63(m,1H),4.99(d,J=10.2Hz,1H),4.86(d,J=17.4Hz,1H),4.80(s,1H),4.68(s,1H),4.64(d,J =15.6Hz,1H),3.75-3.54(m,2H),3.46(d,J=10.8Hz,2H),2.88-2.77(m,2H),2.50(s,3H),2.12-1.92(m,4H), 1.57(s,1H),1.45-1.39(m,4H),0.87-0.85(m,1H),0.65-0.61(m,1H),0.33-0.29(m,1H),0.26-0.19(m,1H). LCMS(ESI + ) m / z: 565.2 [M+H] + ,HPLC Method B: R T =8.49min,purity:88.0%. SFC resolution of compound 7 gave the following two compounds: 7a R T =3.564min; 7b R T =6.246min TIFF2025525290000057.tif58170 Compound 7a (8.3mg, 13.52μmol); SFC retention time t=3.564min. 1H NMR(400MHz,DMSO-d6)δ 10.06(s,1H),8.80(s,1H),7.76(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.59(s,2H),6.71(d,J=8.8Hz,2H),5.72-5.6 2(m,1H),5.00-4.98(m,1H),4.88-4.79(m,2H),4.68(s,1H),4.67-4.61(m,1H),4.80-4.77(m,1H),3.58(d,J=5.2Hz,2H ),3.43(d,J=10.8Hz,2H),3.27(d,J=10.8Hz,2H),2.92-2.76(m,2H),2.46-2.41(m,1H),2.02-1.94(m,4H),1.53(d,J=8 .0Hz,1H),1.46-1.42(m,1H),1.40(s,3H),0.87-0.84(m,1H),0.68-0.60(m,1H),0.34-0.30(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 565.4 [M+H] + ,HPLC Method B: R T =8.36min,purity> 92.1%. Compound 7b (8.3 mg, 13.91 μmol); SFC retention time t = 6.246 min. 1H NMR(400MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.76(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.59(s,2H),6.71(d,J=8.8Hz,2H),5.72-5.6 2(m,1H),5.00-4.98(m,1H),4.88-4.79(m,2H),4.68(s,1H),4.67-4.61(m,1H),4.80-4.77(m,1H),3.58(d,J=5.2Hz,2H ),3.43(d,J=10.8Hz,2H),3.27(d,J=10.8Hz,2H),2.92-2.76(m,2H),2.45-2.40(m,1H),2.02-1.95(m,4H),1.53(d,J=8 .0Hz,1H),1.46-1.42(m,1H),1.40(s,3H),0.87-0.84(m,1H),0.68-0.60(m,1H),0.34-0.30(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 565.4 [M+H] + ,HPLC Method B: R T =8.30min,purity>95.2%.

[0045] Example 8: Synthesis of Compound 8 TIFF2025525290000058.tif64170<Step 1: Synthesis of Compound 8> The same synthesis method as in Step 4 of Example 3 was used, except that 6-4 (15 mg, 36.63 μmol) was used instead of 3-4 in Step 4, and 8-1 (9.02 mg, 43.96 μmol) was used instead of 1-8, to obtain compound 8 (7.4 mg, 12.14 μmol, 33.15% yield). 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.84(s,1H),7.76(d,J=8.4Hz,1H),7.72(s,1H),7.70(s,1H),7.45-7.36(m,1H),6. 99(d,J=8.4Hz,1H),5.72-5.63(m,1H),5.00-4.98(m,1H),,4.91-4.83(m,1H),4.83-4.75(m,1H),4 .70(s,1H),4.67-4.61(m,1H),2.90-2.77(m,6H),2.52-2.45(m,4H),2.25(s,6H),2.01-1.97(m,1 H),1.47-1.38(m,4H),0.87-0.84(m,1H),0.65-0.60(m,1H),0.36-0.29(m,1H),0.23-0.19(m,1H). LCMS(ESI + ) m / z: 567.2 [M+H] + ,HPLC Method B: R T =8.83min,purity:93.0%.

[0046] Example 9: Synthesis of Compound 9 TIFF2025525290000059.tif83170<Step 1: Synthesis of Compound 9-2> Substrate 9-1 (3 g, 18.62 mmol) and DMF (20 mL) were added to a dry one-neck flask and dissolved by stirring. Then, iodomethane (8.7 g, 61.43 mmol), TBAHS (630 mg, 18.62 mmol), and potassium carbonate (8.48 g, 61.43 mmol) were added and the reaction was stirred at 70 °C for 15 h. The reaction was monitored by LC-MS. After completion of the reaction, water was added to quench the reaction, and EA was added and extracted three times. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 9-2 (3.4 g, 16.73 mmol, 89.87% yield). LCMS (ESI) + ) m / z: 204 [M+H] + . <Step 2: Synthesis of Compound 9-3> Substrate 9-2 (3.4 g, 16.73 mmol) and HSO (10 mL) were added to a dry one-neck flask and dissolved with stirring. HNO (1.02 g, 16.24 mmol) was then slowly added dropwise at 0 °C. The reaction was stirred at 0 °C and monitored by TLC. After completion of the reaction, water was added to quench the reaction at 0 °C. EA was added and extracted three times. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 9-3 (3.9 g, 15.71 mmol, 96.76% yield).

[0047] <Step 3: Synthesis of Compound 9-4> Substrate 9-3 (270 mg, 1.09 mmol) and THF (10 mL) were added to a dry one-neck flask and dissolved by stirring. Then, BMS (334.8 mg, 4.35 mmol) was added and the reaction was stirred at 70 °C for 24 hours, and monitored by LC-MS. After completion of the reaction, the reaction was quenched by adding saturated sodium sulfite solution, and extracted three times with EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 9-4 (200 mg, 907.99 μmol, 83.48% yield), LCMS (ESI) + ) m / z: 220 [M+H] + . <Step 4: Synthesis of Compound 9-5> Substrate 9-4 (200 mg, 907.99 μmol) and ethanol (10 mL) were added to a dry one-neck flask and dissolved by stirring. Pd / C (110.28 mg, 907.99 μmol) was then added and the reaction was stirred at room temperature for 4 hours under H2 with stirring. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to give crude product 9-5 (170 mg, crude). LCMS (ESI) + ) m / z: 191 [M+H] + . <Step 5: Synthesis of Compound 9> The same synthesis method as in Step 4 of Example 3 was used, except that 9-5 (8.66 mg, 45.51 μmol) was used instead of 1-8 in Step 4, to obtain the following: Compound 9 (1.7 mg, 2.98 μmol, 7.84% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),8.87(s,1H),7.88(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.54(s,1H),7.42(d,J= 8.4Hz,1H),7.29(d,J=8.4Hz,1H),5.75-5.65(m,1H),5.04(s,1H),5.04-5.00(m,1H),4.91-4.86 (m,1H),4.80-4.67(m,1H),4.61-4.56(m,1H),3.45-3.37(m,2H),2.91(s,2H),2.43-2.28(m,5H) ,1.26-1.20(m,9H),0.95-0.90(m,1H),0.72-0.67(m,1H),0.61-0.56(m,1H),,0.49-0.45(m,1H). LCMS(ESI + ) m / z: 538.3 [M+H] + ,HPLC Method B: R T =8.20min,purity:94.1%.

[0048] Example 10: Synthesis of Compound 10 TIFF2025525290000060.tif64170<Step 1: Synthesis of Compound 10> The same synthesis method as in Step 4 of Example 3 was used, except that 8-1 (9.34 mg, 45.51 μmol) was used instead of 1-8 in Step 4, to obtain compound 10 (7.6 mg, 13.11 μmol, 34.55% yield). 1H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),8.85(s,1H),7.89(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.66(s,1H),7.47-7.39(m,1H), 6.99(d,J=8.4Hz,1H),5.75-5.65(m,1H),5.03(s,1H),5.03-4.97(m,1H),4.90-4.86(m,1H),4.74(d,J=1 5.6Hz,1H),4.63-4.57(m,1H),2.89(d,J=2.4Hz,2H),2.83(t,J=4.8Hz,4H),2.58-2.51(m,4H),2.28(s,3 H),2.24(s,3H),1.22(s,3H),0.95-0.90(m,1H),0.71-0.66(m,1H),0.60-0.56(m,1H),0.48-0.45(m,1H). LCMS(ESI + ) m / z: 553.4 [M+H] + ,HPLC Method B: R T =7.62min,purity:95.3%.

[0049] Example 11: Synthesis of Compound 11 TIFF2025525290000061.tif58170<Step 1: Synthesis of Compound 11> The same synthesis method as in Step 4 of Example 3 was used, except that 11-1 (15.74 mg, 60.69 μmol) was used instead of 1-8 in Step 4, to obtain the following compound 11 (5.33 mg, 8.16 μmol, 16.14% yield). 1H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.82(s,1H),7.91(s,1H),7.69(d,J=8.4Hz,1H),7.58(s,2H),6.91(d,J=8.4Hz,2H ),5.72-5.66(m,1H),5.03-4.99(m,2H),4.87(d,J=17.4Hz,1H),4.76-4.73(m,1H),4.61-4.59(m 1H),3.09-3.07(m,4H),2.92-2.86(m,2H),2.43-2.39(m,4H),2.64(s,3H),1.55-1.49(m,8H ),1.22(s,3H),0.94-0.91(m,1H),0.70-0.67(m,1H),0.59-0.56(m,1H),0.48-0.46(m,1H). LCMS(ESI + )m / z: 607.3 [M+H] + ,HPLC Method B: R T =8.06min,purity: 93.4%. Compound 11をSFC splits the following two compounds: 11a R T =3.475min; 11b R T =5.377min TIFF2025525290000062.tif52170 Compound 11a (12.86 mg, 21.19 μmol); SFC retention time t = 3.475 min. 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.82(s,1H),7.91(d,J=7.2Hz,1H),7.70(d,J=8.0Hz,1H),7.56(s,2H),6.91(d,J=9. 2Hz,2H),5.74-5.64(m,1H),5.02-4.99(m,2H),4.88(dd,J=17.2,1.2Hz,1H),4.72-4.58(m,2H),3.0 8(t,J=5.6Hz,4H),2.94-2.85(m,2H),2.29(s,4H),2.16(s,3H),1.53(t,J=5.6Hz,4H),1.46(t,J=5 .6Hz,4H),1.22(s,3H),0.95-0.90(m,1H),0.71-0.66(m,1H),0.60-0.55(m,1H),0.48-0.43(m,1H). LCMS(ESI)m / z: 607.3 [M+H] + ,HPLC Method B: R T =8.35min,purity>94.6%. Compound 11b (12.1 mg, 19.94 μmol); SFC retention time t = 5.377 min. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.82(s,1H),7.91(d,J=7.2Hz,1H),7.69(d,J=8.0Hz,1H),7.56(s,2H),6.91(d,J=9. 2Hz,2H),5.74-5.64(m,1H),5.02-4.99(m,2H),4.88(dd,J=17.2,1.2Hz,1H),4.72-4.58(m,2H),3.0 8(t,J=5.6Hz,4H),2.94-2.85(m,2H),2.29(s,4H),2.16(s,3H),1.53(t,J=5.6Hz,4H),1.46(t,J=5 .6Hz,4H),1.22(s,3H),0.95-0.90(m,1H),0.71-0.66(m,1H),0.60-0.55(m,1H),0.48-0.43(m,1H). LCMS(ESI)m / z: 607.3 [M+H] + ,HPLC Method B: R T =7.89min,purity>97.2%.

[0050] Example 12: Synthesis of Compound 12 TIFF2025525290000063.tif58170<Step 1: Synthesis of Compound 12> According to the synthesis method of Step 4 in Example 3, except that 12-1 (16.64 mg, 75.86 μmol) was used instead of 1-8 in Step 4, the same synthesis method was used to obtain the following: Compound 12 (9.38 mg, 15.64 μmol, 30.93% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.82(s,1H),7.92-7.90(m,1H),7.69(d,J=7.8Hz,1H),7.58(s,2H),6.92(d,J=9.0Hz,2H ),5.72-5.66(m,1H),5.03-4.99(m,2H),4.87(d,J=17.4Hz,1H),4.73(s,1H),4.61-4.58(m,1H),3.68(d ,J=12.0Hz,2H),2.92-2.86(m,2H),2.63(t,J=12.0Hz,2H),2.38-2.32(m,7H),1.91-1.87(m,2H),1.55 -1.49(m,2H),1.22(s,3H),0.94-0.91(m,1H),0.70-0.67(m,1H),0.59-0.56(m,1H),0.48-0.46(m,1H). LCMS(ESI + ) m / z: 567.2 [M+H] + ,HPLC Method B: R T =7.29min,purity: 93.3%.

[0051] Example 13: Synthesis of Compound 13 TIFF2025525290000064.tif58170<Step 1: Synthesis of Compound 13> The same synthesis method as in Step 4 of Example 3 was used, except that 7-5 (19.76 mg, 97.21 μmol) was used instead of 1-8 in Step 4, to obtain the following compound 13 (14 mg, 22.88 μmol, 47.08% yield). 1H NMR(600MHz,Chloroform-d)δ 8.81(s,1H),7.69-7.67(m,2H),7.49(s,2H),6.72(d,J=9.0Hz,2H),5.74-5.68( m,1H),5.02(d,J=9.6Hz,1H),4.94(d,J=17.4Hz,1H),4.84-4.80(m,2H),4.03(s, 2H),3.64-3.58(m,4H),2.95(d,J=6.6Hz,2H),2.32(s,3H),1.77(s,2H),1.41(s, 3H),1.12-1.08(m,1H),0.91-0.87(m,1H),0.70-0.67(m,1H),0.60-0.56(m,1H). LCMS(ESI + ) m / z: 551.2 [M+H] + ,HPLC Method B: R T =7.16min,purity: 90.0%.

[0052] Example 14: Synthesis of Compound 14 TIFF2025525290000065.tif77170<Step 1: Synthesis of Compound 14-3> Substrate 14-1 (217.24 mg, 1 mmol) was added to a dry one-neck flask and dissolved in methanol (3 mL). 14-2 (200.32 mg, 2 mmol) and acetic acid (3.00 mg, 50.00 μmol) were added and the mixture was stirred at room temperature for 0.5 h. NaBHCN (94.26 mg, 1.50 mmol) was added, and the mixture was heated to 50 °C and reacted for 4 h. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was evaporated, and the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 14-3 (200 mg, 663.57 μmol, 66.36% yield). LCMS (ESI) + ) m / z: 302 [M+H] + . <Step 2: Synthesis of Compound 14-4> In a dry one-neck flask, substrate 14-3 (200 mg, 663.57 μmol) was dissolved in DCM (1 mL), and TFA (756.61 mg, 6.64 mmol) was added. The reaction was stirred at room temperature for 0.5 h and monitored by LC-MS. After completion of the reaction, the solvent was evaporated to give crude product 14-4 (100 mg, 496.81 μmol, 74.87% yield), LCMS (ESI+) m / z: 202 [M+H]+.

[0053] <Step 3: Synthesis of Compound 14-5> Substrate 14-4 (140 mg, 695.54 μmol) and DMSO (3 mL) were added to a dry one-neck flask and dissolved by stirring. Then, parafluoronitrobenzene (98.14 mg, 695.54 μmol) and potassium carbonate (288.38 mg, 2.09 mmol) were added and the reaction was stirred at 80 °C for 4 h. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 14-5 (95 mg, 294.69 μmol, 42.37% yield), LCMS (ESI) + ) m / z: 322 [M+H] + . <Step 4: Synthesis of Compound 14-6> Substrate 14-5 (95 mg, 294.69 μmol) and methanol (5 mL) were added to a dry one-neck flask and dissolved by stirring. Pd / C (10.74 mg, 88.41 μmol) was then added and the reaction was stirred at room temperature for 12 hours under H2 and monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to give crude product 14-6 (73 mg, crude). LCMS (ESI) + ) m / z: 293 [M+H] + . <Step 5: Synthesis of Compound 14> The same synthesis method as in Step 4 of Example 3 was used, except that 14-6 (15 mg, 51.30 μmol) was used instead of 1-8 in Step 4, to obtain the following compound 14 (4.1 mg, 5.72 μmol, 22.31% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),8.82(s,1H),7.91(s,1H),7.70(d,J=8.0Hz,1H),7.57(s,2H),6.92(d,J=8.8Hz,2H),5.75-7.64(m,1H) ),,5.13-4.97(m,3H),4.88(d,J=17.2Hz,1H),4.73(s,1H),4.60(d,J=15.2Hz,1H),3.88(t,J=12.4Hz,1H),3.75(d,J =12.4Hz,1H),2.90(d,J=2.4Hz,2H),2.78-2.69(m,1H),2.60(s,4H),2.42-2.22(m,6H),2.15(s,3H),1.94-1.81(m,6 H),1.75(d,J=12.4Hz,1H),1.22(s,3H),0.95-0.84(m,6H),0.73-0.66(m,6H),0.61-0.53(m,1H),0.48-0.43(m,1H). LCMS(ESI + ) m / z: 640.3 [M+H] + ,HPLC Method B: R T =6.63min,purity: 89.4%.

[0054] Example 15: Synthesis of Compound 15 TIFF2025525290000066.tif40170<Step 1: Synthesis of Compound 15-3> Substrate 15-1 (181.83 mg, 1.42 mmol) and DMF (10 mL) were added to a dry one-neck flask and dissolved by stirring. Then, 15-2 (200 mg, 1.29 mmol) and potassium carbonate (534.53 mg, 3.87 mmol) were added and the reaction was stirred at 90 °C for 3 h and monitored by LC-MS. After completion of the reaction, the mixture was extracted three times with water and EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, and evaporated to give crude product 15-3 (100 mg, crude). LCMS (ESI) + ) m / z: 263 [M+H] + . <Step 2: Synthesis of Compound 15-4> Substrate 15-3 (100 mg, 379.75 μmol) and methanol (5 mL) were added to a dry one-neck flask and dissolved by stirring. Pd / C (230.60 mg, 1.90 mmol) was then added and the reaction was stirred at room temperature for 0.5 h under H 2 . The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to give crude product 15-4 (109 mg, crude). LCMS (ESI) + ) m / z: 234 [M+H] + . <Step 3: Synthesis of Compound 15> The same synthesis method as in Step 4 of Example 3 was used, except that 15-4 (8.85 mg, 37.93 μmol) was used instead of 1-8 in Step 4, to obtain compound 15 (1.75 mg, 2.59 μmol, 10.23% yield). 1H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.85(s,1H),7.88(d,J=8.4Hz,1H),7.71(d,J=8.0Hz,1H),7.65(s,1H),7.43-7.40(m,1H),6.97(d ,J=8.8Hz,1H),5.74-5.66(m,1H),5.03(s,1H),5.03-5.00(m,1H),4.90-4.85(m,1H),4.77-4.71(m,1H),4.62-4. 57(m,1H),3.03(d,J=12.0Hz,2H),2.89-2.87(m,2H),2.59-2.53(m,2H),2.24-2.18(m,10H),1.83(d,J=11.6Hz, 2H),1.58-1.49(m,2H),1.22(s,3H),0.95-0.89(m,1H),0.71-0.66(m,1H),0.61-0.56(m,1H),0.48-0.44(m,1H). LCMS(ESI + ) m / z: 581.3 [M+H] + ,HPLC Method B: R T =8.41min,purity: 88.68%.

[0055] Example 16: Synthesis of Compound 16 TIFF2025525290000067.tif40170<Step 1: Synthesis of Compound 16-1> Substrate 2-5 (60 mg, 0.21 mmol) and THF (1 mL) were added to a dry one-neck flask and dissolved by stirring. Then, borane tetrahydrofuran complex (1 mL) was added and the reaction was stirred at room temperature for 5 hours. The reaction was monitored by LC-MS. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 16-1 (40 mg, 0.15 mmol, 70.18% yield). LCMS (ESI) + ) m / z: 267 [M+H] + . <Step 2: Synthesis of Compound 16-2> The same synthesis method as in step 5 of Example 2 was used, except that 16-1 (40 mg, 0.15 mmol) was used instead of 2-5 in step 5, to obtain the following compound 16-2 (30 mg, 73.43 μmol, 48.83% yield). + ) m / z: 409 [M+H] + .

[0056] <Step 3: Synthesis of Compound 16> The same synthesis method as in Step 4 of Example 3 was used, except that 16-2 (30 mg, 73.43 μmol) was used instead of 3-4 in Step 4, to obtain compound 16 (6.31 mg, 11.44 μmol, 15.58% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.78(s,1H),7.71(s,1H),7.70-7.52(m,2H),7.98-7.82 (m,3H),5.72-7.68(m,1H),5.05(d,J=10.2Hz,2H),4.93(d,J=16.8Hz,1 H),4.51(s,2H),3.62(s,2H),3.31(d,J=14.4Hz,1H),3.08(s,4H),2.46 (s,4H),2.45(s,2H),2.28(s,3H),2.20(t,J=14.4Hz,3H),2.03-1.99(m ,2H),1.09(t,J=7.2Hz,3H).LCMS(ESI + ) m / z: 552.4 [M+H] + ,HPLC Method B: R T =7.03min,purity: 95.7%.

[0057] Example 17: Synthesis of Compound 17 TIFF2025525290000068.tif95170<Step 1: Synthesis of Compound 17-1> Substrate 2-4 (200 mg, 829.6 μmol) and DMF (10 mL) were added to a dry one-neck flask and dissolved by stirring. NaH (119.5 mg, 4.98 mmol) was then added and the reaction was continued for 0.5 hours with stirring at 0 °C. 1,3-diiodopropane (736.4 mg, 2.48 mmol) was then added and the reaction was continued for 0.5 hours with stirring at room temperature. The reaction was monitored by LC-MS. Upon completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with EA. The organic phases were combined, treated with anhydrous sodium sulfate, filtered, evaporated, and purified by reverse-phase column chromatography to give product 17-1 (70 mg, 250 μmol, 29.87% yield). LCMS (ESI) + ) m / z: 281 [M+H] + . <Step 2: Synthesis of Compound 17-2> The same synthesis method as in Step 5 of Example 2 was used, except that 17-1 (70 mg, 250 μmol) was used instead of 2-5 in Step 5, to obtain the following compound 17-2 (25 mg, 59.17 μmol, 23.69% yield), LCMS (ESI + ) m / z: 423 [M+H] + .

[0058] <Step 3: Synthesis of Compound 17> The same synthesis method as in Step 4 of Example 3 was used, except that 17-2 (25 mg, 59.17 μmol) was used instead of 3-4 in Step 4, to obtain compound 17 (5 mg, 8.84 μmol, 14.94% yield). 1H NMR(600MHz,DMSO-d6)δ 10.25(s,1H),8.85(s,1H),8.22(s,1H),7.73(s,1H),7.62(s,2H),6.92(d,J=8.6Hz ,2H),5.75-5.65(m,1H),5.08-5.03(m,1H),4.95-4.89(m,1H),4.59(d,J=5.9Hz,2H) ,4.16(t,J=6.0Hz,2H),3.82(q,J=7.0Hz,2H),3.10(t,J=4.9Hz,4H),2.82(t,J=6.1H z,2H),2.46(t,J=4.9Hz,4H),2.22(s,3H),2.20-2.15(m,2H),1.15(t,J=7.1Hz,3H). LCMS(ESI + ) m / z: 598.2 [M+MeOH+H] + ,HPLC Method B: R T =7.23min,purity: 80.0%.

[0059] Example 18: Synthesis of Compound 18 TIFF2025525290000069.tif71170<Step 1: Synthesis of Compound 18-1> Substrate 3-2 (100 mg, 516.45 μmol) was added to a dry three-neck flask, dissolved in anhydrous tetrahydrofuran (2 mL), and cooled to 0 °C under nitrogen protection. A solution of ethylmagnesium bromide in tetrahydrofuran (2.07 mmol, 1.04 mL, 2 M) was then slowly added dropwise, and the reaction was continued for 1 hour while maintaining the temperature. The reaction mixture was monitored by LC-MS. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 18-1 (112.00 mg, 500.67 μmol). LCMS (ESI) m / z: 224.2 [M+H] + . <Step 2: Synthesis of Compound 18-2> Substrate 18-1 (112.00 mg, 500.67 μmol), substrate IM-1 (111.00 mg, 499.40 μmol), cuprous iodide (190.22 mg, 998.80 μmol), sodium iodide (149.71 mg, 998.80 μmol), potassium carbonate (172.29 mg, 1.25 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (284.48 mg, 2.00 mmol) were added to a dry microwave tube, followed by anisole (3 mL). The reaction was heated in a nitrogen atmosphere at 130 °C in a microwave oven for 3 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, washed twice with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 18-2 (90 mg, 220.31 μmol). LCMS (ESI) m / z: 410.2 [M+H] + .

[0060] <Step 3: Synthesis of Compound 18> Substrate 18-2 (16 mg, 39.07 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (12.14 mg, 70.33 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (50.40 mg, 390.72 μmol) and the substrate 4-(4-methylpiperidino)aniline (8.97 mg, 46.89 μmol) were then added to the reaction mixture and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 18 (5.41 mg, 9.79 μmol). 1H NMR(600MHz,DMSO-d6)δ 10.16(s,1H),8.83(s,1H),7.90(s,1H),7.72-7.70(d,J=8.4Hz,1H),7.60(s,2H),6.95-6.93( d,J=8.4Hz,2H),5.72-5.64(m,1H),5.02-5.01(m,1H),4.95(s,1H),4.89-4.86(m,1H),4.84-4. 71(m,1H),4.60-4.52(m,1H),3.26-3.05(m,4H),3.01(m,1H),2.74(m,1H),2.48-2.31(m,7H), 1.78-1.73(m,1H),1.60-1.54(m,1H),0.96-0.95(m,1H),0.71-0.69(m,5H),0.41-0.39(m,1H). LCMS(ESI)m / z: 553.3 [M+H] + ,HPLC Method B: R T =7.26min,purity: >97.4%.

[0061] Example 19: Synthesis of Compound 19 TIFF2025525290000070.tif47170<Step 1: Synthesis of Compound 19-2> Substrate 19-1 (142.09 mg, 570.04 μmol) was added to a dry one-neck flask, then methanol (2 mL) was added and dissolved, and the mixture was cooled to 0 °C. Sodium borohydride (86.26 mg, 2.28 mmol) was added, and the reaction was continued for 1 hour while maintaining the temperature constant. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 19-2 (130 mg, 517.35 μmol). LCMS (ESI) m / z: 252.3 [M+H] + . <Step 2: Synthesis of Compound 19-3> Substrate 19-2 (125.64 mg, 0.5 mmol) was added to a dry one-neck flask and dissolved in methanol (2 mL). Palladium on carbon (20 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 19-3 (100 mg, 451.88 μmol). LCMS (ESI) m / z: 222.3 [M+H] + . <Step 3: Synthesis of Compound 19> Substrate 3-4 (10 mg, 25.29 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (9.60 mg, 55.63 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (32.68 mg, 252.86 μmol) and substrate 19-3 (33.57 mg, 151.72 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 19 (4 mg, 6.57 μmol). 1 H NMR(600MHz,DMSO-d6)δ 10.20(s,1H),8.85(s,1H),8.01(s,1H),7.88(d,J=7.8Hz,1H),7.79(d,J=7.8Hz,1H),7.45-7.48(m,1H) ,7.03(d,J=8.4Hz,1H),5.74-5.67(m,1H),5.12(s,1H),5.02-4.99(m,2H),4.87(d,J=16.8Hz,1H),4.75( s,1H),4.63-4.60(m,1H),4.57(d,J=4.2Hz,2H),2.88(d,J=5.4Hz,2H),2.82(t,J=4.8Hz,4H),2.46(s,4H) ),2.23(s,3H),1.21(s,3H),0.93-0.90(m,1H),0.70-0.66(m,1H),0.60-0.57(m,1H),0.47-0.44(m,1H). LCMS(ESI)m / z: 569.3 [M+H] + ,HPLC Method B: RT =6.37min,purity: >93.4%.

[0062] Example 20: Synthesis of Compound 20 TIFF2025525290000071.tif89170<Step 1: Synthesis of Compound 20-2> Substrate 20-1 (100 mg, 683.97 μmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (2 mL). Then, parafluoronitrobenzene (96.51 mg, 683.97 μmol) and potassium carbonate (94.53 mg, 683.97 μmol) were added and the mixture was reacted at 80 °C for 4 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 20-2 (120 mg, 448.94 μmol). LCMS (ESI) m / z: 267.1 [M+H] + . <Step 2: Synthesis of Compound 20-3> Substrate 20-2 (110 mg, 411.52 μmol) was added to a dry one-neck flask and dissolved in methanol (2 mL). Palladium / carbon (15 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 20-3 (90 mg, 379.24 μmol). LCMS (ESI) m / z: 238.2 [M+H] + . <Step 3: Synthesis of Compounds 20a & 20b> Substrate 3-4 (10 mg, 25.29 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (0.5 mL). Metachloroperbenzoic acid (6.55 mg, 37.93 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (32.68 mg, 252.86 μmol) and substrate 20-3 (12.00 mg, 50.57 μmol) were then added to the reaction mixture and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 20a (1.0 mg, 1.47 μmol). (20a and 20b are diastereomers, and the products were obtained by direct separation. The structures are depicted arbitrarily and the absolute configurations are not identified; the same applies hereinafter.) 1 H NMR(600MHz,DMSO-d6)δ 10.13(s,1H),8.82(s,1H),7.92(s,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.92(d,J=8.4Hz,2H),5.73-5.66(m,1H), 5.09-4.96(m,3H),4.88(d,J=17.4Hz,1H),4.74(d,J=12.6Hz,1H),4.60(s,1H),3.88(t,J=12.6Hz,1H),3.74(d,J=12. 0Hz,1H),2.95-2.86(m,2H),2.85-2.76(m,1H),2.68(t,J=11.4Hz,1H),2.40-2.31(m,1H),2.28(s,6H),1.90-1.83(m, 1H),1.76(d,J=12.6Hz,1H),1.22(s,3H),0.94-0.90(m,1H),0.70-0.64(m,1H),0.60-0.55(m,1H),0.49-0.42(m,1H). LCMS(ESI)m / z: 567.2 [M+H] + ,HPLC Method B: R T =8.69min,purity>88.7%. Compound 20b (1.0 mg, 1.50 μmol). 1H NMR(600MHz,DMSO-d6)δ 10.15(s,1H),8.83(s,1H),7.93(s,1H),7.69(d,J=8.4Hz,1H),7.60(s,2H),6.96(d,J=8.4Hz,2H),5.72 -5.66(m,1H),5.04-4.85(m,3H),4.80-4.74(m,1H),4.73-4.64(m,1H),4.60(s,1H),3.87(s,1H),3.57(d ,J=12.0Hz,1H),2.90(d,J=5.4Hz,2H),2.71-2.59(m,3H),2.30(s,6H),1.82(s,1H),1.60-1.54(m,1H), 1.22(s,3H),0.94-0.90(m,1H),0.70-0.67(m,1H),0.62-0.55(m,1H),0.48-0.45(m,1H).LCMS(ESI)m / z: 567.2 [M+H] + ,HPLC Method B: R T =8.70min,purity>90.2%.

[0063] Example 21: Synthesis of Compound 21 TIFF2025525290000072.tif83170<Step 1: Synthesis of Compound 21-2> Substrate 21-1 (80 mg, 385.25 μmol) was added to a dry three-neck flask, dissolved in anhydrous tetrahydrofuran (4.5 mL), and cooled to 0 °C under nitrogen protection. A solution of ethylmagnesium bromide in tetrahydrofuran (1.54 mmol, 0.77 mL, 2 M) was then slowly added dropwise, and the reaction was continued for 2 hours while maintaining the temperature. The reaction mixture was monitored by LC-MS. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 21-2 (68 mg, 286.05 μmol). LCMS (ESI) m / z: 238.1 [M+H] + . <Step 2: Synthesis of Compound 21-3> Substrate 21-2 (68 mg, 286.05 μmol), substrate IM-1 (73.86 mg, 332.29 μmol), cuprous iodide (108.95 mg, 572.09 μmol), sodium iodide (85.75 mg, 572.09 μmol), potassium carbonate (98.83 mg, 715.11 μmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (162.75 mg, 1.14 mmol) were added to a dry microwave tube, followed by anisole (3 mL). The reaction was heated in a nitrogen atmosphere at 130 °C in a microwave oven for 4 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, washed twice with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 21-3 (57 mg, 134.58 μmol). LCMS (ESI) m / z: 424.2 [M+H] + . <Step 3: Synthesis of Compound 21> Substrate 21-3 (20 mg, 47.44 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (16.37 mg, 94.89 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (61.75 mg, 477.78 μmol) and the substrate 4-(4-methylpiperidino)aniline (40 mg, 209.13 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 21 (12 mg, 20.54 μmol). 1H NMR(400MHz,Chloroform-d)δ 8.81(s,1H),7.64-7.58(m,2H),7.47(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),5.76-5.66(m,1H),5.08 -5.05(m,1H),5.00-4.94(m,1H),4.75-4.61(m,2H),3.56(s,1H),3.28(t,J=4.8Hz,4H),3.04-2.95(m ,1H),2.91-2.85(m,1H),2.73(t,J=4.8Hz,4H),2.50-2.43(m,4H),2.02-1.93(m,1H),1.80-1.71(m,1 H),1.19-1.14(m,1H),1.02(t,J=7.6Hz,3H),0.75-0.71(m,1H),0.49-0.44(m,1H),0.07-0.01(m,1H). LCMS(ESI)m / z: 567.3 [M+H] + ,HPLC Method B: R T =8.54min,purity>97.0%.

[0064] Example 22: Synthesis of Compound 22 TIFF2025525290000073.tif113170<Step 1: Synthesis of Compound 22-2> Substrate 22-1 (90 mg, 410.51 μmol) was added to a dry one-neck flask and dissolved in 1,2-dichloroethane (5 mL). Acetic acid (49.30 mg, 821.02 μmol) and cyclobutanone (143.86 mg, 2.05 mmol) were added and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (435.02 mg, 2.05 mmol) was then added and the mixture was heated at 50 °C for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The aqueous phase was then extracted four times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 22-2 (93 mg, 340.25 μmol). LCMS (ESI) m / z: 274.1 [M+H] + . <Step 2: Synthesis of Compound 22-3> Substrate 22-2 (93 mg, 340.25 μmol) was added to a dry one-neck flask and dissolved in methanol (3 mL). Palladium / carbon (10 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 22-3 (80 mg, 328.74 μmol). LCMS (ESI) m / z: 244.2 [M+H] + . <Step 3: Synthesis of Compounds 22a & 22b> Substrate 22-3 (18 mg, 43.96 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (15.17 mg, 87.91 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (28.40 mg, 219.78 μmol) and substrate 21-3 (16.04 mg, 65.93 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 22a (2.40 mg, 3.62 μmol). 11H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.80 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.64 - 7.55 (m, 2H), 6.79 - 6.68 (m, 1H), 5.74 - 5.64 (m, 1H), 5.03 - 5.01 (m, 1H), 4.95 (s, 1H), 4.88 (d, J = 17.2 Hz, 1H), 4.81 - 4.71 (m, 1H), 4.59 - 4.53 (m, 1H), 3.89 - 3.76 (m, 2H), 3.48 - 3.42 (m, 4H), 3.03 - 2.99 (m, 1H), 2.75 - 2.71 (m, 1H), 2.48 (s, 1H), 2.19 - 2.12 (m, 2H), 1.79 - 1.73 (m, 1H), 1.61 - 1.52 (m, 2H), 0.99 - 0.94 (m, 1H), 0.85 - 0.79 (m, 1H), 0.73 - 0.68 (m, 5H), 0.41 - 0.35 (m, 3H), 0.08 - 0.05 (m, 2H). LCMS (ESI) m / z: 605.3 [M + H] + , HPLC method B: R T = 8.26 min, purity > 91.2%. Compound 22b (6.40 mg, 10.03 μmol). 1 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.80 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.60 (s, 2H), 6.69 (d, J = 7.2 Hz, 1H), 5.74 - 5.64 (m, 1H), 5.03 - 5.01 (m, 1H), 4.95 (s, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.70 - 4.77 (m, 1H), 4.59 - 4.53 (m, 1H), 3.81 - 3.71 (m, 2H), 3.19 - 3.08 (m, 4H), 3.01 (d, J = 16.4 Hz, 2H), 2.73 (d, J = 16.4 Hz, 1H), 2.42 - 2.37 (m, 1H), 2.03 - 1.91 (m, 2H), 1.79 - 1.73 (m, 5H), 1.61 - 1.52 (m, 2H), 0.99 - 0.94 (m, 1H), 0.72 - 0.68 (m, 5H), 0.39 - 0.35 (m, 2H). LCMS (ESI) m / z: 605.3 [M + H] + , HPLC method B: RT =8.37min,purity>94.8%.

[0065] Example 23: Synthesis of Compound 23 TIFF2025525290000074.tif58170<Step 1: Synthesis of Compounds 23a & 23b> Substrate 6-4 (30 mg, 73.26 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (22.76 mg, 131.87 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (94.68 mg, 732.59 μmol) and substrate 23-1 (30.08 mg, 146.52 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 23a (12.00 mg, 18.78 μmol); SFC retention time t = 2.302 min. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.83(s,1H),7.79-7.57(m,3H),7.41-7.38(m,1H),6.98(d,J=8.8Hz,1H ),5.72-5.60(m,1H),5.01-4.96(m,1H),4.88-4.77(m,2H),4.69(s,1H),4.67-4.58(m ,1H),2.92-2.74(m,6H),2.47(s,4H),2.24(s,3H),2.23(s,3H),2.03-1.92(m,1H),1. 39(s,4H),0.86-0.82(m,1H),0.64-0.62(m,1H),0.30-0.29(m,1H),0.22-0.20(m,1H). LCMS(ESI)m / z: 567.2 [M+H] + ,HPLC Method B: R T =8.69min,purity>86.0%. Compound 23b (11.00mg, 17.51μmol); SFC retention time t=3.705min. 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.83(s,1H),7.79-7.57(m,3H),7.41-7.38(m,1H),6.98(d,J=8.8Hz ,1H),5.72-5.60(m,1H),5.01-4.86(m,1H),4.89-4.74(m,2H),4.72-4.57(m,2H),2 .94-2.77(m,6H),2.46(s,4H),2.24(s,3H),2.22(s,3H),2.03-1.92(m,1H),1.39( s,4H),0.86-0.82(m,1H),0.64-0.62(m,1H),0.31-0.29(m,1H),0.22-0.20(m,1H). LCMS(ESI)m / z: 567.4 [M+H] + ,HPLC Method B: R T =8.70min,purity >87.8%.

[0066] Example 24: Synthesis of Compound 24 Substrate 18-2 (10 mg, 24.42 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (8.43 mg, 48.84 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (31.56 mg, 244.20 μmol) and substrate 24-1 (21.76 mg, 122.10 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 24 (4 mg, 6.92 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.15(s,1H),8.83(s,1H),7.91(d,J=12.4Hz,1H),7.71(d,J=12.4Hz,1H),7.61(s,2H),6.93(d,J= 13.2Hz,2H),5.74-5.64(m,1H),5.04-5.00(m,1H),4.95(s,1H),4.90-4.85(m,1H),4.77(s,1H),4. 59-4.53(m,1H),3.76-3.73(m,4H),3.08-3.06(m,4H),3.01(d,J=25.2Hz,1H),2.74(d,J=24.4Hz,1 H),1.81-1.72(m,1H),1.61-1.52(m,1H),0.99-0.94(m,1H),0.73-0.68(m,5H),0.40-0.35(m,1H). LCMS(ESI)m / z: 540.2 [M+H] + ,HPLC Method B: R T =7.49min,purity>93.2%.

[0067] Example 25: Synthesis of Compound 25 TIFF2025525290000076.tif113170<Step 1: Synthesis of Compound 25-2> Substrate 25-1 (332 mg, 1.56 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (5 mL). Then, parafluoronitrobenzene (242.73 mg, 1.72 mmol) and potassium carbonate (648.42 mg, 4.69 mmol) were added, and the reaction was carried out at 80 °C for 12 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 25-2 (512 mg, 1.54 mmol). LCMS (ESI) m / z: 278.1 [M+H] + . <Step 2: Synthesis of Compound 25-3> Substrate 25-2 (640 mg, 1.92 mmol) was added to a dry one-neck flask and dissolved in methanol (10 mL). Palladium / carbon (60 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 12 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 25-3 (570 mg, 1.88 mmol). LCMS (ESI) m / z: 248.2 [M+H] + .

[0068] <Step 3: Synthesis of Compound 25-4> Substrate 25-3 (200 mg, 659.20 μmol) was added to a dry three-neck flask, dissolved in anhydrous tetrahydrofuran (5 mL), and cooled to 0 °C under nitrogen protection. Lithium aluminum hydride in tetrahydrofuran (3.3 mL, 3.30 mmol, 1 M) was then slowly added dropwise, and the reaction was heated to reflux at 65 °C for 4 hours. LC-MS monitoring was performed. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was stirred for half an hour. The mixture was then dried over anhydrous sodium sulfate, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 25-4 (89 mg, 409.55 μmol). LCMS (ESI) m / z: 218.2 [M+H] + . <Step 4: Synthesis of Compound 25> Substrate 18-2 (10 mg, 24.42 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (7.59 mg, 43.96 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (31.56 mg, 244.20 μmol) and substrate 25-4 (10.60 mg, 48.78 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 25 (2 mg, 2.98 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.09(s,1H),8.81(s,1H),7.90(d,J=7.6Hz,1H),7.71(d,J=8.0Hz,1H),7.55(s,2H),6.78(d,J=8.8Hz,2H ),5.73-5.62(m,1H),5.02(dd,J=10.0,1.6Hz,1H),4.95(s,1H),4.87(d,J=17.2Hz,1H),4.77(s,1H),4.61 -4.49(m,1H),3.20(s,2H),3.01(d,J=16.4Hz,1H),2.76(dd,J=18.0,13.6Hz,3H),2.22(s,3H),1.98-1.90 (m,2H),1.80-1.72(m,1H),1.66-1.53(m,3H),0.99-0.93(m,1H),0.70(t,J=7.2Hz,5H),0.42-0.33(m,1H). LCMS(ESI)m / z: 579.4 [M+H] + ,HPLC Method B: R T =7.93min,purity>86.1%.

[0069] Example 26: Synthesis of Compound 26 TIFF2025525290000077.tif70170<Step 1: Synthesis of Compound 26-2> Substrate 26-1 (200 mg, 857.39 μmol) was added to a dry one-neck flask and dissolved in methanol (5 mL). Palladium / carbon (20 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 12 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 26-2 (170 mg, 836.28 μmol). LCMS (ESI) m / z: 204.1 [M+H] + . <Step 2: Synthesis of Compound 26> Substrate 18-2 (10 mg, 24.42 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (9.27 mg, 53.72 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (15.78 mg, 122.10 μmol) and substrate 26-2 (10.92 mg, 53.72 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 26 (2.03 mg, 3.59 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),8.79(s,1H),7.88(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.51-7.48(m,2H),6.55(d,J =8.8Hz,2H),5.73-5.64(m,1H),5.03-5.00(m,1H),4.95(s,1H),4.88(d,J=17.2Hz,1H),4.80-4.77(m 1H),4.58-4.52(m,1H),4.26(s,1H),3.41(s,1H),3.33-3.30(m,1H),3.12(d,J=9.2Hz,1H),3.01(d,J=16.4Hz,1H),2.78-2.72(m,2H) ,2.47-2.44(m,1H),2.23(s,3H),1.84(d,J=9.2Hz,1H),1.79-1.74(m,1H),1.61-1.52(m,1H),0.98-0.93(m,1H),0.72-0.68(m,5H),0. 39-0.34(m,1H).LCMS(ESI)m / z: 565.3 [M+H] + ,HPLC Method B: R T =7.65min,purity>95.9%.

[0070] Example 27: Synthesis of Compound 27 Substrate 18-2 (30 mg, 73.26 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (25.28 mg, 146.52 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (94.68 mg, 732.59 μmol) and substrate 11-1 (38.01 mg, 146.52 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 27 (15.00 mg, 22.64 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.82(s,1H),7.91(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.57(s,2H),6.91(d,J=9.2Hz,2H),5.74-5 .63(m,1H),5.03-5.00(m,1H),4.95(s,1H),4.87(dd,J=17.3,1.7Hz,1H),4.77(s,1H),4.55(dd,J=16.0,6.7Hz,1H) ,3.08(t,J=5.7Hz,4H),3.01(d,J=16.6Hz,1H),2.74(d,J=16.6Hz,1H),2.28(t,J=5.4Hz,4H),2.15(s,3H),1.79-1. 74(m,7.3Hz,1H),1.62-1.50(m,5H),1.46(t,J=5.6Hz,4H),0.97-0.93(m,1H),0.73-0.68(m,5H),0.40-0.36(m,1H). LCMS(ESI)m / z: 621.2 [M+H] + ,HPLC Method B: R T =8.72min,purity>93.7%.

[0071] Example 28: Synthesis of Compound 28 TIFF2025525290000079.tif113170<Step 1: Synthesis of Compound 28-2> Substrate 28-1 (500 mg, 2.36 mmol) was added to a dry one-neck flask and dissolved in N,N-dimethylformamide (7 mL). Then, parafluoronitrobenzene (302.12 mg, 2.14 mmol) and potassium carbonate (887.73 mg, 6.42 mmol) were added, and the mixture was reacted at 90 °C for 12 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 28-2 (670 mg, 2.01 mmol). LCMS (ESI) m / z: 278.1 [M+H-56]. + . <Step 2: Synthesis of Compound 28-3> Substrate 28-2 (670 mg, 2.01 mmol) was added to a dry one-neck flask, dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure to give crude compound 28-3 (670 mg, 2.87 mmol). LCMS (ESI) m / z: 234.2 [M+H] + .

[0072] <Step 3: Synthesis of Compound 28-4> Substrate 28-3 (670 mg, 2.87 mmol) was dissolved in methanol (8 mL) in a dry one-neck flask. Acetic acid (344.96 mg, 5.74 mmol) and aqueous formaldehyde (862.42 mg, 28.72 mmol, 37%) were added and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (360.99 mg, 5.74 mmol) was then added and the mixture was reacted at 50 °C for 3 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The aqueous phase was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 28-4 (520 mg, 2.10 mmol). LCMS (ESI) m / z: 248.2 [M+H] + . <Step 4: Synthesis of Compound 28-5> Substrate 28-4 (520 mg, 2.10 mmol) was added to a dry one-neck flask and dissolved in methanol (7 mL). Palladium / carbon (50 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 3 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 28-5 (400 mg, 1.84 mmol). LCMS (ESI) m / z: 218.1 [M+H] + . <Step 5: Synthesis of Compound 28> Substrate 18-2 (15 mg, 36.63 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (13.91 mg, 80.59 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (47.34 mg, 366.30 μmol) and substrate 28-5 (17.51 mg, 80.59 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 28 (8.09 mg, 11.21 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),8.80(s,1H),7.88(d,J=7.6Hz,1H),7.71(d,J=8.4Hz,1H),7.54(s,2H),6.63(d,J=8.8 Hz,2H),5.74-5.64(m,1H),5.03-5.00(m,1H),4.95(s,1H),4.89-4.85(m,1H),4.80-4.77(m,1H),4.5 8-4.53(m,1H),3.31(s,2H),3.06-2.99(m,3H),2.89-2.84(m,2H),2.74(d,J=17.2Hz,1H),2.58-2.5 5(m,2H),2.40-2.37(m,2H),2.22(s,3H),1.79-1.74(m,1H),1.59-1.54(m,1H),0.98-0.94(m,1H),0. 72-0.68(m,5H),0. 39-0.31(m,1H). LCMS(ESI)m / z: 579.4 [M+H] + ,HPLC Method B: R T =8.17,purity>80.2%.

[0073] Example 29: Synthesis of Compound 29 TIFF2025525290000080.tif83170<Step 1: Synthesis of Compound 29-2> Sodium hydride (696.50 mg, 17.41 mmol, 60%) was added to a dry three-neck flask, and N,N-dimethylformamide (50 mL) was added and dissolved. The mixture was cooled to 0 °C under nitrogen protection. Then, a solution of substrate 29-1 (1.05 g, 4.98 mmol) and 1,2-dibromoethane (3.27 g, 17.41 mmol) in N,N-dimethylformamide (20 mL) was slowly added dropwise. The reaction was allowed to proceed for 2 h while maintaining the temperature. The reaction mixture was monitored by LC-MS. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted four times with dichloromethane. The organic phase was washed three times with water and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 29-2 (820 mg, 3.46 mol). LCMS(ESI)m / z: 238.2 [M+H] + . <Step 2: Synthesis of Compound 29-3> Substrate 29-2 (800 mg, 3.46 mol) was added to a dry three-neck flask, and tetrahydrofuran (10 mL) was added to dissolve the substrate. The mixture was cooled to 0 °C under nitrogen protection. Then, a solution of ethylmagnesium bromide in tetrahydrofuran (2 M, 6.92 mL) was slowly added dropwise, and the reaction was continued for 1 hour while maintaining the temperature. LC-MS monitoring was performed. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 29-3 (665 mg, 2.49 mmol). LCMS (ESI) m / z: 268.1 [M+H] + .

[0074] <Step 3: Synthesis of Compound 29-4> Substrate 29-3 (30 mg, 112.29 μmol), substrate IM-1 (26.21 mg, 117.91 μmol), cuprous iodide (42.77 mg, 224.58 μmol), sodium iodide (33.66 mg, 224.58 μmol), potassium carbonate (38.80 mg, 280.73 μmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (63.89 mg, 449.17 μmol) were added to a dry microwave tube, followed by anisole (1 mL). The reaction was heated in a microwave oven at 130 °C under a nitrogen atmosphere for 3.5 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 29-4 (8 mg, 19.58 μmol). LCMS (ESI) m / z: 409.1 [M+H] + . <Step 4: Synthesis of Compound 29> Substrate 29-4 (8 mg, 19.58 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (6.08 mg, 35.25 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (25.31 mg, 195.83 μmol) and the substrate 4-(4-methylpiperidino)aniline (7.49 mg, 39.17 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 29 (2.9 mg, 4.38 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.80(s,1H),7.55(s,2H),7.41-7.29(m,2H),7.24(s,1H),6.85(d,J=9.2Hz,2H),5.74- 5.63(m,1H),5.13-5.07(m,1H),4.94(d,J=17.2Hz,1H),4.86(s,1H),4.23(d,J=12.0Hz,1H),3.05(t, J=5.2Hz,4H),2.45(d,J=4.8Hz,4H),2.22(s,3H),1.67(dd,J=13.9,7.2Hz,1H),1.59-1.54(m,1H),1. 23(s,3H),0.93(d,J=6.4Hz,1H),0.72(t,J=7.2Hz,3H),0.67(d,J=7.2Hz,2H),0.33(t,J=5.2Hz,1H). LCMS(ESI)m / z: 552.3 [M+H] + ,HPLC Method B: R T =7.57,purity>83.3%.

[0075] Example 30: Synthesis of Compound 30 TIFF2025525290000081.tif58170<Step 1: Synthesis of Compound 30-2> Substrate 30-1 (230 mg, 2.01 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (5 mL). Then, parafluoronitrobenzene (298.42 mg, 2.11 mmol) and potassium carbonate (1.39 g, 10.07 mmol) were added, and the reaction was carried out at 100 °C for 4 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 30-2 (450 mg, 1.91 mmol). LCMS (ESI) m / z: 236.2 [M+H] + . <Step 2: Synthesis of Compound 30-3> Substrate 30-2 (450 mg, 1.91 mmol) was added to a dry one-neck flask and dissolved in methanol (3 mL). Palladium / carbon (40 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 30-3 (380 mg, 1.85 mmol). LCMS (ESI) m / z: 206.1 [M+H] + . <Step 3: Synthesis of Compound 30> Substrate 18-2 (20 mg, 48.84 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (15.17 mg, 87.91 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (63.12 mg, 488.40 μmol) and substrate 30-3 (20.05 mg, 97.68 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 30 (4.9 mg, 8.32 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),8.83(s,1H),7.92(s,1H),7.71(d,J=8.0Hz,1H),7.58(s,2H),6.92(d,J=8.8Hz,2H),5.73-5.63(m, 1H),5.02(dd,J=10.2,1.5Hz,1H),4.97(s,1H),4.87(d,J=17.2Hz,1H),4.78(s,1H),4.56(d,J=15.6Hz,1H),3.48 (s,2H),3.02(d,J=16.4Hz,1H),2.84-2.69(m,4H),2.37-2.30(m,2H),2.21(s,3H),1.77(dd,J=13.6,7.2Hz,1H), 1.56(dd,J=13.6,7.2Hz,1H),1.05(d,J=6.0Hz,3H),0.98-0.91(m,1H),0.70(t,J=7.2Hz,5H),0.42-0.31(m,1H). LCMS(ESI)m / z: 567.3 [M+H] + ,HPLC Method B: R T =7.57,purity>96.1%.

[0076] Example 31: Synthesis of Compound 31 TIFF2025525290000082.tif71170<Step 1: Synthesis of Compounds 31a & 31b> Substrate 18-2 (20 mg, 48.84 μmol) was dissolved in tetrahydrofuran (2 mL) in a dry one-neck flask. Metachloroperbenzoic acid (15.18 mg, 87.91 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (63.00 mg, 488.40 μmol) and substrate 31-1 (12.09 mg, 58.61 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 31a (5.1 mg, 8.92 μmol); SFC retention time t = 2.264 min. 1H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.83(s,1H),7.91(s,1H),7.72-7.70(m,1H),7.60(s,2H),6.94-6.92(d,J=8.8Hz,2H),5.74-5.64(m,1H),5.0 3-5.00(m,1H),4.97(s,1H),4.89-4.85(m,1H),4.82-4.72(m,1H),4.58-4.53(m,1H),3.74-3.66(m,2H),3.55-3.50(m,2H), 3.05-2.98(m,1H),2.76-2.72(m, 1H),2.24-2.18(m,2H),1.79-1.74(m,1H),1.59-1.53(m,1H),1.19-1.26(m,6H),0.98-0.93(m,1H),0.72-0.68(m,5H),0.41-0.32(m,1H). LCMS(ESI)m / z: 568.4 [M+H] + ,HPLC Method B: R T =8.29min,purity>99.3%. Compound 31b (5.1 mg, 17.60 μmol); SFC retention time t = 3.730 min. 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.83(s,1H),8.00-7.88(m,1H),7.72-7.70(m,1H),7.66-7.55(m,2H),6.94-6.91(d,J=8.8Hz,2H),5.74-5.64(m,1H ),5.03-5.00(m,1H),4.97(s,1H),4.89-4.85(m,1H),4.85-4.72(m,1H),4.63-4.50(m,1H),3.74-3.66(m,2H),3.55-3.50(m,2H), 3.06-2.98(m,1H),2.79-2.71(m,1H),2.26-2.17(m,2H),1.82-1.72(m,1H),1.61-1.5 1(m,1H),1.19-1.12(m,6H),0.98-0.92(m,1H),0.74-0.66(m,5H),0.43-0.32(m,1H). LCMS(ESI)m / z: 568.3 [M+H] + ,HPLC Method B: R T=8.30min,purity>95.7%.

[0077] Example 32: Synthesis of Compound 32 TIFF2025525290000083.tif83170<Step 1: Synthesis of Compound 32> Substrate 3-2 (200 mg, 1.03 mol) was placed in a dry three-neck flask, and tetrahydrofuran (5 mL) was added to dissolve the mixture. The mixture was cooled to 0°C under nitrogen protection, and then (trifluoromethyl)trimethylsilane (732.28 mg, 5.15 mol) and tetrabutylammonium fluoride (1.03 mL, 1M) were slowly added dropwise. The reaction was continued for 1 hour while maintaining the temperature. The reaction mixture was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 32-1 (220 mg, 834.47 μmol). LCMS (ESI) m / z: 264.1 [M+H] + . <Step 2: Synthesis of Compound 32-2> Substrate 32-1 (220 mg, 834.47 μmol), substrate IM-1 (194.75 mg, 876.19 μmol), cuprous iodide (318.05 mg, 1.67 mmol), sodium iodide (250.32 mg, 1.67 mmol), potassium carbonate (288.86 mg, 2.09 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (475.08 mg, 3.34 mmol) were added to a dry microwave tube, followed by anisole (4 mL). The reaction was heated in a nitrogen atmosphere at 130 °C in a microwave oven for 3.5 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 32-2 (150 mg, 333.74 μmol). LCMS (ESI) m / z: 450.2 [M+H] + . <Step 3: Synthesis of Compound 32> Substrate 32-2 (20 mg, 44.50 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (13.82 mg, 80.10 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (57.40 mg, 444.99 μmol) and substrate 4-(4-methylpiperidino)aniline (1-8, 10.21 mg, 53.40 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 32 (6.2 mg, 9.65 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),8.84(s,1H),8.14-8.00(m,1H),7.94-7.87(m,1H),7.67-7.50 (m,2H),6.96-6.90(m,2H),6.80-6.60(m,1H), 5.74-5.60(m,1H),5.03-4.94 (m,1H),4.90-4.72(m,2H),4.63-4.50(m,1H),3.14-3.04(m,4H),2.78-2.69(m,1H),2.48-2.41(m,4H),2.22(s,3H), 1.94-1.76(m,1H),1.09-0.99(m,2H),0.94-0.86(m,1H),0.52-0.44(m,1H).LCMS(ESI)m / z: 593.3 [M+H] + ,HPLC Method B: R T =7.79min,purity>92.3%.

[0078] Example 33: Synthesis of Compound 33 TIFF2025525290000084.tif71170<Step 1: Synthesis of Compound 33-2> Substrate 33-1 (160 mg, 668.77 μmol) was added to a dry one-neck flask and dissolved in methanol (5 mL). Palladium / carbon (20 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 33-2 (68 mg, 324.95 μmol). LCMS (ESI) m / z: 210.2 [M+H] + . <Step 2: Synthesis of Compound 33> Substrate 18-2 (20 mg, 36.63 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (16.55 mg, 65.93 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (45.56 mg, 352.52 μmol) and substrate 33-2 (30 mg, 143.36 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 33 (6.37 mg, 11.16 μmol). 1 H NMR (400 MHz, Chloroform-d) δ 8.78(s,1H),7.81-7.70(m,3H),6.99-6.85(m,2H),5.75-5.65(m,1H),5.0 3(d,J=10.4Hz,1H),4.95-4.85(m,2H),4.70-4.64(m,1H),3.18-3.10(m,5H ),2.80-2.76(m,5H),2.47(s,3H),1.99-1.90(m,1H),1.79-1.70(m,1H),1 .19-1.14(m,1H),0.94-0.89(m,1H),0.85-0.79(m,4H),0.51-0.46(m,1H). LCMS(ESI)m / z: 571.3 [M+H] + ,HPLC Method B: R T =7.71min,purity>87.6%.

[0079] Example 34: Synthesis of Compound 34 TIFF2025525290000085.tif150170<Step 1: Synthesis of Compound 34-2> Substrate 34-1 (100.00 g, 904.08 mmol) was added to a dry one-neck flask, followed by iodomethane (256.65 g, 1.81 mol) and the mixture was allowed to react at room temperature for 48 hours to produce a yellow solid. Methyl tert-butyl ether was added to the reaction mixture, which was then slurried, filtered, and dried under vacuum to give compound 34-2 (189.00 g, 748.40 mmol). <Step 2: Synthesis of Compound 4-2> Substrate 4-1 (30.00 g, 203.84 mmol) was added to a dry three-neck flask, followed by dissolution in tetrahydrofuran (750 mL) and t-butanol (1500 mL). The mixture was cooled to -40 °C under nitrogen protection. A solution of potassium t-butanol (73.19 g, 652.29 mmol) in tetrahydrofuran (650 mL) was added dropwise to the reaction mixture, and the reaction was continued for 40 minutes while maintaining the temperature constant. Triethylbenzylammonium chloride (4.64 g, 20.38 mmol) and substrate 34-2 (77.22 g, 305.72 mmol) were then added, and the reaction was continued at room temperature for 18 hours. The reaction was monitored by TLC until completion. Saturated ammonium chloride solution was slowly added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove the organic phase. The aqueous phase was extracted four times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1 elution) to obtain the following: Compound 4-2 (11.00 g, 63.51 mmol). LCMS (ESI + ) m / z: 174.1 [M+H] + . Compounds 4-3 to 4-8 were synthesized according to the synthesis method in Example 4.

[0080] <Step 3: Synthesis of Compound 34-3> Substrate 4-8 (27.50 g, 131.12 mmol) was dissolved in dichloromethane (300 mL) in a dry one-neck flask. Dess-Martin oxidant (83.42 g, 196.68 mmol) was added under ice bath cooling. The reaction was allowed to proceed at room temperature for 2 hours and monitored by TLC until completion. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 34-3 (18.55 g, 89.33 mmol). LCMS (ESI) + ) m / z: 208.1 [M+H] + . <Step 4: Synthesis of Compound 34-4> Substrate 34-3 (18.55 g, 89.33 mmol) was added to a dry one-neck flask, then methanol (270 mL) was added and dissolved. The mixture was cooled to 0 °C, and sodium borodeuteride (4.48 g, 107.20 mmol) was slowly added. The reaction was continued for 1 hour while maintaining the temperature constant, and the reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in water and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 34-4 (18.00 g, 85.44 mmol). LCMS (ESI) + ) m / z: 211.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.63(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),5.35(s,1H),2.86-2.67(m,2H),2.22-2. 15(m,1H), 1.12-1.06(m,1H), 0.73-0.62(m,1H), 0.44-0.40(m,1H), 0.38-0.30(m,2H). <Step 5: Synthesis of Compound 34-5> Substrate 34-4 (5 g, 23.73 mmol), substrate IM-1 (5.55 g, 24.92 mmol), cuprous iodide (4.5 g, 23.73 mmol), sodium iodide (7.14 g, 47.46 mmol), potassium carbonate (8.2 g, 59.33 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (6.76 g, 47.46 mmol) were added to a dry sealed tube, followed by anisole (80 mL). The reaction was conducted under a nitrogen atmosphere at 110 °C for 18 hours and monitored by TLC until completion. The reaction mixture was cooled to room temperature, filtered, and washed twice with ethyl acetate. The filtrate was washed twice with aqueous ammonia and twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 elution) to give compound 34-5 (4.60 g, 11.60 mmol). LCMS (ESI + ) m / z: 397.1 [M+H] + . <Step 6: Synthesis of Compounds 34, 34a, and 34b> Substrate 34-5 (57 mg, 143.77 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (5 mL). Metachloroperbenzoic acid (44.66 mg, 258.78 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (46 mg, 177.34 μmol) and substrate 7-5 (43.84 mg, 215.66 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 34 (4.2 mg, 6.40 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.06(s,1H),8.78(s,1H),7.81(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.66-7.45(m,2H),6.71(d,J=8.8Hz,2H), 5.73-5.64(m,1H),5.28(s,1H),5.00(dd,J=10.0,1.6Hz,1H),4.89(dd,J=17.2,1.6Hz,1H),4.74-4.56(m,2H),3.59 (d,J=6.0Hz,2H),3.44(d,J=11.2Hz,2H),3.29-3.25(m,2H),2.88-2.80(m,2H),2.47-2.39(m,1H),2.29-2.22(m,1 H),2.00(s,3H),1.54(d,J=8.4Hz,1H),1.16-1.08(m,1H),0.71-0.64(m,1H),0.45-0.40(m,1H),0.40-0.31(m,2H). LCMS(ESI)m / z: 552.3 [M+H] + ,HPLC Method B: R T =7.26min,purity>84.0%. 34 was synthesized in a similar manner and further subjected to chiral resolution by supercritical fluid chromatography to give compound 34a (10.1 mg, 18.31 μmol); SFC retention time t=4.312 min. 1H NMR(600MHz,DMSO-d6)δ 10.07(s,1H),8.78(s,1H),7.81(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.61(s,2H),6.71(d,J=8.4Hz,2H),5.74-5 .64(m,1H),5.29(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.70(s,1H),4.64-4.54(m,1H),3.59(d,J= 6.0Hz,2H),3.44(d,J=11.4Hz,2H),3.28(d,J=10.8Hz,2H),2.92-2.81(m,2H),2.43(d,J=7.2Hz,1H),2.41-2.29(m, 1H),2.00(s,3H),1.54(d,J=8.4Hz,1H),1.15-1.07(m,1H),0.72-0.63(m,1H),0.45-0.41(m,1H),0.40-0.31(m,2H). LCMS(ESI)m / z: 552.3 [M+H] + ,HPLC Method B: R T =7.29min,purity>94.5%. Compound 34b (10.5 mg, 19.03 μmol); SFC retention time t = 7.619 min. 1 H NMR(600MHz,DMSO-d6)δ 10.07(s,1H),8.79(s,1H),7.81(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.61(s,2H),6.71(d,J=9.0Hz,2H),5.73 -5.63(m,1H),5.40-5.18(m,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.76-4.54(m,2H),3.59(d,J=6.0 Hz,2H),3.44(d,J=11.4Hz,2H),3.28(d,J=10.8Hz,2H),2.91-2.81(m,2H),2.44(d,J=7.2Hz,1H),2.41-2.30(m,1H ),2.00(s,3H),1.54(d,J=8.4Hz,1H),1.14-1.08(m,1H),0.71-0.63(m,1H),0.45-0.41(m,1H),0.40-0.31(m,2H). LCMS(ESI)m / z: 552.3 [M+H]+ ,HPLC Method B: R T =7.38min,purity>84.4%.

[0081] Example 35: Synthesis of Compound 35 TIFF2025525290000086.tif58170<Step 1: Synthesis of Compounds 35a & 35b> Substrate 6-4 (40 mg, 97.68 μmol) was dissolved in tetrahydrofuran (4 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.34 mg, 175.82 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (126.24 mg, 976.79 μmol) and substrate 35-1 (25.22 mg, 131.87 μmol) were then added and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 35a (10.0 mg, 14.69 μmol); SFC retention time t = 3.112 min. 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),7.79-7.67(m,2H),7.59(s,2H),6.69(d,J=8.8Hz,2H),5.74-5.62(m,1H),5. 02-4.98(m,1H),4.90-4.73(m,2H),4.68(s,2H),3.71(d,J=6.0Hz,2H),3.42(d,J=11.2Hz,2H),3.24(d,J =11.2Hz,2H),2.93-2.75(m,2H),2.49-2.44(m,1H),2.35(q,J=6.4Hz,1H),2.04-1.93(m,1H),1.50(d,J= 8.0Hz,1H),1.40(s,4H),0.88(d,J=6.0Hz,7H),0.66-0.58(m,1H),0.36-0.27(m,1H),0.25-0.17(m,1H). LCMS(ESI)m / z: 593.2 [M+H] + ,HPLC Method B: R T=8.55min,purity>85.5%. Compound 35b (10.0 mg, 14.21 μmol); SFC retention time t = 4.854 min. 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),7.87-7.67(m,2H),7.59(s,2H),6.69(d,J=8.8Hz,2H),5.74-5.64(m,1H),4.99(d d,J=10.4,1.6Hz,1H),4.91-4.75(m,2H),4.72-4.57(m,2H),3.71(d,J=6.0Hz,2H),3.42(d,J=11.2Hz,2H),3 .24(d,J=11.2Hz,2H),2.93-2.77(m,2H),2.49-2.44(m,1H),2.35(q,J=6.4Hz,1H),2.05-1.91(m,1H),1.50( d,J=8.0Hz,1H),1.40(s,4H),0.88(d,J=6.0Hz,7H),0.65-0.58(m,1H),0.34-0.27(m,1H),0.23-0.17(m,1H). LCMS(ESI)m / z: 593.2 [M+H] + ,HPLC Method B: R T =8.59min,purity>84.0%.

[0082] "Example 36: Synthesis of Compound 36" TIFF2025525290000087.tif58170<Project 1: Synthesis of Compounds 36a&36b> Substrate 21-3 (45 mg, 106.25 μmol) was dissolved in tetrahydrofuran (2 mL) in a dry one-neck flask. Metachloroperbenzoic acid (33.00 mg, 191.25 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (137.32 mg, 1.06 mmol) and substrate 35-1 (49.16 mg, 212.50 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 36a (14.24 mg, 23.47 μmol); SFC retention time t = 2.868 min. 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.78(s,1H),7.77(d,J=8.8Hz,1H),7.68(d,J=8.4Hz,1H) ,7.58(s,2H),6.69(d,J=8.8Hz,2H),5.74-7.63(m,1H),5.03-4.96(m,1 H),4.85(d,J=17.2Hz,1H),4.75(d,J=16.0Hz,1H),4.61(d,J=15.6Hz,1H),4.40(s,1H),3.71(d,J=6.0Hz,2H),3.42(d,J=11.2Hz,2H),3.24(d, J=11.2Hz,2H),2.95-2.80(m,1H),2.83(dd,J=17.2,6.0Hz,1H),2.47(d,J=6.0Hz,1H),2.38-2.28(m,2H),1.95-1.88(m,1H),1.79-1.71(m,1H) ,1.50(d,J=8.0Hz,1H),1.17-1.11(m,1H),0.93(t,J=7.2Hz,3H),0.88( d,J=6.0Hz,7H),0.61(d,J=5.6Hz,1H),0.43-0.38(m,1H),0.00(s,1H). LCMS(ESI)m / z: 607.2 [M+H] + ,HPLC Method B: R T =9.29min,purity >89.7%. Compound 36b (13.16 mg, 21.69 μmol); SFC retention time t = 3.896 min. 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.78(s,1H),7.77(d,J=8.4Hz,1H),7.68(d,J=8.2Hz,1H), 7.59(s,2H),6.69(d,J=8.6Hz,2H),5.72-5.60(m,1H),5.00(dd,J=10.2,1 .6Hz,1H),4.85(d,J=17.1Hz,1H),4.75(d,J=15.3Hz,1H),4.62(s,1H),4. 40(s,1H),3.71(d,J=5.9Hz,2H),3.42(d,J=11.0Hz,2H),3.24(d,J=11.0H z,2H),2.95-2.80(m,1H),2.83(dd,J=17.0,5.9Hz,1H),2.49-2.44(m,1H ),2.38-2.28(m,2H),1.95-1.88(m,1H),1.79-1.71(m,1H),1.50(d,J=8.0 Hz,1H),1.16-1.11(m,1H),0.93(t,J=7.4Hz,3H),0.88(d,J=6.0Hz,6H),0 .85(d,J=5.8Hz,1H),0.65-0.58(m,1H),0.43-0.38(m,1H),-0.00(s,1H). LCMS (ESI) m / z: 607.2 [M+H] + ,HPLC Method B: R T =9.31min,purity>87.9%.

[0083] "Example 37: Synthesis of Compound 37" TIFF2025525290000088.tif64170<Project 1: Synthesis of Compounds 37a&37b> Substrate 34-5 (4.10 g, 10.35 mmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (55 mL). Then, metachloroperbenzoic acid (3.79 g, 18.63 mmol) was added and the reaction mixture was allowed to react at room temperature for 1 hour. N,N-diisopropylethylamine (5.33 g, 41.29 mmol) and substrate 11-1 (3.22 g, 12.41 mmol) were added to the reaction mixture and the reaction mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (acetonitrile / 0.01% aqueous ammonium bicarbonate eluent, 60 mL / min) to obtain the compound. The compound was further subjected to chiral separation by supercritical fluid chromatography to obtain the following: Compound 37a (1.30 g, 2.14 mmol), SFC retention time t = 5.043 min. LCMS (ESI + ) m / z: 608.2 [M+H] + , 1 H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.80(s,1H),7.83(s,1H),7.70(d,J=8.4Hz,1H),7.64-7.42(m,2H),6.91(d,J=9.0Hz,2H ),5.70-5.64(m,1H),5.30(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.69-4.62(m,2H),3 .11-3.07(m,4H),2.86-2.81(m,2H),2.27(q,J=12.6,9.0Hz,5H),2.15(s,3H),1.53(t,J=5.4Hz,4H),1 .46(t,J=5.4Hz,4H),1.13-1.10(m,1H),0.69-0.65(m,1H),0.49-0.42(m,1H),0.39-0.32(m,2H),HPLC Method B: RT=8.83min,purity >94.1%. Compound 37b (1.50g, 2.47mmol), SFC retention time t=9.666min. LCMS(ESI + ) m / z: 608.2 [M+H] + , 1H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.80(s,1H),7.83(s,1H),7.70(d,J=8.4Hz,1H),7.66-7.47(m,2H),6.91(d,J=8.4Hz,2H),5.70-5 .64(m,1H),5.29(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.69(s,1H),4.62(d,J=15.0Hz,1H),3. 09(t,J=5.4Hz,4H),2.88-2.79(m,2H),2.29(d,J=6.0Hz,4H),2.24(d,J=17.4Hz,1H),2.16(s,3H),1.54(t,J=5. 4Hz,4H),1.47(t,J=5.4Hz,4H),1.13-1.09(m,1H),0.69-0.66(m,1H),0.46-0.42(m,1H),0.39-0.33(m,2H),HPLC Method B: RT=8.09min,purity >96.5%.

[0084] Example 38: Synthesis of Compound 38 TIFF2025525290000089.tif64170<Step 1: Synthesis of Compounds 38a & 38b> Substrate 4-9 (80 mg, 202.29 μmol) was dissolved in tetrahydrofuran (10 mL) in a dry one-neck flask. Metachloroperbenzoic acid (61.60 mg, 303.43 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (260.58 mg, 2.02 mmol) and substrate 11-1 (78.71 mg, 303.43 μmol) were then added to the reaction mixture and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 38a (32.43 mg, 53.45 μmol); SFC retention time t = 4.513 min. 1H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.80(s,1H),7.83(d,J=7.8Hz,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.91(d,J=8.4Hz,2H),5. 67-5.65(m,1H),5.31(d,J=5.4Hz,1H),5.01-4.99(m,1H),4.93-4.85(m,1H),4.69(s,1H),4.64-4.64(m,1H),3. 75(d,J=5.4Hz,1H),3.09-3.07(m,4H),2.87-2.80(m,2H),2.30-2.26(m,4H),2.24-2.22(m,1H),2.16(s,3H),1. 54-1.52(m,4H),1.47-1.45(m,4H),1.14-1.10(m,1H),0.69-0.67(m,1H),0.46-0.41(m,1H),0.41-0.30(m,2H). LCMS(ESI)m / z: 607.4 [M+H] + ,HPLC Method B: R T =8.39min,purity >94.4%. Compound 38b (32.44 mg, 53.46 μmol); SFC retention time t = 8.668 min. 1H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.80(s,1H),7.83(d,J=7.8Hz,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.91(d,J=8.4Hz,2H),5.67-5.5 5(m,1H),5.31(d,J=5.4Hz,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.69(s,1H),4.65-4.52(m,1H),3.75(d ,J=5.4Hz,1H),3.09-3.07(m,4H),2.87-2.80(m,2H),2.84-2.77(m,1H),2.35-2.26(m,4H),2.26-2.22(m,1H),2.17(s, 3H),1.54-1.52(m,4H),1.47-1.45(m,4H),1.14-1.10(m,1H),0.68-0.66(m,1H),0.46-0.42(m,1H),0.37-0.35(m,2H). LCMS(ESI)m / z: 607.4 [M+H] + ,HPLC Method B: R T =8.40min,purity >95.7%.

[0085] Example 39: Synthesis of Compound 39 TIFF2025525290000090.tif58170<Step 1: Synthesis of Compounds 39a & 39b> Substrate 34-5 (40 mg, 100.89 μmol) was dissolved in tetrahydrofuran (5 mL) in a dry one-neck flask. Metachloroperbenzoic acid (36.87 mg, 181.60 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (130.39 mg, 1.01 mmol) and substrate 35-1 (46.68 mg, 201.77 μmol) were then added to the reaction mixture and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give the product, which was further purified by supercritical fluid chromatography to give compound 39a (10.1 mg, 16.50 μmol); SFC retention time t = 3.831 min. 1H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.78(s,1H),7.81(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.65-7.41(m,2H),6.69(d,J=8.4Hz,2H),5.70-5.60( m,1H),5.29(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.77-4.64(m,1H),4.62(d,J=15.0Hz,1H),3.71(d,J=6.0Hz ,2H),3.42(d,J=11.4Hz,2H),3.25(d,J=11.4Hz,2H),2.85-2.81(m,2H),2.49-2.46(m,1H),2.35(q,J=6.8Hz,1H),2.26-2.23(m ,1H),1.50(d,J=7.8Hz,1H),1.12-1.10(m,1H),0.88(d,J=6.0Hz,6H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 580.2 [M+H] + ,HPLC Method B: R T =7.43min,purity>94.7%. Compound 39b (10.4 mg, 17.49 μmol); SFC retention time t = 6.371 min. 1H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.78(s,1H),7.81(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.67-7.38(m,2H),6.69(d, J=8.4Hz,2H),5.72-5.60(m,1H),5.29(s,1H),5.04-4.96(m,1H),4.89(d,J=17.4Hz,1H),4.77-4.64 (m,1H),4.62(d,J=15.0Hz,1H),3.71(d,J=6.0Hz,2H),3.42(d,J=10.8Hz,2H ),3.25(d,J=10.8Hz,2H),2.89-2.79(m,2H),2.48-2.44(m,1H),2.35(d,J=1 1.4Hz,1H),2.28-2.22(m,1H),1.50(d,J=7.8Hz,1H),1.13-1.10(m,1H),0.8 8(d,J=6.0Hz,6H),0.71-0.65(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 580.2 [M+H] + ,HPLC Method B: R T =7.44min,purity>97.5%.

[0086] Example 40: Synthesis of Compound 40 TIFF2025525290000091.tif58170<Step 1: Synthesis of Compound 40-2> Substrate 40-1 (180 mg, 1.58 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (3 mL). Then, parafluoronitrobenzene (233.54 mg, 1.66 mmol) and potassium carbonate (1.09 g, 7.88 mmol) were added, and the reaction was carried out at 100 °C for 12 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 40-2 (300 mg, 1.28 mmol). LCMS (ESI) m / z: 236.2 [M+H] + . <Step 2: Synthesis of Compound 40-3> Substrate 40-2 (300 mg, 1.28 mmol) was added to a dry one-neck flask and dissolved in methanol (5 mL). Palladium / carbon (30 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 40-3 (230 mg, 1.12 mmol). LCMS (ESI) m / z: 206.1 [M+H] + . <Step 3: Synthesis of Compound 40> Substrate 18-2 (20 mg, 48.84 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (15.17 mg, 87.91 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (63.12 mg, 488.40 μmol) and substrate 40-3 (20.05 mg, 97.68 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 40 (4 mg, 7.06 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.82(s,1H),7.91(d,J=8.0Hz,1H),7.71(d,J=8.4Hz,1H),7.58(s,2H),6.92(d,J=8.8Hz,2H),5.75-5.64(m,1H),5.03-4.98 (m,1H),4.95(s,1H),4.88(dd,J=17.2,1.6Hz,1H),4.78(d,J=16.4Hz,1H),4.56(dd,J=16.0,6.4Hz,1H),3.48(t,J=10.8Hz,2H),3.02(d,J =16.4Hz,1H),2.82(d,J=11.2Hz,1H),2.75(d,J=13.6Hz,1H),2.72-2.66(m,1H),2.38-2.30(m,1H),2.27(d,J=11.2Hz,1H),2.22(s,3H),2 .13(d,J=8.8Hz,1H),1.80-1.75(m,1H),1.62-1.53(m,1H),1.06(d,J=6.0Hz,3H),0.99-0.92(m,1H),0.76-0.67(m,5H),0.42-0.33(m,1H). LCMS(ESI)m / z: 567.3 [M+H] + ,HPLC Method B: R T =7.59,purity>88.5%.

[0087] "Example 41: Synthesis of Compound 41" TIFF2025525290000092.tif58170<Project 1: Synthesis of Compounds 41a&41b> Substrate 34-5 (40 mg, 100.89 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (3 mL). Metachloroperbenzoic acid (36.87 mg, 181.60 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (130.39 mg, 1.01 mmol) and substrate 41-1 (47.08 mg, 201.77 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 41a (5.1 mg, 8.45 μmol); SFC retention time t = 3.476 min. 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.83(s,1H),7.84-7.78(m,1H),7.76-7.70(m,1H),7.70-7.60(m,1H),7.43-7.37(m,1H),7.00-6.94(m,1H),5.74-5.60(m ,1H),5.29(s,1H),5.03-4.96(m,1H),4.93-4.83(m,1H),4.74-4.58(m,2H),3.10-3.01(m,2H),2.92-2.76(m,2H),2.62-2.5 3(m,2H),2.30-2.20(m,1H),1.90-1.80(m,2H),1.60-1.48(m,2H),1.15-1.14(m,1H),0.71-0.62(s,1H),0.47-0.31(m,3H). LCMS(ESI)m / z: 582.3 [M+H] + ,HPLC Method B: R T =8.13min,purity>96.4%. Compound 41b (5.2mg, 8.47μmol); SFC retention time t=8.440min. 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.83(s,1H),7.88-7.76(m,1H),7.76-7.69(m,1H),7.70-7.55(m,1H),7.44-7.31(m,1H),7.02-6.94(m,1H),5.74-5.60(m ,1H),5.29(s,1H),5.03-4.96(m,1H),4.93-4.83(m,1H),4.77-4.56(m,2H),3.10-3.01(m,2H),2.92-2.76(m,2H),2.62-2.5 3(m,2H),2.30-2.20(m,1H),1.90-1.79(m,2H),1.60-1.48(m,2H),1.17-1.06(m,1H),0.71-0.62(s,1H),0.47-0.31(m,3H). LCMS(ESI)m / z: 582.4 [M+H] + ,HPLC Method B: R T =8.56min,purity>94.8%.

[0088] Example 42: Synthesis of Compound 42 TIFF2025525290000093.tif58170<Step 1: Synthesis of Compounds 42a & 42b> Substrate 3-4 (30 mg, 75.86 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1.5 mL). Metachloroperbenzoic acid (26.18 mg, 151.72 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (98.04 mg, 758.58 μmol) and substrate 41-1 (17.70 mg, 75.86 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 42a (4.0 mg, 6.39 μmol); SFC retention time t = 2.339 min. 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.85(s,1H),7.88(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.65(s,1H),7.43-7.40(m,1H),6. 97(d,J=8.4Hz,1H),5.74-5.65(m,1H),5.03-4.99(m,2H),4.90-4.85(m,1H),4.74(d,J=16.4Hz,1H),4.62- 4.57(m,1H),3.04(d,J=11.6Hz,2H),2.89(s,2H),2.60-2.49(m,2H),2.23(s,9H),1.84(d,J=12.0Hz,2H),1 .58-1.50(m,2H),1.22(s,4H),0.95-0.90(m,1H),0.70-0.66(m,1H),0.61-0.56(m,1H),0.48-0.43(m,1H). LCMS(ESI)m / z: 581.3[M+H] + ,HPLC Method B: R T =8.01min,purity>92.7%. Compound 42b (4.0 mg, 6.40 μmol); SFC retention time t = 5.345 min. 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.84(s,1H),7.88(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.65(s,1H),7.43-7.40(m,1H),6.9 7(d,J=8.8Hz,1H),5.74-5.65(m,1H),5.03-4.99(m,2H),4.74(d,J=16.0Hz,1H),4.62-4.57(m,1H),3.04(d, J=11.6Hz,2H),2.89(d,J=2.0Hz,2H),2.60-2.54(m,2H),2.23(d,J=4.0Hz,9H),1.84(d,J=12.4Hz,2H),1.57 -1.49(m,2H),1.26-1.22(m,4H),0.95-0.90(s,1H),0.72-0.66(m,1H),0.60-0.56(m,1H),0.48-0.43(m,1H). LCMS(ESI)m / z: 581.3 [M+H] + ,HPLC Method B: R T=8.11min,purity>92.9%.

[0089] Example 43: Synthesis of Compound 43 TIFF2025525290000094.tif54170<Step 1: Synthesis of Compounds 43, 43a, and 43b> Substrate 6-4 (105 mg, 256.41 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (5 mL). Metachloroperbenzoic acid (79.65 mg, 461.54 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (330.24 mg, 2.56 mmol) and substrate 28-5 (111.44 mg, 512.82 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 43 (20.09 mg, 28.74 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),7.77-7.68(m,2H),7.53(s,2H),6.63(d,J=8.8Hz,2H),5.72-5.62(m, 1H),4.99(dd,J=10.2,1.6Hz,2H),4.88-4.79(m,2H),4.69-4.61(m,2H),3.31(s,2H),3.06-3.03 (m,2H),2.93-2.76(m,4H),2.59-2.55(m,2H),2.40-2.37(m,2H),2.22(s,3H),2.02-1.95(m,1H) ,1.45-1.40(m,4H),1.87-0.84(m,1H),0.65-0.61(m,1H),0.34-0.30(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 579.3 [M+H] + ,HPLC Method B: R T =8.97min,purity>82.8%. Compound 43 was synthesized in a similar manner and further subjected to chiral resolution by supercritical fluid chromatography to give: Compound 43a (2.3 mg, 3.50 μmol); SFC retention time t=3.946 min. 1 H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),7.76(s,1H),7.69(d,J=8.4Hz,1H),7.54(s,2H),6.64(d,J=8.4Hz,2H),5.73-5.64(m,1H) ,4.99(dd,J=10.2,1.8Hz,1H),4.86(d,J=17.4Hz,1H),4.80(s,1H),4.68(s,1H),4.64(d,J=13.8Hz,1H),3.06-3.01( m,2H),2.90-2.84(m,3H),2.82-2.78(m,1H),2.59-2.55(m,2H),2.38(dd,J=9.0,3.0Hz,2H),2.22(s,3H),2.02-1.95 (m,1H),1.45-1.42(m,1H),1.40(s,3H),0.88-0.84(m,1H),0.65-0.61(m,1H),0.34-0.30(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 579.4 [M+H] + ,HPLC Method B: R T =8.76min,purity>88.0%. Compound 43b (9.3mg, 13.90μmol); SFC retention time t=6.047min. 1H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),7.76(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.54(s,2H),6.63(d,J=8.4Hz,2H),5.72-5 .62(m,1H),4.99(dd,J=10.2,1.8Hz,1H),4.86(d,J=17.4Hz,1H),4.80(s,1H),4.68(s,1H),4.67-4.59(m,1H),3.08- 3.02(m,2H),2.90-2.84(m,3H),2.82-2.78(m,1H),2.57(t,J=7.8Hz,2H),2.42-2.37(m,2H),2.22(s,3H),2.02-1.95 (m,1H),1.46-1.42(m,1H),1.40(s,3H),0.87-0.84(m,1H),0.66-0.61(m,1H),0.35-0.30(m,1H),0.24-0.19(m,1H). LCMS(ESI)m / z: 579.4 [M+H] + ,HPLC Method B: R T =8.81min,purity>82.1%.

[0090] Example 44: Synthesis of Compound 44 TIFF2025525290000095.tif59170<Step 1: Synthesis of Compounds 44, 44a, and 44b> Substrate 6-4 (90 mg, 219.78 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (4 mL). Metachloroperbenzoic acid (68.27 mg, 395.06 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (282.51 mg, 2.19 mmol) and substrate 11-1 (114.02 mg, 439.56 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 44 (21.5 mg, 34.63 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.10(s,1H),8.81(s,1H),7.78(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.56(s,2H),6.92(d,J=8.8Hz,2H) ,5.73-5.62(m,1H),5.03-4.98(m,1H),4.92-4.75(m,2H),4.69-4.58(m,2H),3.09(t,J=5.6Hz,4H),2.92-2. 76(m,2H),2.38-2.28(m,4H),2.19(s,3H),2.04-1.96(m,1H),1.54(t,J=5.6Hz,4H),1.47(t,J=5.6Hz,4H), 1.45-1.42(m,1H),1.40(s,3H),0.88-0.82(m,1H),0.65-0.59(m,1H),0.36-0.29(m,1H),0.25-0.18(m,1H). LCMS(ESI)m / z: 621.2 [M+H] + ,HPLC Method B: R T =9.63min,purity>96.8%. Compound 44 was synthesized in a similar manner and further subjected to chiral resolution by supercritical fluid chromatography to give: Compound 44a (1.6 mg, 2.23 μmol); SFC retention time t=3.819 min. 1H NMR(600MHz,DMSO-d6)δ 10.10(s,1H),8.80(s,1H),7.82-7.73(m,1H),7.71-7.65(m,1H),7.63-7.48(m,2H),6.96-6.86(m,2H),5.72-5.62(m ,1H),5.03-4.95(m,1H),4.91-4.74(m,2H),4.73-4.58(m,2H),3.29(s,1H),3.10-3 .06(m,4H),2.93-2.84(m,1H),2.83-2.76(m,1H),2.36-2.25(m,3H),2.24-2.13(m,3 H),2.03-1.95(m,1H),1.56-1.51(m,4H),1.50-1.45(m,4H),1.40(s,3H),1.25-1.21 (m,1H),0.88-0.82(m,1H),0.66-0.58(m,1H),0.35-0.29(m,1H),0.24-0.18(m,1H). LCMS(ESI)m / z: 621.4 [M+H] + ,HPLC Method B: R T =10.05min,purity>86.7%. Compound 44b (1.5 mg, 2.21 μmol); SFC retention time t = 6.629 min. 1H NMR(600MHz,DMSO-d6)δ 10.10(s,1H),8.80(s,1H),7.82-7.73(m,1H),7.71-7.65(m,1H),7.61-7.49 (m,2H),6.96-6.86(m,2H), 5.71-5.61(m ,1H),5.03-4.95(m,1H),4.89-4.83(m,1H),4.83-4.74(m,1H),4.73-4.67(m,1H),4.67-4. 59(m,1H),3.10-3.06(m,4H),2.92-2.85(m,1H),2.83-2.76(m,1H),2.32-2.27(m,3H),2.2 0-2.13(m,3H),2.02-1.95(m,1H),1.56-1.51(m,4H),1.50-1.45(m,4H),1.40(s,3H),1.26 -1.17(m,2H),0.88-0.82(m,1H),0.66-0.58(m,1H),0.35-0.29(m,1H),0.24-0.18(m,1H). LCMS(ESI)m / z: 621.4 [M+H] + ,HPLC Method B: R T =10.03min,purity>91.4%.

[0091] Example 45: Synthesis of Compound 45 TIFF2025525290000096.tif58170<Step 1: Synthesis of Compounds 45a & 45b> Substrate 6-4 (40 mg, 97.68 μmol) was dissolved in tetrahydrofuran (4 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.34 mg, 175.82 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (126.01 mg, 976.79 μmol) and substrate 45-1 (39.71 mg, 195.36 μmol) were then added and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 45a (8.52 mg, 14.66 μmol); SFC retention time t = 3.602 min.1 H NMR(600MHz,DMSO-d6)δ 10.00(s,1H),8.78(s,1H),7.79-7.62(m,2H),7.57-7.31(m,2H),6.56(d,J=7.8Hz,2H),5.72-5.60(m ,1H),5.04-4.94(m,1H),4.91-4.72(m,2H),4.72-4.56(m,2H),4.27(s,1H),3.42-3.40(m,2H),3.16-3.10(m,1H),2 .92-2.82(m,1H),2.82-2.74(m,2H),2.48-2.44(m,1H),2.24(s,3H),2.02-1.92(m,1H),1.90-1.81(m,1H),1.79-1. 71(m,1H),1.47-1.37(m,4H),0.90-0.80(m,1H),0.66-0.58(m,1H),0.36-0.26(m,1H),0.24-0.15(m,1H). LCMS(ESI)m / z: 565.4[M+H] + , HPLC method B Rt=8.36min,purity >97.13%. Compound 45b (7.8 mg, 13.39 μmol); SFC retention time t = 7.195 min. 1 H NMR(600MHz,DMSO-d6)δ 10.00(s,1H),8.78(s,1H),7.79-7.62(m,2H),7.57-7.15(m,2H),6.57-6.41(m,2H),5.72-5.60(m ,1H),5.04-4.94(m,1H),4.91-4.72(m,2H),4.72-4.56(m,2H),4.27(s,1H),3.42-3.40(m,2H),3.16-3.10(m,1H),2 .92-2.82(m,1H),2.82-2.74(m,2H),2.48-2.44(m,1H),2.25(s,3H),2.02-1.92(m,1H),1.90-1.81(m,1H),1.79-1. 71(m,1H),1.47-1.37(m,4H),0.90-0.80(m,1H),0.66-0.58(m,1H),0.36-0.26(m,1H),0.24-0.15(m,1H). LCMS(ESI)m / z: 565.3[M+H] +, HPLC method B Rt=8.317min,purity >96.94%.

[0092] Example 46: Synthesis of Compound 46 TIFF2025525290000097.tif58170<Step 1: Synthesis of Compound 46-2> Substrate 46-1 (400 mg, 2.02 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (5 mL). 2-Fluoro-5-nitrotoluene (310 mg, 2.00 mmol) and potassium carbonate (390.35 mg, 2.82 mmol) were then added and the mixture was reacted at 120 °C for 6 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 46-2 (290 mg, 869.87 μmol). LCMS (ESI) m / z: 278.2 [M+H-56] + . <Step 2: Synthesis of Compound 46-3> Substrate 46-2 (290 mg, 869.87 μmol) was added to a dry one-neck flask and dissolved in methanol (5 mL). Palladium / carbon (30 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 46-3 (240 mg, 791.03 mmol). LCMS (ESI) m / z: 248.0 [M+H-56] + .

[0093] <Step 3: Synthesis of Compound 46-4> Substrate 46-3 (120 mg, 395.52 μmol) was added to a dry three-neck flask, dissolved in anhydrous tetrahydrofuran (3 mL), and cooled to 0 °C under nitrogen protection. Lithium aluminum hydride in tetrahydrofuran (1.98 mL, 1.98 mmol, 1 M) was then slowly added dropwise, and the reaction was heated to reflux at 65 °C for 4 hours. LC-MS monitoring was performed. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was stirred for half an hour. The mixture was then dried over anhydrous sodium sulfate, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 46-4 (38 mg, 174.87 μmol). LCMS (ESI) m / z: 218.2 [M+H] + . <Step 4: Synthesis of Compound 46> Substrate 3-4 (15 mg, 37.93 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (7.59 mg, 68.27 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (48.93 mg, 379.30 μmol) and substrate 46-4 (16.49 mg, 75.86 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 46 (2.0 mg, 3.10 μmol). 1H NMR(600MHz,DMSO-d6)δ 10.15(s,1H),8.85(s,1H),7.88(d,J=7.8Hz,1H),7.74-7.70(m,2H),7.48-7.42(m,1H),7.29(d,J=8.4 Hz,1H),5.73-5.67(m,1H),5.03-5.00(m,2H),4.88(d,J=16.8Hz,1H),4.73-4.58(m,2H),3.52(d,J=10 .8Hz,4H),3.17(d,J=4.8Hz,1H),3.04-3.03(m,2H),2.92-2.86(m,2H),2.27(s,3H),2.20(s,3H),1.99 -1.96(m,1H),1.22(s,3H),0.94-0.90(m,1H),0.70-0.67(m,1H),0.59-0.56(m,1H),0.47-0.44(m,1H). LCMS(ESI)m / z: 565.3 [M+H] + ,HPLC Method B: R T =7.66min,purity>87.6%.

[0094] Example 47: Synthesis of Compound 47 TIFF2025525290000098.tif77170<Step 1: Synthesis of Compound 47-2> Substrate 47-1 (300 mg, 1.15 mmol) was added to a dry one-neck flask and dissolved in methanol (5 mL). Palladium / carbon (30 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 47-2 (230 mg, 994.23 μmol). LCMS (ESI) m / z: 232.2 [M+H] + . <Step 2: Synthesis of Compound 47> Substrate 6-4 (15 mg, 36.63 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (11.38 mg, 65.93 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (47.34 mg, 366.30 μmol) and substrate 47-2 (16.95 mg, 73.26 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 47 (4.0 mg, 6.75 μmol). 1 H NMR(400MHz,DMSO-d6)δ 8.97-8.66(m,1H),7.79-7.45(m,3H),7.35(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H),6.68-6.47(m,2H), 5.68-5.59(m,2H),5.00(d,J=10.4Hz,1H),4.86(d,J=14.8Hz,1H),4.76-4.57(m,2H),4.16(s,3H),3.8 5(d,J=10.0Hz,1H),3.78-3.66(m,1H),3.59(s,3H),3.23(s,3H),2.85-2.71(m,2H),2.16(s,2H),1.99 -1.89(m,3H),1.40(s,4H),0.85-0.83(m,1H),0.64-0.62(m,1H),0.34-0.31(m,1H),0.26-0.18(m,1H). LCMS(ESI)m / z: 593.4 [M+H] + ,HPLC Method BR T =7.58min,purity >98.6%. LCMS(ESI)m / z: 593.4 [M+H] + ,HPLC Method B: R T =7.55min,purity>98.8%.

[0095] Example 48: Synthesis of Compound 48 TIFF2025525290000099.tif58170<Step 1: Synthesis of Compounds 48a & 48b> Substrate 4-9 (20 mg, 50.57 μmol) was dissolved in tetrahydrofuran (2 mL) in a dry one-neck flask. Metachloroperbenzoic acid (17.45 mg, 101.14 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (65.36 mg, 505.72 μmol) and substrate 41-1 (11.80 mg, 50.57 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product. The product was further purified by supercritical fluid chromatography to obtain compound 48a (4.93 mg, 7.62 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),8.83(s,1H),7.80(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.67-7.66(m,1H),7.42-7.39(m,1H),6.97(d,J =8.8Hz,1H),5.72-5.62(m,1H),5.31(d,J=5.6Hz,1H),5.01(dd,J=1.2,10.4Hz,1H),4.88(dd,J=10.4,1.2Hz,1H),4.72- 4.64(m,2H),3.74(d,J=5.6Hz,1H),3.04(d,J=12.0Hz,2H),2.87-2.84(m,1H),2.57(t,J=10.8Hz,2H),2.28-2.18(m,11H) ),1.83(d,J=11.2Hz,2H),1.57-1.52(m,2H),1.15-1.09(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 581.2 [M+H] + ,HPLC Method B: R T =8.46min,purity>89.8%. Compound 48b (4.43 mg, 6.42 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.83(s,1H),7.80(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.67-7.66(m,1H),7.42-7.39(m,1H),6.97(d,J =8.8Hz,1H),5.72-5.62(m,1H),5.31(d,J=5.6Hz,1H),5.01(dd,J=1.2,10.4Hz,1H),4.88(dd,J=10.4,1.2Hz,1H),4.72- 4.60(m,2H),3.74(d,J=5.6Hz,1H),3.04(d,J=12.0Hz,2H),2.87-2.84(m,1H),2.57(t,J=10.8Hz,2H),2.28-2.18(m,11H) ),1.83(d,J=11.2Hz,2H),1.57-1.52(m,2H),1.15-1.09(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 581.2 [M+H] + ,HPLC Method B: R T =8.50min,purity>84.1%.

[0096] Example 49: Synthesis of Compound 49 TIFF2025525290000100.tif107170<Step 1: Synthesis of Compound 49-2> Substrate 49-1 (416 mg, 2.10 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (5 mL). 2-Fluoro-5-nitroanisole (342 mg, 2.00 mmol) and potassium carbonate (386.68 mg, 2.80 mmol) were then added and the mixture was reacted at 110 °C for 4 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 49-2 (470 mg, 1.35 mmol). LCMS (ESI) m / z: 294.3 [M+H-56]. + . <Step 2: Synthesis of Compound 49-3> Substrate 49-2 (200 mg, 572.44 μmol) was added to a dry one-neck flask, dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure to give crude compound 49-3 (140 mg, 561.65 μmol). LCMS (ESI) m / z: 250.1 [M+H] + .

[0097] <Step 3: Synthesis of Compound 49-4> Substrate 49-3 (140 mg, 561.65 μmol) was dissolved in methanol (5 mL) in a dry one-neck flask. Acetic acid (0.5 mL) and aqueous formaldehyde (191.30 mg, 5.62 mmol, 37%) were added and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (105.88 mg, 1.68 mmol) was then added and the mixture was reacted at 50 °C for 6 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The aqueous phase was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 49-4 (32 mg, 121.54 μmol). LCMS (ESI) m / z: 264.2 [M+H] + . <Step 4: Synthesis of Compound 49-5> Substrate 49-4 (32 mg, 121.54 μmol) was added to a dry one-neck flask and dissolved in methanol (3 mL). Palladium on carbon (5 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 49-5 (25.0 mg, 107.15 μmol). LCMS (ESI) m / z: 234.1 [M+H] + . <Step 5: Synthesis of Compound 49> Substrate 4-9 (20 mg, 50.57 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (15.54 mg, 90.03 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (138.49 mg, 1.07 mmol) and substrate 49-5 (25.0 mg, 107.15 μmol) were then added to the reaction mixture and the mixture was allowed to react at 25 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 49 (3.0 mg, 4.71 μmol). 1 H NMR(600MHz,Chloroform-d)δ 8.83(s,1H),7.67-7.63(m,2H),7.17(s,1H),7.10-7.09(m,1H),7.00-6.98(m,1H),5.76-5.69(m,1H),5. 06(d,J=10.2Hz,1H),4.98(dd,J=17.4,1.2Hz,1H),4.69-4.63(m,2H),4.28(s,1H),3.80(d,J=4.2Hz,2H) ,3.77(s,3H),3.75-3.72(m,2H),3.59(d,J=9.6Hz,2H),2.91-2.89(m,2H),2.76(s,1H),2.35(s,3H),2.0 4(s,1H),2.00-1.95(m,2H),1.63-1.59(m,1H),0.84-0.83(m,1H),0.68-0.66(m,1H),0.48-0.44(m,2H). LCMS(ESI)m / z: 581.3 [M+H] + ,HPLC Method B: R T =7.19min,purity>91.1%.

[0098] Example 50: Synthesis of Compound 50 TIFF2025525290000101.tif77170<Step 1: Synthesis of Compounds 50a & 50b> Substrate 6-4 (30 mg, 73.26 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (22.76 mg, 131.87 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (81.02 mg, 626.91 μmol) and substrate 50-1 (29 mg, 125.38 μmol) were then added to the reaction mixture and the mixture was allowed to react at 25 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 50a (10.1 mg, 16.68 μmol); SFC retention time t = 6.088 min. 1 H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.76(s,1H),7.70(d,J=7.8Hz,1H),7.58(s,2H),6.68(d,J=9.0Hz,2H),5.70-5.63(m,1H),4.99( d,J=10.2Hz,1H),4.87-4.80(m,2H),4.68(s,1H),4.65-4.63(m,2H),4.40(s,1H),3.70(d,J=9.6Hz,1H),3.60(d,J=9.6Hz,1 H),3.49(d,J=10.8Hz,1H),3.31(s,1H),2.91-2.86(m,1H),2.81-2.78(m,1H),2.64-2.61(m,1H),2.01-1.96(m,1H),1.82(s ,3H),1.58(d,J=8.4Hz,1H),1.45-1.40(m,4H),0.86-0.84(m,1H),0.64-0.61(m,1H),0.33-0.30(m,1H),0.22-0.19(m,1H). LCMS(ESI)m / z: 593.3 [M+H] + ,HPLC Method B: R T =7.16min,purity>97.9%. Compound 54b (9.5mg, 15.44μmol); SFC retention time t=9.232min. 1H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.76(s,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.68(d,J=8.4Hz,2H),5.70-5.63(m,1H),5.00-4 .98(d,J=10.2Hz,1H),4.87-4.80(m,2H),4.68(s,1H),4.65-4.63(m,2H),4.40(s,1H),3.70(d,J=10.2Hz,1H),3.60(d,J=10.2 Hz,1H),3.49(d,J=10.8Hz,1H),3.30(s,1H),2.91-2.86(m,1H),2.81-2.78(m,1H),2.64-2.61(m,1H),2.01-1.96(m,1H),1.82 (s,3H),1.58(d,J=8.4Hz,1H),1.45-1.40(m,4H),0.86-0.84(m,1H),0.64-0.61(m,1H),0.33-0.30(m,1H),0.22-0.19(m,1H). LCMS(ESI)m / z: 581.3 [M+H] + ,HPLC Method B: R T =7.17min,purity>96.3%.

[0099] "Example 51: Synthesis of Compound 51" TIFF2025525290000102.tif71170<Project 1: Synthesis of Compounds 51a&51b> Substrate 6-4 (30 mg, 73.26 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (22.76 mg, 131.87 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (89.21 mg, 690.26 μmol) and substrate 51-1 (30 mg, 138.05 μmol) were then added to the reaction mixture and the mixture was allowed to react at 25 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 51a (9.1 mg, 14.28 μmol); SFC retention time t = 3.568 min. 1 H NMR(400MHz,Chloroform-d)δ 8.81(s,1H),7.66(d,J=12.0Hz,1H),7.57(d,J=12.0Hz,1H),7.46(s,2H),6.72(d,J=13.8Hz,2H),5.78-5.68(m,1H) ,5.07(dd,J=15.6,1.2Hz,1H),4.99(dd,J=25.2,1.8Hz,1H),4.78-4.61(m,2H),3.97(s,2H),3.59(d,J=16.8Hz,2H), 3.43(d,J=16.8Hz,2H),3.02-2.93(m,1H),2.86-2.80(m,2H),2.54-2.52(m,2H),2.36-2.28(m,1H),1.54(s,3H),1. 30-1.24(m,2H),1.10(t,J=10.8Hz,3H),1.03-0.98(m,1H),0.88-0.83(m,1H),0.44-0.39(m,1H),0.25-0.20(m,1H). LCMS(ESI)m / z: 579.3 [M+H] + ,HPLC Method B: R T =8.55min,purity>90.8%. Compound 51b (7.9mg, 13.65μmol); SFC retention time t=5.059min. 1H NMR(400MHz,Chloroform-d)δ 8.81(s,1H),7.65(d,J=12.0Hz,1H),7.57(d,J=12.0Hz,1H),7.49(s,2H),6.72(d,J=13.8Hz,2H),5.77-5.68(m,1H),5. 07(dd,J=15.6,1.2Hz,1H),4.98(dd,J=25.2,1.8Hz,1H),4.78-4.61(m,2H),4.06(s,2H),3.62(d,J=16.8Hz,2H),3.48( d,J=16.8Hz,2H),3.34(s,1H),3.02-2.93(m,1H),2.86-2.80(m,2H),2.60-2.59(m,2H),2.36-2.28(m,1H),1.54(s,3H) ,1.30-1.24(m,2H),1.15(t,J=10.8Hz,3H),1.03-0.98(m,1H),0.88-0.83(m,1H),0.44-0.39(m,1H),0.25-0.20(m,1H). LCMS(ESI)m / z: 579.3 [M+H] + ,HPLC Method B: R T =8.40min,purity>95.4%.

[0100] Example 52: Synthesis of Compound 52 TIFF2025525290000103.tif58170<Step 1: Synthesis of Compounds 52a & 52b> Substrate 6-4 (30 mg, 73.26 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (31.61 mg, 183.15 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (94.68 mg, 732.59 μmol) and substrate 41-1 (34.19 mg, 146.52 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 52a (6.2 mg, 9.00 μmol); SFC retention time t = 3.064 min.1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.83(s,1H),7.75(d,J=8.4Hz,1H),7.72-7.65(m,2H),7.41-7.38(m,1H),6.97(d,J=8.8Hz,1H),5 .72-5.62(m,1H),4.99(dd,J=10.4,1.2Hz,1H),4.88-4.83(m,2H),4.70(s,1H),4.66-4.61(m,1H),3.04(d,J=12. 0Hz,1H),2.93-2.77(m,2H),2.59-2.54(m,2H),2.25-2.15(m,11H),2.02-1.95(m,1H),1.83(d,J=11.6Hz,2H),1 .58-1.48(m,2H),1.46-1.40(m,4H),0.87-0.84(m,1H),0.65-0.60(m,1H),0.35-0.30(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 595.4 [M+H] + ,HPLC Method B: R T =10.14min,purity>86.3%. Compound 52b (6.56 mg, 9.89 μmol); SFC retention time t = 5.193 min. 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.83(s,1H),7.75(d,J=8.4Hz,1H),7.72-7.65(m,2H),7.41-7.38(m,1H),6.97(d,J=8.8Hz,1H),5 .72-5.62(m,1H),4.99(dd,J=10.4,1.2Hz,1H),4.88-4.78(m,2H),4.70(s,1H),4.67-4.61(m,1H),3.04(d,J=12. 0Hz,1H),2.93-2.77(m,2H),2.59-2.54(m,2H),2.25-2.15(m,11H),2.02-1.95(m,1H),1.83(d,J=11.6Hz,2H),1 .58-1.48(m,2H),1.46-1.40(m,4H),0.87-0.84(m,1H),0.65-0.60(m,1H),0.35-0.30(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 595.4 [M+H]+ ,HPLC Method B: R T =10.32min,purity>89.7%.

[0101] Example 53: Synthesis of Compound 53 TIFF2025525290000104.tif84170<Step 1: Synthesis of Compound 53-1> Substrate 34-3 (180 mg, 866.82 μmol) was added to a dry three-neck flask, and tetrahydrofuran (5 mL) was added to dissolve the substrate. The mixture was cooled to 0 °C under nitrogen protection. Then, (trifluoromethyl)trimethylsilane (616.28 mg, 4.33 mmol) and tetrabutylammonium fluoride (1 M, 866.82 μL) were slowly added dropwise, and the reaction was continued for 1 hour while maintaining the temperature. The reaction mixture was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 53-1 (209 mg, 752.69 μmol). LCMS (ESI) m / z: 278.1 [M+H] + . <Step 2: Synthesis of Compound 53-2> Substrate 53-1 (209 mg, 752.69 μmol), substrate IM-1 (175.66 mg, 790.33 μmol), cuprous iodide (286.70 mg, 1.51 mmol), sodium iodide (225.64 mg, 1.51 mmol), potassium carbonate (260.07 mg, 1.88 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (428.25 mg, 3.01 mmol) were added to a dry microwave tube, followed by anisole (15 mL). The reaction was heated in a nitrogen atmosphere at 130 °C in a microwave oven for 3 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 53-2 (210 mg, 453.10 μmol). LCMS (ESI) m / z: 464.3 [M+H] + . <Step 3: Synthesis of Compounds 53a & 53b> Substrate 53-2 (40 mg, 86.30 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (4 mL). Metachloroperbenzoic acid (31.54 mg, 155.35 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (111.54 mg, 863.05 μmol) and the substrate 4-(4-methylpiperidino)aniline (33.02 mg, 172.61 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 53a (12.6 mg, 18.88 μmol); SFC retention time t = 2.141 min. 1 H NMR(600MHz,Methanol-d4)δ 10.17(s,1H),8.83(s,1H),8.06-7.92(m,1H),7.89(d,J=8.4Hz,1H),7.58(s,2H),6.94(d,J=8.4Hz,2H ),6.03(s,1H),5.73-5.62(m,1H),4.97(d,J=10.2Hz,1H),4.88-4.73(m,2H),4.59(dd,J=16.2,7.2Hz,1 H),3.11(t,J=4.8Hz,4H),3.05-2.99(m,1H),2.93(dd,J=17.2,6.0Hz,1H),2.47(t,J=4.8Hz,4H),2.23 (s,3H),1.25-1.17(m,2H),1.05-1.09(m,1H),0.74-0.72(m,1H),0.60-0.52(m,1H),0.22-0.20(m,1H). LCMS(ESI)m / z: 607.5 [M+H] + ,HPLC Method B: R T =8.74min,purity>90.9%. Compound 53b (13.7mg, 20.60μmol); SFC retention time t=3.522min. 1H NMR(600MHz,Methanol-d4)δ 10.17(s,1H),8.83(s,1H),8.07-7.92(m,1H),7.89(d,J=8.4Hz,1H),7.58(s,2H),6.94(d,J=8.4Hz,2 H),6.03(s,1H),5.73-5.62(m,1H),5.02-4.93(m,1H),4.86-4.73(m,2H),4.59(dd,J=16.2,7.2Hz,1H) ,3.11(t,J=4.8Hz,4H),3.05-2.99(m,1H),2.93(dd,J=17.2,6.0Hz,1H),2.46(t,J=4.8Hz,4H),2.23( s,3H),1.25-1.16(m,2H),1.05-1.09(m,1H),0.74-0.72(m,1H),0.60-0.52(m,1H),0.22-0.20(m,1H). LCMS(ESI)m / z: 607.1 [M+H] + ,HPLC Method B: R T =8.77min,purity>91.2%.

[0102] Example 54: Synthesis of Compound 54 TIFF2025525290000105.tif58170<Step 1: Synthesis of Compounds 54a & 54b> Substrate 53-2 (40 mg, 86.30 μmol) was dissolved in tetrahydrofuran (4 mL) in a dry one-neck flask. Metachloroperbenzoic acid (31.54 mg, 155.35 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (111.54 mg, 863.05 μmol) and substrate 12-1 (37.86 mg, 172.61 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 54a (8.2 mg, 12.61 μmol); SFC retention time t = 2.764 min. 1H NMR(600MHz,Methanol-d4)δ 10.17(s,1H),8.83(s,1H),8.06-7.92(m,1H),7.89(d,J=8.4Hz,1H),7.58(s,2H),6.94(d,J=8.4Hz,2H ),6.03(s,1H),5.73-5.62(m,1H),4.97(d,J=10.2Hz,1H),4.88-4.73(m,2H),4.59(dd,J=16.2,7.2Hz,1 H),3.11(t,J=4.8Hz,4H),3.06-2.98(m,1H),2.93(dd,J=17.2,6.0Hz,1H),2.47(t,J=4.8Hz,4H),2.23 (s,3H),1.25-1.17(m,2H),1.03-0.97(m,1H),0.70-0.75(m,1H),0.60-0.52(m,1H),0.23-0.18(m,1H). LCMS(ESI)m / z: 635.4 [M+H] + ,HPLC Method B: R T =9.66min,purity>97.6%. Compound 54b (10.0 mg, 14.98 μmol); SFC retention time t = 4.157 min. 1 H NMR(600MHz,Methanol-d4)δ 10.17(s,1H),8.83(s,1H),8.07-7.92(m,1H),7.89(d,J=8.4Hz,1H),7.58(s,2H),6.94(d,J=8.4Hz,2 H),6.03(s,1H),5.73-5.62(m,1H),5.02-4.93(m,1H),4.86-4.73(m,2H),4.59(dd,J=16.2,7.2Hz,1H) ,3.11(t,J=4.8Hz,4H),3.06-2.98(m,1H),2.93(dd,J=17.2,6.0Hz,1H),2.46(t,J=4.8Hz,4H),2.23( s,3H),1.25-1.16(m,2H),1.03-0.97(m,1H),0.70-0.75(m,1H),0.60-0.52(m,1H),0.23-0.18(m,1H). LCMS(ESI)m / z: 635.4 [M+H] + ,HPLC Method B: R T =9.75min,purity>95.1%. Example 55: Synthesis of Compound 55 TIFF2025525290000106.tif71170<Step 1: Synthesis of Compound 55> Substrate 32-2 (40 mg, 89.00 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (38.40 mg, 222.49 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (115.02 mg, 889.98 μmol) and substrate 28-5 (38.68 mg, 178.00 μmol) were then added to the reaction mixture and the mixture was incubated at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 55 (12.38 mg, 17.33 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.82(s,1H),8.04-8.02(m,1H),7.91(d,J=8.0Hz,1H),7.53(s,2H),6.69(s,1H),6.54(d,J =8.4Hz,2H),5.72-5.62(m,1H),4.98(d,J=10.0Hz,1H),4.82(d,J=16.8Hz,2H),4.57(dd,J=7.2,16.0Hz, 1H),3.30(s,2H),3.22-3.18(m,1H),3.05(d,J=8.8Hz,2H),2.87-2.86(m,2H),2.75-2.71(m,1H),2.56(t ,J=8.8Hz,2H),2.40-2.22(m,2H),2.22(s,3H),1.04-0.99(m,2H),0.91-0.88(m,1H),0.49-0.47(m,1H). LCMS(ESI)m / z: 619.3 [M+H] + ,HPLC Method B: R T =8.79min,purity>86.6%.

[0103] Example 56: Synthesis of Compound 56 TIFF2025525290000107.tif58170<Step 1: Synthesis of Compounds 56a & 56b> Substrate 34-5 (35 mg, 88.28 μmol) was dissolved in tetrahydrofuran (1 mL) in a dry one-neck flask. Metachloroperbenzoic acid (27.42 mg, 158.90 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (114.09 mg, 882.76 μmol) and substrate 30-3 (36.25 mg, 176.55 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give the product, which was then chirally resolved by supercritical fluid chromatography to give compound 56a (11.0 mg, 19.87 μmol); SFC retention time t = 3.027 min. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),7.83(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.58(s,2H),6.92(d,J=9.2Hz,2H),5.74-5. 62(m,1H),5.29(s,1H),5.02-4.97(m,1H),4.93-4.85(m,1H),4.68(s,1H),4.61(dd,J=15.9,5.7Hz,1H),3.52-3.43( m,2H),2.89-2.78(m,3H),2.72-2.65(m,1H),2.37-2.31(m,1H),2.30-2.22(m,2H),2.21(s,3H),2.17-2.10(m,J=9.7 ,6.3,2.9Hz,1H),1.14-1.08(m,1H),1.06(d,J=6.2Hz,3H),0.71-0.63(m,1H),0.46-0.41(m,1H),0.40-0.32(m,2H). LCMS(ESI)m / z: 554.2 [M+H] + ,HPLC Method B: R T =7.15min,purity>82.1%. Compound 56b (10.8mg, 19.51μmol); SFC retention time t=5.117min. 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),7.83(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.58(s,2H),7.01-6.79(m,2H),5.73-5.62(m, 1H),5.29(s,1H),5.02-4.97(m,1H),4.94-4.85(m,1H),4.68(s,1H),4.61(dd,J=15.7,5.7Hz,1H),3.49(d,J=11.0Hz,2H ),2.88-2.78(m,3H),2.72-2.64(m,1H),2.34(dd,J=11.6,9.9Hz,1H),2.30-2.23(m,2H),2.21(s,3H),2.17-2.10(m,J= 9.7,6.3,2.9Hz,1H),1.15-1.08(m,1H),1.06(d,J=6.2Hz,3H),0.71-0.62(m,1H),0.47-0.41(m,1H),0.40-0.33(m,2H). LCMS(ESI)m / z: 554.2 [M+H] + ,HPLC Method B: R T =7.15min,purity>87.6%.

[0104] Example 57: Synthesis of Compound 57 TIFF2025525290000108.tif58170<Step 1: Synthesis of Compounds 57a & 57b> Substrate 34-5 (35 mg, 88.28 μmol) was dissolved in tetrahydrofuran (1 mL) in a dry one-neck flask. Metachloroperbenzoic acid (15.23 mg, 88.28 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (114.09 mg, 882.76 μmol) and substrate 57-1 (38.72 mg, 176.55 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give the product, which was then chirally resolved by supercritical fluid chromatography to give compound 57a (12.5 mg, 22.02 μmol); SFC retention time t = 3.149 min.1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),7.83(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.64-7.49(m,2H),6.91(d,J=9.2Hz, 2H),5.74-5.63(m,1H),5.29(s,1H),5.00(dd,J=10.2,1.6Hz,1H),4.89(dd,J=17.2,1.6Hz,1H),4.64(dd,J=17 .2,1.2Hz,2H),3.09(t,J=4.8Hz,4H),2.90-2.81(m,2H),2.71-2.64(m,1H),2.58(t,J=5.2Hz,4H),2.29-2.21 (m,1H),1.14-1.08(m,1H),1.02(s,3H),1.00(s,3H),0.70-0.64(m,1H),0.47-0.41(m,1H),0.39-0.30(m,2H). LCMS(ESI)m / z: 568.2 [M+H] + ,HPLC Method B: R T =7.64min,purity>86.5%. Compound 57b (12.4 mg, 21.84 μmol); SFC retention time t = 4.956 min. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),7.83(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.91(d,J=8.8Hz,2H), 5.74-5.64(m,1H),5.29(s,1H),5.00(dd,J=10.2,1.6Hz,1H),4.89(dd,J=17.2,1.6Hz,1H),4.64(dd,J=17.2 ,1.6Hz,2H),3.09(t,J=4.8Hz,4H),2.89-2.79(m,2H),2.71-2.64(m,1H),2.58(t,J=5.0Hz,4H),2.29-2.21( m,1H),1.14-1.07(m,1H),1.02(s,3H),1.00(s,3H),0.70-0.64(m,1H),0.47-0.41(m,1H),0.39-0.31(m,2H). LCMS(ESI)m / z: 568.2 [M+H] + ,HPLC Method B: RT =7.63min,purity>88.6%.

[0105] Example 58: Synthesis of Compound 58 TIFF2025525290000109.tif58170<Step 1: Synthesis of Compounds 58a & 58b> Substrate 53-2 (40 mg, 86.30 μmol) was dissolved in tetrahydrofuran (2 mL) in a dry one-neck flask. Metachloroperbenzoic acid (37.23 mg, 215.76 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (111.54 mg, 863.05 μmol) and substrate 28-5 (18.75 mg, 86.30 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 58a (7.25 mg, 9.60 μmol); SFC retention time t = 3.125 min. 1 H NMR(400MHz,DMSO-d6)δ 10.09(s,1H),8.81(s,1H),7.94-7.88(m,2H),7.52(s,2H),6.64(d,J=8.4Hz,1H),6.02(s,1H),5. 69-5.59(m,1H),4.96(d,J=9.6Hz,1H),4.80-4.76(m,2H),4.61-4.56(m,1H),3.30(s,2H),3.06(d ,J=8.8Hz,2H),2.99-2.88(m,3H),2.57(t,J=8.4Hz,2H),2.46(s,1H),2.39(d,J=7.6Hz,2H),2.22 (s,3H),1.23(s,1H),1.02-0.97(m,1H),0.74-0.71(m,1H),0.59-0.54(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 633.3 [M+H] + ,HPLC Method B: R T =10.11min,purity>83.8%. Compound 58b (6.7mg, 8.65μmol); SFC retention time t=4.825min. 1 H NMR(400MHz,DMSO-d6)δ 10.09(s,1H),8.81(s,1H),7.94-7.88(m,2H),7.53-7.37(m,2H),6.64(d,J=8.4Hz,1H),6.02(s,1H),5.69-5.59(m,1H),4.96(d,J=9.6Hz, 1H),4.80-4.76(m,2H),4.61-4.56(m,1H),3.30(s,2H),3.06(d,J=8.8Hz,2H),2.99-2.88(m,3H),2.59(t,J=8.4Hz,2H),2.47-2.41(m,3H), 2.24(s,3H),1.26-1.23(m,2H),1.03-0.97(m,1H),0.74-0.71(m,1H),0.59-0.54(m,1H),0.23-0.19(m,1H). LCMS(ESI)m / z: 633.2 [M+H] + ,HPLC Method B: R T =10.14min,purity>81.7%.

[0106] Example 59: Synthesis of Compound 59 TIFF2025525290000110.tif67170<Step 1: Synthesis of Compound 59-2> Substrate 59-1 (66 mg, 301.04 μmol) was added to a dry one-neck flask and dissolved in acetone (2 mL). 1-Fluoro-2-iodoethane (57 mg, 327.67 μmol) and potassium carbonate (58 mg, 419.68 μmol) were added, and the mixture was heated at 50 °C for 6 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 59-2 (55 mg, 207.33 μmol). LCMS (ESI) m / z: 266.2 [M+H] + . <Step 2: Synthesis of Compound 59-3> Substrate 59-2 (55 mg, 207.33 μmol) was added to a dry one-neck flask and dissolved in methanol (5 mL). Palladium / carbon (10 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 59-3 (30 mg, 127.50 μmol). LCMS (ESI) m / z: 236.2 [M+H] + . <Step 3: Synthesis of Compounds 59a & 59b> Substrate 6-4 (30 mg, 73.26 μmol) was dissolved in tetrahydrofuran (2 mL) in a dry one-neck flask. Metachloroperbenzoic acid (22.76 mg, 131.87 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (54.67 mg, 423.03 μmol) and substrate 59-3 (30 mg, 127.50 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was further purified by supercritical fluid chromatography to give compound 59a (10.8 mg, 16.54 μmol); SFC retention time t = 3.435 min. 1H NMR(400MHz,Chloroform-d)δ 8.81(s,1H),7.68-7.57(m,2H),7.49-7.47(m,2H),6.73(d,J=8.8Hz,2H),5.77-5.68(m,1H),5.08-5.06 (m,1H),5.01-4.96(m,1H),4.79-4.57(m,4H),4.03-4.02(m,2H),3.68(d,J=11.2Hz,2H),3.45(d,J=11.2 Hz,2H),3.34(s,1H),3.02-2.94(m,1H),2.89-2.76(m,4H),2.36-2.28(m,1H),1.73(d,J=8.8Hz,1H),1.5 5(s,3H),1.29-1.24(m,2H),1.03-0.99(m,1H),0.88-0.84(m,1H),0.44-0.39(m,1H),0.25-0.20(m,1H). LCMS(ESI)m / z: 597.2 [M+H] + ,HPLC Method B: R T =7.95min,purity>91.4%. Compound 59b (13.6 mg, 22.22 μmol); SFC retention time t = 4.794 min. 1 H NMR(400MHz,Chloroform-d)δ 8.81(s,1H),7.67(d,J=8.4Hz,1H),7.58(d,J=8.0Hz,1H),7.48-7.47(m,2H),6.73(d,J=8.8Hz,2H),5.77-5.68( m,1H),5.08-5.05(m,1H),5.01-4.96(m,1H),4.79-4.54(m,4H),3.98(d,J=4.0Hz,2H),3.67(d,J=11.2Hz,2H),3 .43(d,J=11.2Hz,2H),3.34(s,1H),3.02-2.95(m,1H),2.85-2.73(m,4H),2.36-2.28(m,1H),1.70(d,J=8.8Hz,1 H),1.54(s,3H),1.29-1.24(m,2H),1.03-0.99(m,1H),0.88-0.83(m,1H),0.44-0.39(m,1H),0.25-0.22(m,1H). LCMS(ESI)m / z: 597.2[M+H] + ,HPLC Method B: R T=7.96min,purity>97.5%.

[0107] Example 60: Synthesis of Compound 60 TIFF2025525290000111.tif71170<Step 1: Synthesis of Compounds 60a & 60b> Substrate 6-4 (30 mg, 73.26 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (22.76 mg, 131.87 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (54.67 mg, 423.03 μmol) and substrate 60-1 (35 mg, 147.48 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 60a (8.16 mg, 11.67 μmol). 1 H NMR(400MHz,Chloroform-d)δ 8.81(s,1H),7.66-7.58(m,2H),7.46(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),5.77-5.67(m,1H), 5.15-4.96(m,3H),4.80-4.63(m,2H),4.00-3.94(m,1H),3.76(d,J=12.0Hz,1H),3.35(s,1H),3.0 3-2.76(m,4H),2.48(s,6H),2.40-2.28(m,2H),2.22-2.12(m,1H),1.95-1.92(m,2H),1.54(s,3H) ),1.30-1.25(m,1H),1.02-1.00(m,1H),0.88-0.83(m,1H),0.44-0.39(m,1H),0.26-0.21(m,1H). LCMS(ESI)m / z: 599.2 [M+H] + ,HPLC Method B: R T =7.91min,purity>85.6%. Compound 60b (2 mg, 2.84 μmol). 1H NMR(400MHz,Chloroform-d)δ 8.82(s,1H),7.65-7.58(m,2H),7.48(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),5.77-5.67(m,1H),5.08-5 .06(m,1H),5.00-4.96(m,1H),4.90-4.61(m,3H),3.96-3.90(m,1H),3.63-3.60(m,1H),3.30(s,1H),3. 03-2.95(m,1H),2.88-2.70(m,4H),2.52(s,6H),2.32-2.29(m,1H),2.06(s,1H),1.80-1.70(m,1H),1.5 5(s,3H),1.31-1.25(m,2H),1.03-0.98(m,1H),0.88-0.83(m,1H),0.44-0.40(m,1H),0.26-0.21(m,1H). LCMS(ESI)m / z: 599.2 [M+H] + ,HPLC Method B: R T =8.26min,purity>85.1%.

[0108] Example 61: Synthesis of Compound 61 TIFF2025525290000112.tif113170<Step 1: Synthesis of Compound 61-2> Substrate 61-1 (0.5 g, 1.97 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (10 mL). Then, para-2-fluoro-5-nitrotoluene (304.93 mg, 1.97 mmol) and potassium carbonate (543.33 mg, 3.93 mmol) were added, and the reaction was carried out at 80 °C for 16 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 61-2 (740 mg, 1.90 mmol). LCMS (ESI) m / z: 390.2 [M+H] + . <Step 2: Synthesis of Compound 61-3> In a dry one-neck flask, substrate 61-2 (740 mg, 1.90 mmol) was added and dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added and the mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 9. The aqueous phase was then extracted four times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 61-3 (550 mg, 1.90 mmol). LCMS (ESI) m / z: 290.2 [M+H] + .

[0109] <Step 3: Synthesis of Compound 61-4> Substrate 61-3 (550 mg, 1.90 mmol) was added to a dry one-neck flask and dissolved in methanol (15 mL). Acetic acid (3 mL) and aqueous formaldehyde (1.91 g, 20.73 mmol, 37%) were added and stirred at room temperature for 1 hour. Sodium cyanoborohydride (260.60 mg, 4.15 mmol) was then added and the mixture was allowed to react at room temperature for 18 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The aqueous phase was then extracted four times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 61-4 (400 mg, 1.32 mmol). LCMS (ESI) m / z: 304.2 [M+H] + . <Step 4: Synthesis of Compound 61-5> Substrate 61-4 (400 mg, 1.32 mmol) was added to a dry one-neck flask and dissolved in methanol (10 mL). Palladium on carbon (50 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 16 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 61-5 (340 mg, 1.24 mmol). LCMS (ESI) m / z: 274.4 [M+H] + . <Step 5: Synthesis of Compounds 61a & 61b> Substrate 34-5 (33.35 mg, 84.12 μmol) was dissolved in tetrahydrofuran (3 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.74 mg, 151.42 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (108.72 mg, 841.21 μmol) and substrate 61-5 (46 mg, 168.24 μmol) were then added and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 61a (8.1 mg, 11.75 μmol); SFC retention time t = 3.216 min. 1 H NMR(600MHz,DMSO-d6)δ 10.13(s,1H),8.83(s,1H),7.81(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.65(s,1H),7.43-7.42(m,1H),7.0 1(d,J=8.4Hz,1H),5.70-5.64(m,1H),5.29(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.77-4.5 7(m,2H),2.90-2.82(m,2H),2.75(t,J=5.4Hz,4H),2.32(s,4H),2.26-2.22(m,4H),2.18(s,3H),1.55(t,J=5 .4Hz,4H),1.51(t,J=5.4Hz,4H),1.16-1.09(m,1H),0.69-0.66(m,1H),0.44-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 622.4 [M+H] + ,HPLC Method B: R T =9.98min,purity >90.2%. Compound 61b (7.9mg, 11.60μmol); SFC retention time t=5.557min. 1H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.83(s,1H),7.81(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.65(s,1H),7.43-7.42(m,1H),7.0 1(d,J=8.4Hz,1H),5.70-5.64(m,1H),5.30(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.73-4.5 8(m,2H),2.90-2.81(m,2H),2.75(t,J=5.4Hz,4H),2.34(s,4H),2.27-2.22(m,4H),2.19(s,3H),1.55(t,J=5 .4Hz,4H),1.51(t,J=5.4Hz,4H),1.16-1.09(m,1H),0.69-0.66(m,1H),0.44-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 622.4 [M+H] + ,HPLC Method B: R T =10.05min,purity >91.3%.

[0110] Example 62: Synthesis of Compounds 62a and 62b TIFF2025525290000113.tif113170<Step 1: Synthesis of Compound 62-1> Substrate 61-1 (0.5 g, 1.97 mmol) was added to a dry one-neck flask and dissolved in dimethyl sulfoxide (10 mL). 3,4-Difluoronitrobenzene (312.72 mg, 1.97 mmol) and potassium carbonate (326.00 mg, 2.36 mmol) were then added and the mixture was reacted at 80 °C for 16 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 62-1 (730 mg, 1.86 mmol). LCMS (ESI) m / z: 394.2 [M+H] + . <Step 2: Synthesis of Compound 62-2> In a dry one-neck flask, substrate 62-1 (730 mg, 1.86 mmol) was added and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added and the mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 9. The aqueous phase was then extracted four times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 62-2 (540 mg, 1.84 mmol). LCMS (ESI) m / z: 294.1 [M+H] + .

[0111] <Step 3: Synthesis of Compound 62-3> Substrate 62-2 (540 mg, 1.84 mmol) was added to a dry one-neck flask and dissolved in methanol (15 mL). Acetic acid (3 mL) and aqueous formaldehyde (1.73 g, 18.75 mmol, 37%) were added and stirred at room temperature for 1 hour. Sodium cyanoborohydride (235.66 mg, 3.75 mmol) was then added and the mixture was allowed to react at room temperature for 18 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The aqueous phase was then extracted four times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 62-3 (500 mg, 1.63 mmol). LCMS (ESI) m / z: 308.1 [M+H] + . <Step 4: Synthesis of Compound 62-4> Substrate 62-3 (500 mg, 1.63 mmol) was added to a dry one-neck flask and dissolved in methanol (10 mL). Palladium / carbon (60 mg) was then added and the mixture was reacted under a hydrogen atmosphere at room temperature for 16 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 62-4 (450 mg, 1.62 mmol). LCMS (ESI) m / z: 278.4 [M+H] + . <Step 5: Synthesis of Compounds 62a & 62b> Substrate 34-5 (33.34 mg, 84.09 μmol) was dissolved in tetrahydrofuran (3 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.73 mg, 151.36 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (108.68 mg, 840.91 μmol) and substrate 62-4 (46.65 mg, 168.18 μmol) were then added and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 62a (6.0 mg, 8.32 μmol); SFC retention time t = 3.230 min. 1 H NMR(600MHz,DMSO-d6)δ 10.31(s,1H),8.87(s,1H),7.81(d,J=8.4Hz,1H),7.75-7.66(m,2H),7.39(d,J=8.4Hz,1H),7..04-7.01 (m,1H),5.72-5.63(m,1H),5.30(s,1H),5.00(dd,J=10.2,1.8Hz,1H),4.89(dd,J=17.4,1.8Hz,1H),4.74 -4.57(m,2H),2.92(t,J=5.4Hz,4H),2.88-2.80(m,2H),2.35-2.23(m,5H),2.18(s,3H),1.56(t,J=5.4Hz ,4H),1.49(t,J=5.4Hz,4H),1.13-1.10(m,1H),0.68-0.66(m,1H),0.45-0.43(m,1H),0.39-0.33(m,2H). LCMS(ESI)m / z: 626.2 [M+H] + ,HPLC Method B: R T =9.55min,purity >86.8%. Compound 62b (6.2mg, 8.76μmol); SFC retention time t=5.103min. 1H NMR(600MHz,DMSO-d6)δ 10.31(s,1H),8.87(s,1H),7.81(d,J=8.4Hz,1H),7.75-7.66(m,2H),7.39(d,J=8.4Hz,1H),7.04-7.01( m,1H),5.72-5.63(m,1H),5.30(s,1H),5.00(dd,J=10.2,1.8Hz,1H),4.89(dd,J=17.4,1.8Hz,1H),4.74- 4.58(m,2H),2.92(t,J=5.4Hz,4H),2.88-2.81(m,2H),2.33-2.23(m,5H),2.16(s,3H),1.56(t,J=5.4Hz ,4H),1.49(t,J=5.4Hz,4H),1.13-1.10(m,1H),0.68-0.66(m,1H),0.45-0.43(m,1H),0.40-0.33(m,2H). LCMS(ESI)m / z: 626.2 [M+H] + ,HPLC Method B: R T =9.50min,purity >88.4%.

[0112] Example 63: Synthesis of Compounds 63a and 63b TIFF2025525290000114.tif64170<Step 1: Synthesis of Compounds 63a & 63b> Substrate 34-5 (33.33 mg, 83.99 μmol) was dissolved in tetrahydrofuran (3 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.69 mg, 151.18 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (108.55 mg, 839.88 μmol) and substrate 28-5 (36.50 mg, 167.98 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 63a (6.9 mg, 10.11 μmol); SFC retention time t = 3.357 min. 1H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.81(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.55(s,2H),6.64(d,J=8 .4Hz,2H),5.72-5.63(m,1H),5.28(s,1H),5.04-4.96(m,1H),4.89(d,J=17.4Hz,1H),4.82-4.54(m ,2H),3.11-3.03(m,2H),2.92-2.79(m,4H),2.66-2.57(m,2H),2.53-2.50(m,2H),2.46-2.39(m,2 H),2.29-2.21(m,4H),1.13-1.10(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 566.4 [M+H] + ,HPLC Method B: R T =7.83min,purity >82.9%. Compound 63b (6.8 mg, 10.53 μmol); SFC retention time t = 5.596 min. 1 H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.81(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.55(s,2H),6.64(d,J=8.4H z,2H),5.72-5.63(m,1H),5.29(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.76-4.58(m, 2H),3.07(d,J=8.4Hz,2H),2.93-2.81(m,4H),2.62(d,J=7.2Hz,2H),2.52-2.59(m,2H),2.47-2.38(m ,2H),2.29-2.21(m,4H),1.13-1.10(m,1H),0.69-0.66(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 566.4 [M+H] + ,HPLC Method B: R T =7.78min,purity >87.6%.

[0113] Example 64: Synthesis of Compounds 64a and 64b TIFF2025525290000115.tif58170<Step 1: Synthesis of Compounds 64a & 64b> Substrate 21-3 (40 mg, 94.44 μmol) was dissolved in tetrahydrofuran (1 mL) in a dry one-neck flask. Metachloroperbenzoic acid (29.34 mg, 170.00 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (122.06 mg, 944.44 μmol) and substrate 7-5 (38.40 mg, 188.89 μmol) were then added and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 64a (10.1 mg, 17.45 μmol); SFC retention time t = 2.944 min. 1H NMR (600 MHz, DMSO-d6) δ 10.06(s,1H),8.79(s,1H),7.77(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7. 60(s,2H),6.71(d,J=8.4Hz,2H),5.72-5.63(m,1H),5.00(d,J=10.2Hz,1H) ,4.85(d,J=17.4Hz,1H),4.75(s,1H),4.61(d,J=16.2Hz,1H),4.40(s,1H), 3.84(s,2H),3.64-3.55(m,2H),3.44(d,J=10.8Hz,2H),3.27(d,J=10.8Hz,2 H),2.95-2.89(m,1H),2.86-2.80(m,1H),2.42(d,J=17.4Hz,1H),2.35-2.2 9(m,1H),2.00(s,3H),1.92(dd,J=14.4,7.2Hz,1H),1.75(dd,J=14.4,7.2H z,1H),1.54(d,J=8.4Hz,1H),1.15-1.11(m,1H),0.93(t,J=7.2Hz,3H),0.8 7-0.85(m,1H),0.64-0.57(m,1H),0.42-0.36(m,1H),0.00(d,J=3.5Hz,1H). LCMS (ESI) m / z: 579.4 [M+H] + ,HPLC Method B: R T =9.34min,purity>86.7%. Compound 64b (8.7 mg, 15.03 μmol); SFC retention time t = 4.409 min. 1H NMR(600MHz,DMSO-d6)δ 10.06(s,1H),8.79(s,1H),7.77(s,1H),7.69(d,J=8.4Hz,1H),7.60(s,2H),6.71(d,J=8.4Hz,2H),5.72-5.63(m,1H),5.04-4.97(m,1H), 4.85(d,J=17.4Hz,1H),4.74(s,1H),4.66-4.54(m,1H),4.40(s,1H),3.58(d,J=6.0Hz,2H),3.43(d,J=10.8Hz,2H),3.27(d,J=10.8Hz,2H ),2.95-2.89(m,1H),2.87-2.81(m,1H),2.46-2.40(m,1H),2.35-2.29(m,1H),1.99(s,3H),1.96-1.90(m,1H),1.75(dd,J=14.4,7.2Hz,1 H),1.53(d,J=8.4Hz,1H),1.15-1.11(m,1H),0.93(t,J=7.2Hz,3H),0.87-0.84(m,1H),0.64-0.57(m,1H),0.42-0.36(m,1H),0.00(s,1H). LCMS(ESI)m / z: 579.4 [M+H] + ,HPLC Method B: R T =9.25min,purity>91.1%.

[0114] "Example 65: Synthesis of Compound 65" TIFF2025525290000116.tif58170<Project 1: Synthesis of Compounds 65a&65b> Substrate 6-4 (40 mg, 97.68 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (30.34 mg, 175.82 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (126.24 mg, 976.79 μmol) and substrate 12-1 (42.85 mg, 195.36 μmol) were then added to the reaction mixture and the mixture was allowed to react at 50 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 65a (14.3 mg, 24.62 μmol); SFC retention time t = 3.425 min. 1 H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),7.78(s,1H),7.69(d,J=8.4Hz,1H),7.56(s,2H),6.93(d,J=8.4Hz,2H),5.70-5.62(m,1H),4.99(dd,J =10.2,1.8Hz,1H),4.89-4.84(m,1H),4.83-4.73(m,1H),4.69(s,1H),4.64(dd,J=16.2,6.0Hz,1H),3.66(d,J=12.0Hz,2H),2.93 -2.86(m,1H),2.83-2.77(m,1H),2.67-2.59(m,2H),2.19(s,6H),2.18(d,J=3.6Hz,1H),2.03-1.96(m,1H),1.83(d,J=12.0Hz,2H) ),1.52-1.45(m,2H),1.45-1.42(m,1H),1.40(s,3H),0.91-0.84(m,1H),0.68-0.60(m,1H),0.35-0.30(m,1H),0.23-0.18(m,1H). LCMS(ESI)m / z: 581.4 [M+H] + ,HPLC Method B: R T =8.79min,purity>93.5%. Compound 65b (15.6mg, 26.86μmol); SFC retention time t=5.024min. 1H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),7.78(d,J=7.8Hz,1H),7.69(d,J=8.4Hz,1H),7.64-7.41(m,2H),6.93(d,J=8.4Hz,2H),5.70-5.62(m,1H) ,4.99(d,J=10.2Hz,1H),4.86(d,J=17.4Hz,1H),4.81(d,J=15.6Hz,1H),4.69(s,1H),4.64(dd,J=16.2,6.0Hz,1H),3.66(d,J=12.0Hz ,2H),2.93-2.86(m,1H),2.83-2.77(m,1H),2.67-2.59(m,2H),2.20(s,6H),2.19-2.13(m,1H),1.96(m,1H),1.86-1.81(m,2H),1.48 (dd,J=11.8,3.7Hz,2H),1.45-1.42(m,1H),1.41(s,3H),0.91-0.84(m,1H),0.67-0.60(m,1H),0.35-0.30(m,1H),0.23-0.18(m,1H). LCMS(ESI)m / z: 581.4 [M+H] + ,HPLC Method B: R T =8.86min,purity>93.6%.

[0115] "Example 66: Synthesis of Compound 66" TIFF2025525290000117.tif58170<Project 1: Synthesis of Compounds 66a&66b> Substrate 34-5 (40 mg, 100.89 μmol) was dissolved in tetrahydrofuran (1 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.72 mg, 151.33 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (65.19 mg, 504.43 μmol) and substrate 12-1 (33.19 mg, 151.33 μmol) were then added and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 66a (12.12 mg, 21.35 μmol); SFC retention time t = 3.579 min. 1 H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.81(d,J=3.6Hz,1H),7.83(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.98-6.90(m,2H) ),5.73-5.63(m,1H),5.30(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.69(s,1H),4.65-4.56(m,1H) ),3.66(d,J=12.0Hz,2H),3.04(s,1H),2.87-2.78(m,2H),2.65-2.59(m,2H),2.29-2.20(m,1H),2.19(s,6H),1. 88-1.80(m,2H),1.53-1.44(m,2H),1.13-1.09(m,1H),0.71-0.62(m,1H),0.45-0.42(m,1H),0.39-0.32(m,2H). LCMS(ESI)m / z: 568.2 [M+H] + ,HPLC Method B: R T =7.48min,purity >86.1%. Compound 66b (12.56mg, 22.12μmol); SFC retention time t=5.858min. 1H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.81(s,1H),7.83(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.58(s,2H),6.92(d,J=8.4Hz,2H), 5.73-5.63(m,1H),5.29(s,1H),5.00(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4.69(s,1H),4.65-4.54(m,1H) ),3.66(d,J=12.0Hz,2H),3.07(s,1H),2.87-2.79(m,2H),2.65-2.59(m,2H),2.29-2.20(m,1H),2.19(s,6H) ,1.82(s,2H),1.53-1.44(m,2H),1.13-1.10(m,1H),0.71-0.62(m,1H),0.45-0.42(m,1H),0.39-0.32(m,2H). LCMS(ESI)m / z: 568.2 [M+H] + ,HPLC Method B: R T =7.50min,purity >89.5%.

[0116] Example 67: Synthesis of Compound 67 TIFF2025525290000118.tif64170<Step 1: Synthesis of Compound 67> Substrate 4-9 (20 mg, 50.57 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (15.4 mg, 75.86 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (65.15 mg, 0.51 mmol) and substrate 67-1 (16.48 mg, 75.86 μmol) were then added to the reaction mixture and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 67 (6.8 mg, 12.02 μmol). 1H NMR(600MHz,DMSO-d6)δ 10.18(s,1H),8.85(s,1H),7.80(d,J=8.4Hz,1H),7.77-7.62(m,2H),7.46(d,J=8.4Hz,1H),7.34(d,J= 9.0Hz,1H),5.71-5.65(m,1H),5.33(d,J=5.4Hz,1H),5.01(d,J=10.2Hz,1H),4.89(d,J=17.4Hz,1H),4 .71-4.62(m,2H),3.75(d,J=4.8Hz,1H),3.65-3.65(m,2H),3.23-3.02(m,4H),2.86-2.80(m,2H),2.52 (s,3H),2.33-2.21(m,6H),1.14-1.10(m,1H),0.70-0.66(m,1H),0.45-0.42(m,1H),0.39-0.34(m,2H). LCMS(ESI)m / z: 565.2 [M+H] + ,HPLC Method B: R T =8.22min,purity >87.8%.

[0117] Example 68: Synthesis of Compound 68 TIFF2025525290000119.tif58170<Step 1: Synthesis of Compounds 68a & 68b> Substrate 4-9 (40 mg, 101.14 μmol) was dissolved in tetrahydrofuran (1 mL) in a dry one-neck flask. Metachloroperbenzoic acid (30.80 mg, 151.72 μmol) was then added and the mixture was incubated at room temperature for 1 hour. N,N-Diisopropylethylamine (65.36 mg, 505.72 μmol) and substrate 40-3 (31.15 mg, 151.72 μmol) were then added and the mixture was incubated at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 68a (10.48 mg, 518.96 μmol); SFC retention time t = 3.121 min. 1H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.81(s,1H),7.83(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.64-7.46(m,2H),6.92(d,J=8.4Hz,2H),5.69- 5.64(m,6.0Hz,1H),5.32(d,J=5.4Hz,1H),5.03-4.98(m,1H),4.91-4.85(m,1H),4.69(s,1H),4.63-4.60(m,5.4Hz,1H),3 .75(d,J=5.4Hz,1H),3.47(d,J=13.2Hz,2H),2.88-2.80(m,3H),2.71-2.70(m,1H),2.35-2.33(m,1H),2.27-2.23(m,2H), 2.22(s,3H),2.17-2.11(m,1H),1.13-1.11(m,1H),1.06(s,3H),0.70-0.66(m,1H),0.46-0.42(m,1H),0.39-0.35(m,2H). LCMS(ESI)m / z: 553.3 [M+H] + ,HPLC Method B: R T =7.23min,purity >96.1%. Compound 68b (12.34 mg, 22.33 μmol); SFC retention time t = 5.185 min. 1H NMR(600MHz,DMSO-d6)δ 10.12(s,1H),8.81(s,1H),7.84(d,J=8.4Hz,1H),7.75-7.67(m,1H),7.59(s,2H),6.92(d,J=8.4Hz,2H),5.69-5 .66(m,1H),5.31(d,J=5.4Hz,1H),5.05-4.96(m,1H),4.94-4.87(m,1H),4.69(s,1H),4.62-4.60(m,1H),3.75(d, J=5.4Hz,1H),3.48-3.45(m,2H),2.86-2.81(m,3H),2.74-2.69(m,1H),2.36-2.34(m,1H),2.29-2.23(m,2H),2. 22(s,3H),2.15(s,1H),1.14-1.10(m,1H),1.06(s,3H),0.69-0.67(m,1H),0.44-0.42(m,1H),0.39-0.36(m,2H). LCMS(ESI)m / z: 553.3 [M+H] + ,HPLC Method B: R T =7.24min,purity >94.1%.

[0118] Example 69: Synthesis of Compound 69 TIFF2025525290000120.tif64170<Step 1: Synthesis of Compounds 69a & 69b> Substrate 21-3 (40 mg, 94.44 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (28.76 mg, 141.67 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (61.03 mg, 472.22 μmol) and substrate 11-1 (36.75 mg, 141.67 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product, which was then chirally resolved by supercritical fluid chromatography to give compound 69a (1.1 mg, 1.73 μmol); SFC retention time t = 3.897 min. 1H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.81(d,J=4.2Hz,1H),7.79(s,1H),7.67(d,J=8.4Hz,1H),7.57(s,2H),6.92(d,J=9.0Hz,2H),5.74-5.62(m,1H),4 .99(dd,J=10.2,1.8Hz,1H),4.85(d,J=17.4Hz,1H),4.74(s,1H),4.62(s,1H),4.40(d,J=4.2Hz,1H),3.09(s,4H),2.98-2.89(m,1 H),2.84(dd,J=17.4,6.0Hz,1H),2.36-2.29(m,4H),2.18(s,3H),1.94-1.89(m,1H),1.75(dd,J=14.4,7.2Hz,1H),1.54(t,J=5.4 Hz,4H),1.47(t,J=5.4Hz,4H),0.93(t,J=7.2Hz,3H),0.87-0.84(m,2H),0.78-0.73(m,2H),0.64-0.58(m,1H),0.43-0.37(m,1H). LCMS(ESI)m / z: 635.4 [M+H] + ,HPLC Method B: R T =7.07min,purity >83.2%. Compound 69b (1.0 mg, 1.58 μmol); SFC retention time t = 5.463 min. 1H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.81(d,J=4.3Hz,1H),7.79(s,1H),7.67(d,J=8.2Hz,1H),7.57(s,2H),6.92(d,J=9.0Hz,2H),5.74-5.62(m,1H),4. 99(dd,J=10.2,1.8Hz,1H),4.85(d,J=17.4Hz,1H),4.74(s,1H),4.61(s,1H),4.40(d,J=4.8Hz,1H),3.13-3.06(m,4H),2.98-2.89( m,1H),2.84(dd,J=16.8,6.0Hz,1H),2.38-2.29(m,4H),2.20(s,3H),1.93-1.89(m,1H),1.75(dd,J=14.4,7.2Hz,1H),1.54(t,J=5. 4Hz,4H),1.48(t,J=5.4Hz,4H),0.93(d,J=7.2Hz,3H),0.87-0.84(m,2H),0.78-0.73(m,2H),0.64-0.58(m,1H),0.43-0.37(m,1H). LCMS(ESI)m / z: 635.4 [M+H] + ,HPLC Method B: R T =7.08min,purity >80.1%.

[0119] Example 70: Synthesis of Compound 70 TIFF2025525290000121.tif58170<Step 1: Synthesis of Compound 70> Substrate 34-5 (68.41 mg, 172.55 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (3 mL). Metachloroperbenzoic acid (59.55 mg, 345.10 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (111.50 mg, 862.75 μmol) and substrate 70-1 (65.67 mg, 345.10 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (basic) to give compound 70 (43.75 mg, 90.97 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.87(s,1H),7.82(d,J=8.4Hz,1H),7.75-7.63(m,3H),7.27-7 .12(m,2H),5.74-5.61(m,1H),5.30(s,1H),5.02-4.99(m,1H),4.91-4.87(m ,1H),4.64-4.51(m,2H),3.22(s,3H),2.93-2.78(m,2H),2.68-2.51(m,5H),2.31-2.20(m,1H),1.88(d,J=1 3.2Hz,2H),1.71-1.69(m,2H),1.13-1.10(m,1H),0.70-0.67(m,1H),0.47-0.40(m,1H),0.39-0.31(m,2H). LCMS(ESI)m / z: 539.2 [M+H] + ,HPLC Method B: R T =6.88min,purity >97.1%.

[0120] Example 71: Synthesis of Compound 71 TIFF2025525290000122.tif71170<Step 1: Synthesis of Compound 71-2> Substrate 71-1 (2.5 g, 9.54 mmol), potassium carbonate (5.27 g, 38.16 mmol), and benzyltriethylammonium chloride (217.34 mg, 0.95 mmol) were added to a one-neck flask, and then acetonitrile (30 mL) was added to dissolve the mixture. After the solution turned yellow, 3-bromopropane (1.58 g, 14.31 mmol) was added and the mixture was stirred at 80 °C for 48 h. The reaction mixture was monitored by LC-MS. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and washed with ethyl acetate. Ethyl acetate and water were added to the filtrate, followed by extraction with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was further recrystallized from petroleum ether and dichloromethane, filtered, and dried under vacuum to obtain the following: Compound 71-2 (2.00 g, 6.57 mmol), LCMS (ESI) m / z: 205.0 [M+H-100]. + . <Step 2: Synthesis of Compound 71-3> Substrate 71-2 (2.00 g, 6.57 mmol) was added to a dry one-neck flask and dissolved in ethanol (40 mL). Hydrazine monohydrate (10 mL) was then added and the mixture was heated at 50 °C for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, washed three times with ethanol, concentrated under reduced pressure, and the residue was dissolved in water and ethyl acetate. Extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 71-3 (1.1 g, 6.31 mmol). LCMS (ESI) m / z: 160.2 [M+H-56+41]. + . <Step 3: Synthesis of Compound 71-5> Substrate 71-3 (1.1 g, 6.31 mmol) and ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (71-4, 1.40 g, 6.01 mmol) were added to a dry one-neck flask and dissolved in tetrahydrofuran (20 mL). N,N-diisopropylethylamine (1.94 g, 15.03 mmol) was then added and the mixture was heated at 80 °C for 16 hours. LC-MS monitoring was performed. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was then dissolved in ethyl acetate and washed five times with 1 M dilute hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 71-5 (2.15 g, 5.81 mmol). LCMS (ESI) m / z: 371.2 [M+H]. + . <Step 4: Synthesis of Compound 71-6> Substrate 71-5 (2.15 g, 5.81 mmol) was added to a dry one-neck flask and dissolved in dichloromethane (30 mL). After cooling in an ice bath, trifluoroacetic acid (10 mL) was added and the reaction was continued at 45 °C for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to 0 °C in an ice bath, and 40% aqueous sodium hydroxide solution was slowly added until the pH was 11. Methanol (30 mL) was then added, and the reaction was continued at room temperature for 6 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic phase. 3 M diluted hydrochloric acid was then added until the pH was 1. A yellow precipitate was formed, which was filtered and washed twice with water. The solid was dried under vacuum to give compound 71-6 (785.00 mg, 3.50 mmol). LCMS (ESI) m / z: 225.2 [M+H] + . <Step 5: Synthesis of Compound 71-7> Substrate 4-8 (183.6 mg, 875.66 μmol), substrate 71-6 (206.21 mg, 919.44 μmol), cuprous iodide (166.77 mg, 875.66 μmol), sodium iodide (262.50 mg, 1.75 mmol), potassium carbonate (302.56 mg, 2.19 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (249.11 mg, 1.75 mmol) were added to a dry sealed tube, followed by anisole (4 mL). The mixture was heated at 110 °C for 18 h under a nitrogen atmosphere and monitored by TLC until completion. The reaction mixture was cooled to room temperature, filtered, and washed twice with ethyl acetate. The filtrate was washed twice with aqueous ammonia and twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 71-7 (132 mg, 332.08 μmol). LCMS (ESI + ) m / z: 398.1 [M+H] + . <Step 6: Synthesis of Compound 77> Substrate 71-7 (132 mg, 332.08 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (5 mL). Metachloroperbenzoic acid (85.96 mg, 498.12 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (214.59 mg, 1.66 mmol) and substrate 11-1 (172.28 mg, 664.16 μmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (basic) to give compound 71 (75.15 mg, 123.45 μmol). 1 H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),8.74(s,1H),7.83(d,J=8.4Hz,1H),7.63-7.45(m,3H),6.88(d,J=9.2Hz,2H),5.24( d,J=5.2Hz,1H),4.23-4.11(m,1H),3.72(d,J=5.2Hz,1H),3.07(t,J=5.6Hz,4H),2.92-2.75(m,2H) ,2.35-2.20(m,5H),2.16(s,3H),1.53(t,J=5.6Hz,4H),1.46(t,J=5.6Hz,4H),1.31(d,J=7.2Hz,6 H),1.14-1.06(m,1H),0.72-0.62(m,1H),0.46-0.41(m,1H),0.40-0.34(m,1H),0.33-0.27(m,1H). LCMS(ESI)m / z: 609.3 [M+H] + ,HPLC Method B: R T =7.55min,purity >95.5%.

[0121] Example 72: Synthesis of Compound 72 TIFF2025525290000123.tif71170<Step 1: Synthesis of Compound 72-1> Substrate 71-1 (2.5 g, 9.54 mmol), potassium carbonate (5.27 g, 38.16 mmol), and benzyltriethylammonium chloride (217.34 mg, 0.95 mmol) were added to a single-neck flask, and then acetonitrile (30 mL) was added to dissolve the mixture. After the solution turned yellow, iodomethane (2.71 g, 19.08 mmol) was added and the mixture was stirred at 60 °C for 24 h. The reaction mixture was monitored by LC-MS. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and washed with ethyl acetate. Ethyl acetate and water were added to the filtrate, followed by extraction with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was further recrystallized from petroleum ether and dichloromethane, filtered, and dried under vacuum to obtain the following: Compound 72-1 (1.80 g, 6.51 mmol), LCMS (ESI) m / z: 177.0 [M+H-100]. + . <Step 2: Synthesis of Compound 72-2> Substrate 72-1 (1.80 g, 6.51 mmol) was added to a dry one-neck flask and dissolved in ethanol (30 mL). Hydrazine monohydrate (8 mL) was then added and the mixture was heated at 50 °C for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, washed three times with ethanol, concentrated under reduced pressure, and the residue was dissolved in water and ethyl acetate. Extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 72-2 (0.91 g, 6.20 mmol). LCMS (ESI) m / z: 132.2 [M+H-56+41]. + .

[0122] <Step 3: Synthesis of Compound 72-3> Substrate 72-2 (0.91 g, 6.20 mmol) and ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (1.37 g, 5.90 mmol) were added to a dry one-neck flask and dissolved in tetrahydrofuran (20 mL). N,N-diisopropylethylamine (1.90 g, 14.75 mmol) was then added and the mixture was heated at 80 °C for 16 hours. LC-MS monitoring was performed. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was then dissolved in ethyl acetate and washed five times with 1 M dilute hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 72-3 (1.96 g, 5.71 mmol). LCMS (ESI) m / z: 343.2 [M+H]. + . <Step 4: Synthesis of Compound 72-4> Substrate 72-3 (1.96 g, 5.71 mmol) was added to a dry one-neck flask and dissolved in dichloromethane (20 mL). After cooling in an ice bath, trifluoroacetic acid (80 mL) was added and the reaction was continued at 45 °C for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was cooled to 0 °C in an ice bath, and 40% aqueous sodium hydroxide solution was slowly added until the pH reached 11. Methanol (20 mL) was then added, and the reaction was continued at room temperature for 6 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic phase. 3 M diluted hydrochloric acid was then added until the pH reached 1. A yellow precipitate was formed, which was filtered and washed twice with water. The solid was dried under vacuum to give compound 72-4 (647.00 mg, 3.30 mmol). LCMS (ESI) m / z: 197.2 [M+H] + . <Step 5: Synthesis of Compound 72-5> Substrate 4-8 (101.76 mg, 485.34 μmol), substrate 72-4 (100.00 mg, 509.61 μmol), cuprous iodide (97.05 mg, 509.61 μmol), sodium iodide (153.00 mg, 1.02 mmol), potassium carbonate (175.82 mg, 1.27 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexylenediamine (144.73 mg, 1.02 mmol) were added to a dry sealed tube, followed by anisole (2 mL). The mixture was heated at 110 °C for 18 h under a nitrogen atmosphere and monitored by TLC until completion. The reaction mixture was cooled to room temperature, filtered, and washed twice with ethyl acetate. The filtrate was washed twice with aqueous ammonia and twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 72-5 (36.00 mg, 97.44 μmol). LCMS (ESI + ) m / z: 370.1 [M+H] + . <Step 6: Synthesis of Compound 72> Substrate 72-5 (36.00 mg, 97.44 μmol) was added to a dry one-neck flask and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (33.63 mg, 194.88 μmol) was then added and the mixture was allowed to react at room temperature for 1 hour. N,N-Diisopropylethylamine (125.70 mg, 974.40 μmol) and substrate 11-1 (50.55 mg, 194.88 mmol) were then added to the reaction mixture and the mixture was allowed to react at 45 °C overnight. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (basic) to give compound 72 (10.23 mg, 36.44 μmol). 1H NMR(400MHz,DMSO-d6)δ 10.07(s,1H),8.79(s,1H),7.86(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.57(s,2H),6.92(d,J =9.2Hz,2H),5.30(d,J=5.2Hz,1H),3.75(d,J=5.2Hz,1H),3.38(s,3H),3.09(t,J=5.6Hz,4H),2 .92-2.81(m,2H),2.39-2.27(m,4H),2.19(s,3H),1.54(t,J=5.6Hz,4H),1.48(t,J=5.6Hz,4H), 1.27-1.21(m,1H),1.18-1.10(m,1H),0.70-0.61(m,1H),0.47-0.40(m,1H),0.39-0.32(m,2H). LCMS(ESI)m / z: 581.6 [M+H] + ,HPLC Method B: R T =6.70min,purity >92.9%.

[0123] <Example of effectiveness test: Biological evaluation measurement> Unless otherwise specified, in some biological evaluation experiments in the following examples, the compounds AZD1775 and ZnC3 are used as controls. The structural information of AZD1775 (CAS No. 955365-80-7) and ZnC3 (CAS No. 2376146-48-2) is as follows: TIFF2025525290000124.tif71170

[0124] <Effectiveness Test Example 1: Evaluation of compounds in the binding between Wee1 protein and Tracer 178 using TR-FRET method> First, compound solutions with different concentration gradients were prepared. Compounds were dissolved in DMSO and diluted 4-fold to a final DMSO level of 0.25% in each reaction well, with DMSO added as a positive control (maximum signal control) and a negative control (minimum signal control). Two parallel replicates were set up for each concentration, resulting in a total of 10 dose points. Compounds were prepared at different concentrations in buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35) WEE1 (ThermoFisher, Cat# PR7373A) protein (final reaction concentration 15 nM). The reaction substrates, Tracer 178 (Invitrogen, PV5593) and MAb Anti-GST-Eu crypate (Cisbio, 61GSTKLA) were added to a 384-well plate (Corning, Cat# 3574). The plate was centrifuged at 1000 rpm for 1 min and then incubated on a shaker at 25°C for 60 min at 300 rpm. In this experiment, Tracer 178 and MAb Anti-GST-Eu crypate were prepared in a buffer solution (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35) to give final reaction concentrations of 50 nM for Tracer 178 and 2 nM for MAb Anti-GST-Eu crypate. A negative control (minimum signal control) was used instead of the protein solution using the same amount of buffer. After incubation was complete, the fluorescence signal was read using a BMG PHERAStar reader (using 337 nm as excitation light and 620 and 665 nm as emission light). The fluorescence signal ratio was calculated: 665 / 620 * 1000 was the final enzyme activity signal value. The TR-FRET signal was normalized to the readings obtained from the positive control (maximum signal control) and negative control (minimum signal control), giving the percent inhibition at different concentrations of compound. The IC50 of enzyme activity inhibition was calculated by fitting a log(inhibitor) vs. response-variable slope model using GraphPad Prism 6. The fitting equation is: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)), where Y represents the known percent remaining enzyme activity and X represents the known compound concentration after Log. The Wee1 inhibitory activity of the compounds of the examples was measured according to the above method, and the test results are shown in Table 2. The IC 50 The results were as follows: "-":I C 50 Measurement value exceeds 10 μM, "+":IC 50 Measurement values below 10 μM and above 1 μM, 「++」:IC 50 Measurement values below 1 μM and above 100 nM, 「+++」:IC 50 Measurement values below 100nM and above 10nM, 「++++」:IC 50 Measurement values below 10nM and above 5nM, 「+++++」:IC 50 Measured value is 5nM or less.

[0125] [Table 2] Conclusion: The compounds of the present invention have excellent Wee1 kinase inhibitory activity.

[0126] <Effectiveness Test Example 2: Evaluation of Anti-Cell Proliferation Activity of Compounds> A. Evaluation of the antiproliferative effects of compounds on BxPC3, HT-29, and OVCAR-3 cells by Cell Titer-Glo method Compound solutions with varying concentrations were prepared. Test compounds at 10 mM and the reference compound AZD1775 at 10 mM were dissolved in DMSO. The compounds were serially diluted with culture medium. Two parallel replicates were set up at each concentration, for a total of nine dose points. A compound-free cell growth group served as a positive control (maximum signal control), and culture medium served as a negative control (minimum signal control). The final DMSO concentration in each reaction well was 0.2%. After removing the medium from the 384-well plate, 25 μl of the prepared compounds at different concentrations was transferred to the well plate. The compounds and cells were then cultured at 37°C in a 5% CO2 cell incubator for 3 days. The 384-well plate was removed from the cell incubator and allowed to equilibrate to room temperature for 1 hour. 25 μl of Cell Titer-Glo assay reagent was added to each well, dissolved on a shaker for 2 minutes, and incubated for 10 minutes before reading (Luminescence) using a BMG PHERAStar. Percent inhibition was calculated from the luminescence signal. The IC was calculated using the formula 93 to determine the cell inhibition rate at different concentrations of the compound. 50 was calculated by fitting a log(inhibitor) versus response-variable slope model in GraphPad Prism 6. The fitted equation is: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) Here, Y represents the inhibition rate, and X represents the concentration of the known compound after Log. The results of the in vitro anti-cell proliferation assay of the exemplary compounds on BxPC3, HT-29 and OVCAR-3 cells using the above-mentioned method are shown in Table 3, and the IC 50 was determined and classified as described below: "-":I C 50 Measurement value exceeds 10 μM, "+":IC 50 Measurement values below 10 μM and above 5 μM, 「++」:IC 50 Measurement values below 5 μM and above 2 μM, 「+++」:IC 50 Measurement values below 2 μM and above 1 μM, 「++++」:IC 50 Measurement values below 1 μM or above 0.1 μM, 「+++++」:IC 50 Measurement value is less than 0.1 μM.

[0127] [Table 3] TIFF2025525290000128.tif129170Conclusion: The compounds of the present invention have excellent inhibitory effects on tumor cell proliferation, and the antiproliferative activity data of some compounds are equivalent to or even superior to the control compound AZD1775.

[0128] B. Evaluation of the antiproliferative effects of compounds on normal cells HUVEC and HK2 using Cell Titer-Glo method The antiproliferative activity was evaluated using the same assay as for tumor cells. The results for the two normal cells are shown in Table 4. [Table 4] Conclusion: The compounds of the present invention have weak inhibitory activity against the proliferation of normal HUVEC cells, but have a certain inhibitory effect against HK2 cells. Compared with the control compounds, the compounds of the present invention show almost the same or lower proliferation inhibitory activity and have better safety.

[0129] <Effectiveness Test Example 3: In vitro evaluation of metabolic stability in liver microsomes (mouse and human)> 1. Preparation of Working Solution Microsomes were removed from a -80°C refrigerator, rapidly thawed in a 37°C water bath, and placed on ice before use. Test articles were diluted with DMSO to prepare 10 mM stock solutions, which were then diluted with acetonitrile to prepare 0.5 mM secondary stock solutions. Microsomes were diluted to 0.75 mg / ml with Buffer C. Compounds were then added to the secondary stock solutions to a final concentration of 1.5 μM, based on n=2, 5 time points, to prepare 350 μL of each compound as a working solution, which was then placed on ice before use. NADPH was diluted with Buffer C to prepare a 6 mM working solution as a starter solution. An acetonitrile solution containing an internal standard was prepared as a precipitant, and verapamil-HCl was selected as the internal standard at a concentration of 4 ng / ml. 2. Experimental Procedure: Using a round-bottom well plate designated as the reaction plate, the prepared working solution for each compound was dispensed into the well plate at 30 μL / well depending on the number of replicates and time points (a zero-hour sample was also added to the reaction plate), and the plate was incubated at 37°C for 10 minutes. To a separate plate with pointed wells designated as the precipitation plate, 135 μL of precipitant was added per well. After 10 minutes of incubation, the zero-hour sample was transferred to the plate, and 15 μL of starter solution was added. The precipitation plate was placed on ice before centrifugation. A sufficient amount of diluted starter solution was added to the dispensing plate to facilitate the suction operation of the plate gun. The reaction was performed on a warm incubation shaker, and 15 μL of starter solution / sample was added to the plate using a volumetric lance. The reaction was started by gently shaking to mix, and the time was accurately recorded using a timer. After the reaction time had elapsed, the solution in the plate was aspirated using a displacement gun and added to the precipitation plate, terminating the reaction. After the entire reaction was completed, the plate was shaken at 600 rpm for 10 minutes to precipitate the protein. The mixture was then centrifuged at maximum speed at 4°C for 15 minutes, and 80 μL of the supernatant was removed, mixed with 320 μL of pure water, and subjected to LC-MS analysis. 3. The measurement results are shown in Table 5. [Table 5] Conclusion: The compounds of the present invention all show excellent metabolic stability in liver microsomes of five species.

[0130] <Effectiveness Test Example 4: Solubility Evaluation> The compound was added to the buffer solution and shaken at a constant temperature for 24 hours. The supernatant was prepared as a solution of the test substance at approximately 100 μg / ml, and the solubility was calculated by reversed-phase high-performance liquid chromatography with gradient elution and the external standard method. Chromatographic conditions: C18 column, mobile phase A: 0.02 M potassium dihydrogen phosphate:acetonitrile = 90:10, mobile phase B: acetonitrile, V: 1.0 ml / min, T: 35°C, λ: 210 nm. The measurement results are shown in Table 6. [Table 6] Conclusion: Under the three pH conditions, the solubility of compound 37b of the present invention was close to that of the control compound ZnC3, and overall the solubility of the compounds of the present invention was obviously superior to that of the control compound AZD1775.

[0131] <Effectiveness Test Example 5: Cell Permeability Evaluation> Caco-2 cells were purchased from the American Model Tissue Cell Collection (Rockville, MD). The cell culture medium was modified Eagle's medium (MEM) containing 10% inactivated fetal bovine serum and 1% non-essential amino acids. Cells were seeded onto polycarbonate filter membranes (product number 3396) and incubated at 37°C in a 5% CO2 incubator. Transport experiments were performed after 21–28 days of incubation. Lucifer Yellow apparent permeability (Papp) was used to characterize and verify cell monolayer density. Compounds were dissolved in DMSO to prepare 10 mM stock solutions, which were then diluted with Hanks Balanced Salt Solution (HBSS, Invitrogen, Cat# 14025-092) containing 25 mM HEPES (pH 7.4) to form working solutions. A 10 μM working solution of the test compound was added to the apical and basolateral sides of Caco-2 cells and incubated at 37°C for 90 min. After incubation, the apical and basolateral samples were diluted and the compound concentrations in the apical and basolateral sides were detected by LC-MS / MS. Compound concentrations were quantified using a standard curve. The measurement results are shown in Table 7. [Table 7] Conclusion: The compounds of the present invention have membrane permeability equivalent to that of the control compound in the Caco2 model. Overall, both the compounds of the present invention and the control compound have poor cell permeability and consistent efflux properties.

[0132] <Effectiveness Test Example 6: Plasma Protein Binding Rate (PPB) Evaluation> 1. Experimental Procedure Sample preparation: Compounds were dissolved in DMSO to give a 10 mM stock solution, then the compounds were diluted in PBS to give a secondary stock solution of 0.02 mM, which was then further diluted to 1 μM with blank plasma to give the samples to be incubated. Preparation of dialysis setup: First, 400 μL of blank PBS was added to the white wells of the equilibrated dialysis plate, and 200 μL of the plasma sample was added to the red wells, and the dialysis plate was then sealed with a sealing film. Recovery Plate Preparation: Two 96-well deep well plates, designated T0 and T5, were prepared. All plasma samples were added in duplicate. 300 μL of acetonitrile (Verapamil-HCl, 4 ng / mL) was added directly to the T0 plate, followed by 50 μL of blank PBS. The plates were mixed for 5 minutes and then placed in a 4°C refrigerator until the end of incubation. Experimental Procedure: The dialysis device and T5 plate were incubated together in a microplate incubator (37°C, 300 rpm or minimum rotation speed) for 5 hours. At the end of the incubation, 300 μL of acetonitrile (verapamil-HCl, 4 ng / mL) and 50 μL of PBS solution were added. After the dialysis incubation, a new 96-well deep-well plate was harvested. 50 μL of plasma was added to the corresponding well of the 96-well plate, followed by 300 μL of acetonitrile and 50 μL of blank PBS. 50 μL of buffer solution was added to the corresponding well of the 96-well plate, followed by 300 μL of acetonitrile and 50 μL of blank plasma. 300 μL of acetonitrile (verapamil-HCl, 4 ng / mL) and 50 μL of PBS solution were added to the plasma-containing well of the T5 plate. The plate was shaken for 5 minutes to completely precipitate the proteins, followed by centrifugation at 20,000 g for 10 minutes at 4°C. 200 μL of the supernatant was added to 200 μL of pure water, mixed well, and subjected to LC-MS / MS analysis. 2. Data Processing and Parameter Calculation Plasma protein binding rate = [(R pe -R b ) / R pe ]×100% Recovery rate = [(R pe +R b ) / R 5h ]×100% ·Stability=(R5 / R0)×100% Among them: ·R pe = Ratio of plasma test sample peak area to internal standard ·R b = Ratio of buffer test sample peak area to internal standard R5 = Ratio of incubator stability sample peak area to internal standard R0 = Ratio of refrigerator stability sample peak area to internal standard 3. The measurement results are shown in Table 8. [Table 8] Conclusion: The compounds of the present invention have good plasma protein binding ability.

[0133] <Effectiveness Test Example 7: Evaluation of the inhibitory effect of compounds on cytochrome P450> Inhibition of CYP450 enzyme activity by small molecule inhibitors was quantified by measuring the fluorescence generated by substrate oxidation by cytochrome P450. Experiments were performed in a 384-well plate (Corning, Cat# 3575) with a reaction buffer of 142.86 mM potassium phosphate, pH 7.4. Solution A components used in the experiment were 26.13 mM NADP+ (Sigma-Aldrich, Cat# N0505), 65.77 mM G6P (J&K, Cat# 968161), and 65.42 mM MgCl2 (Sigma-Aldrich, Cat# M2670). Solution B components used in the experiment were: 40 U / mL G6PDH (Sigma-Aldrich, Cat# G6378). The substrate mixture consisted of 0.05X solution A, 0.01X solution B, 50 mM potassium phosphate, 0.01 mM BOMCC / 0.01 mM EOMCC / 0.001 mM DBOMF. For CYP3A4 and CYP2C9, the reaction mixture was 50 μL or 20 μL, respectively, and contained 3 nM CYP3A4 or 120 nM CYP2C9, the BOMCC substrate mixture, and various concentrations of the test compound. For CYP2C19, CYP2D6, and CYP1A2, the reaction mixture was 20 μL, containing 12.5 nM CYP2C19, 80 nM CYP2D6, or 1 nM CYP1A2, the EOMCC substrate mixture, and various concentrations of the test compound. For CYP2C8, the reaction mixture was 50 μL and contained 1.5 nM CYP2C8, DBOMF substrate mixture, and various concentrations of test compound. After 10 minutes of preincubation with the enzyme, the substrate was added, and the fluorescence signal was read at different wavelengths (BOMCC / EOMC Ex 430 nm / Em 480 nm, DBOMF Ex 490 nm / Em 520 nm) using a BMG PHERAStar. The reaction interval was 30 seconds or more (set according to the number of wells), and the reaction time was 30 minutes. Data were analyzed and processed using GraphPad Prism 6 software to obtain IC50 values. The measurement results are shown in Table 9. [Table 9] Conclusion: None of the compounds of the present invention exhibited significant cytochrome P450 enzyme inhibition. Among them, compound 37b of the present invention exhibited inhibition of all molecular species greater than 10 μM, which was superior to the reference compound AZD1775.

[0134] <Effectiveness Test Example 8: hERG Potassium Channel Inhibition Test> Experimental procedure (1) Experimental materials: A. Cultivation of CHO (Chinese Hamster Ovary Cell) stably transfected cell lines The cell line used for the membrane clamp assay was 10th generation CHO cells overexpressing the hERG potassium channel cDNA. CHO hERG cells were cultured in Petri dishes or flasks in a 37°C, 5% CO2 incubator. 24–48 h before electrophysiological experiments, cells were dropped onto circular slides and cultured in cell culture medium. After the cells became adherent, they were used for the experiments. The composition of the cell culture medium (purchased from Invitrogen) is as follows: -Ham's F12 medium -10%(v / v) heat-inactivated FBS -100μg / ml Hygromycin B (thaumatin) -100 μg / ml Geneticin (Genomycin, G418) B. Compound Preparation The compound powder was dissolved in the extracellular solution, typically with 5–10 min of sonication and shaking to ensure complete dissolution of the compound. The final concentrations of the compounds used in the electrophysiological assays were 5 and 20 μM, with DMSO at 0.1%. (2) Experimental Protocol A. Experimental Procedure for Electrophysiological Recordings Cell membrane currents were recorded using a HEKA EPC-10 USB membrane clamp amplifier (HEKA Elektronik, Germany). 1) A coverslip with a large number of uniformly grown CHO hERG cells on its surface was harvested and placed in a continuous recording cell on an inverted microscope. Extracellular fluid was perfused (approximately 1 ml per minute), and continuous recording was performed after the current stabilized. 2) HERG channel currents were recorded from individual cells using standard whole-cell recording mode. First, the membrane voltage was clamped at -80 mV, and the cell was stimulated to +20 mV for 5 seconds to activate the hERG potassium channel. Then, the cell was repolarized to -50 mV for 5 seconds to generate an outward tail current. The cells were continuously perfused until the current stabilized, at which point the peak value of the tail current was used as the reference current. 3) Next, an extracellular solution containing the test drug was perfused, and recording was continued until the inhibitory effect of the drug on the hERG current reached a steady state, at which point the peak value of the tail current was taken as the current value after drug administration. 4) The cells are again perfused with extracellular solution until the hERG current returns to or approaches pre-drug levels, after which other concentrations or drugs can be tested by continuing the perfusion. One or more concentrations of compounds or drugs can be tested in each cell. 5) Cisapride (C4740-10 mg, Sigma) was used as a positive control in the experiment to confirm that the cells used responded appropriately. (3) Quality control The following criteria must be met for the experimental data reported: Electrophysiological recording parameters a) Sealing resistance>500MΩ b) Contact resistance (Ra)<10MΩ c) Initial tail current amplitude >200 pA d) Current rundown <2% / min e) Leak current <200 pA or 10% of peak hERG current (within 90% of the recording time)

[0135] [Table 10] Conclusion: Some compounds of the present invention (eg, 4b, 37b) have weaker hERG inhibitory activity than the reference compound AZD1775, and their cardiotoxicity risk is relatively low.

[0136] <Effectiveness Test Example 9: Evaluation of Pharmacokinetics> (1) Evaluation of single-dose drug metabolism and kinetics in mice The purpose of this experiment was to study the pharmacokinetics in the plasma of male ICR mice after drug administration. 1. Purpose of the experiment The purpose of this study was to obtain the pharmacokinetic profile of the target compound in ICR mice (intravenous and oral administration). 2. Compliance with laws and regulations In this study (non-GLP study), the test substance assay, DMPK animal experiment and DMPK analysis were performed at the Chengdu Experimental Institute, China, and all experiments followed this experimental protocol and the relevant SOPs of the relevant institutions. 3. Experimental materials, instruments and equipment 3.1 Experimental materials 3.1.1 Experimental materials The following experimental materials are provided by Chengdu Pioneer and are guaranteed to meet the quality requirements. Name / Code: Experimental Compound Properties: Solution Solvent / formulation: 5% DMSO-10% Solutol-85% HPBCD (20%, W / V) Storage conditions: room temperature Preparation concentration: 0.2 mg / ml (intravenous), 1 mg / ml (oral) Preparation liquid volume: 3mL, 3mL 3.1.2 Experimental system Animal species: SPF-grade male ICR mice. Weight / Age: Approx. 30g Number of fish: 6 From laboratory animals: Viton liver 4. Experimental Procedure 4.1 Solvent preparation Medium: 5%DMSO-10%Solutol-85%HPBCD (20%, W / V) "Oral administration solvent / dosage: 5% DMSO - 10% Solutol-85% HPBCD (20%, W / V)." 4.2 Test substance administration (route) Intravenous administration: 1 mg / kg dose, 5 mL / kg dose Oral administration: 10 mg / kg dose, 10 mL / kg dose Ultrasound was administered 5 minutes before administration. 4.3 Preparation of test substance (concentration) Intravenous: 0.2 mg / mL Intravenous: 0.2 mg / mL, Oral: 1 mg / mL The animals were fasted overnight before administration and fed 4 hours after administration. 4.4 Sample Collection At 5 minutes (intravenous administration only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, blood (40-50 μL) was collected by orbital venous puncture into an anticoagulant tube pre-sprayed with EDTA-K2, and within 1 hour, it was centrifuged at 10,000 rpm for 20 minutes (stored on wet ice before and after centrifugation) to obtain the supernatant, i.e., plasma. The plasma was stored in a refrigerator at -20°C or below and subjected to LC-MS / MS analysis. 4.5 Analysis and detection method of drugs in vivo: Analysis and detection were performed using LC-MS / MS. 5. Data Processing Samples were analyzed by LC-MS / MS to determine drug concentrations at each time point. Pharmacokinetic parameters, terminal elimination half-life (t1 / 2), area under the drug-time curve (AUC), apparent volume of distribution (Vd), clearance (CL), mean residence time (MRT), Cmax, and bioavailability (F%), were calculated directly from serum concentration results using a nonatrial model in Phoenix WinNonlin 5.2. Mean ± standard deviation (X ± SD) was used for blood concentrations and pharmacokinetic parameters. Specific assay analytical methods were specified in protocol amendments.

[0137] 6 The test results are shown in Table 11. [Table 11] Conclusion: The pharmacokinetics in mice showed that the compound 37b of the present invention has better pharmacokinetic properties than the control compound AZD1775, with higher drug exposure and slower clearance.

[0138] (2) Evaluation of single-dose drug metabolism and kinetics in rats The same research method as that for the pharmacokinetics in mice was used to evaluate the pharmacokinetic properties of the drug in male SD rats. The results are shown in Table 12: [Table 12] Results: Compound 37b of the present invention and the control compound AZD1775 had similar maximum blood drug concentrations. Regarding drug exposure, compound 37b of the present invention had the advantage of intravenous injection and slower clearance, and compound 37b also had superior oral exposure levels to the control compound AZD1775.

[0139] (3) Evaluation of single-dose pharmacokinetics in beagle dogs The pharmacokinetic properties of the drug in male beagle dogs were evaluated using the same research method as in mice. The basic information is as follows: Beagle dogs: weight 8-11 kg, purchased from Jiangsu Marshall biotechnology Co. LTD Dosage: 2 mg / kg (intravenous injection); 10 mg / kg (oral) Solvent: 5% DMSO + 5% Solutol + 90% (20% HP-β-CD in saline) The measurement results are shown in Table 13. [Table 13] Conclusion: In beagle dogs, the pharmacokinetic properties of compound 37b of the present invention are slightly better than those of the reference compound AZD1775.

[0140] <Effectiveness Test Example 10: In vivo drug efficacy evaluation in animals (CDX model)> (1) In vivo drug efficacy evaluation in female BALB / c nude mice with subcutaneous allografts of human colon cancer HT-29 cells Study objective: To evaluate the tumor suppressive effects of compound 37b and AZD1775 on xenogeneic tumor-bearing (HT-29) nude mice Test method: BALB / c nude mice (provided by Vital River), 7-8 weeks old and weighing 19-22 g, were selected. Count the prepared and cultured HT-29 cells and measure 5 x 10 6 HT-29 cells were mixed in 0.1 mL of PBS solution and inoculated subcutaneously into the right flank of mice. The cells formed tumors with an average tumor volume of 120 mm. 3 When the dose reached 100 mg / kg, the subjects were divided into groups and administered the treatment. Dose: AZD1775, 60 mg / kg, once daily; 37b was divided into three groups, 30 mg / kg, 60 mg / kg, and 120 mg / kg, administered once daily. The endpoint of the study was to determine whether tumor growth was inhibited. The formula for calculating tumor volume was V = 0.5a × b. 2 where a and b represent the long and short diameters of the tumor, respectively. The tumor-inhibitory effect of the compound was evaluated as TGI (%). Calculation of TGI (%): TGI (%) = [1 - (mean tumor volume at the end of treatment for a treatment group - mean tumor volume at the start of treatment for that treatment group) / (mean tumor volume at the end of treatment for the vehicle control group - mean tumor volume at the start of treatment for the vehicle control group)] x 100%. The tumor suppression effects of compound 37b and AZD1775 after 24 days of administration are shown in Table 14. [Table 14] Conclusion: Compound 37b of the present invention had the same tumor-inhibitory effect as the control compound AZD1775 at a dose of 60 mg / kg. Compound 37b of the present invention had a significant tumor growth-inhibitory effect at a dose of 120 mg / kg.

[0141] (2) In vivo drug efficacy evaluation of human pancreatic cancer BxPC3 cell subcutaneous allografts in female BALB / c nude mice Study objective: To evaluate the tumor suppressive effects of compound 37b and AZD1775 on heterologous tumor-bearing (BxPC3) female BALB / c nude mice Test method: BALB / c nude mice (provided by Vital River), 7-8 weeks old and weighing 19-22 g, were selected. Count the prepared and cultured BxPC3 cells and measure 1 x 10 7 BxPC3 cells were mixed in 0.1 mL of PBS solution and inoculated subcutaneously into the right flank of mice. The cells formed tumors with an average tumor volume of 190 mm. 3 When the dose reached 100 mg / kg, the subjects were divided into groups and administered the treatment. Dose: AZD1775, 60 mg / kg, once daily; 37b was divided into three groups, 30 mg / kg, 60 mg / kg, and 120 mg / kg, administered once daily. The endpoint of the study was to determine whether tumor growth was inhibited. The formula for calculating tumor volume was V = 0.5a × b. 2 where a and b represent the long and short diameters of the tumor, respectively. The tumor-inhibitory effect of the compound was evaluated as TGI (%). Calculation of TGI (%): TGI (%) = [1 - (mean tumor volume at the end of treatment for a treatment group - mean tumor volume at the start of treatment for that treatment group) / (mean tumor volume at the end of treatment for the vehicle control group - mean tumor volume at the start of treatment for the vehicle control group)] x 100%. The tumor-inhibitory effects of compound 37b and AZD1775 after 40 days of administration are shown in Table 15. [Table 15] Conclusion: At the doses of 30 mg / kg and 30 mg / kg, compound 37b of the present invention has a stronger tumor inhibitory effect than the reference compound AZD1775; compound 37b has a significant tumor growth inhibitory effect at the dose of 120 mg / kg.

[0142] <Effectiveness Test Example 11: Toxicity Evaluation of Compounds> (1) Single-dose toxicity in rats - evaluation of the maximum tolerated dose Study objective: To evaluate the tolerability of single-dose compounds AZD1775 and 37b in rats Test animals: SD rats (provided by Vital River), 6-8 weeks old, 180-220 grams. Test method: A single oral administration of the planned dose was given to rats, and then the survival status of the rats was observed (observation continued for a maximum of 14 days). See Table 16 for the test procedure and results. [Table 16] Test results: In a single administration to rats, compound 37b of the present invention has a higher maximum tolerated dose than the reference compound AZD1775, and has excellent safety advantages.

[0143] (2) Toxicity evaluation by 14-day continuous administration to rats Study objective: To evaluate the tolerability and toxicity of compounds AZD1775, ZnC3 and 37b when administered consecutively in rats Test animals: SD rats (provided by Vital River), 6-8 weeks old, 180-220 grams. Test method: The rats are given a predetermined dose orally once a day, and then the survival and weight changes of the rats are observed (administration is continued for up to 14 days). See Table 17 for the test plan. [Table 17] Among them, a sampling of toxicokinetic studies is as follows: First and last dose sampling Sampling time points: 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h.

[0144] Test results: 1. Overall survival of rats Following the above administration procedure, the rats were administered for 14 consecutive days, and it was discovered that some of the rats in the administration groups died. The results are shown in Table 18. [Table 18] Results: The survival rate of rats in the present invention compound 37b group was significantly higher than that of the control compound AZD1775 group and the control compound ZnC3 group.

[0145] 2. Toxicokinetic parameters The toxicokinetic results of the three compounds in rats are shown in Table 19 (female rats) and Table 20 (male rats). [Table 19] [Table 20] Conclusion: Based on the results of the maximum tolerated dose of a single dose in rats and the toxicity study of 14-day continuous administration in rats, compound 37b of the present invention has obvious advantages in terms of drug safety compared with the reference compounds AZD1775 and ZnC3.

Claims

1. A compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Among them, R １ But, -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, —C ０～２ Alkylene groups -CN, -C ０～２ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ alkylene-(3- to 10-membered heterocycloalkyl) groups, R ２ is selected from the group consisting of formula 2, X is O, NH or CH ２ selected from the group consisting of X １ is selected from the group consisting of CH or N; R ２１ , R ２２ , R ２９ are each independently hydrogen, deuterium, halogen, cyano group, nitro group, —OH, —C １～６ Alkyl group, halogen-substituted C １～６ alkyl group, -C ０～２ Alkylene groups -OH, -O(C １～６ alkyl group), -O(halogen-substituted C １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -C ０～２ Alkylene group -N(C １～６ alkyl group) (C １～６ alkyl group), -C ０～２ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ alkylene-(3- to 10-membered heterocycloalkyl) groups, R ２３ , R ２４ together with the atom(s) directly linked thereto form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; R ２５ , R ２６ together with the atom(s) directly linked thereto form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; R ２７ , R ２８ together with the atom(s) directly linked thereto form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; R ３ is hydrogen, deuterium, halogen, cyano group, nitro group, -C １～６ Alkyl group, halogen-substituted C １～６ alkyl group, -C ０～２ Alkylene groups -OH, -O(C １～６ alkyl group), -O(halogen-substituted C １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -C ０～２ Alkylene group -N(C １～６ alkyl group) (C １～６ alkyl groups), R ４ is selected from the group consisting of 3- to 12-membered heterocycloalkyl groups, said heterocycloalkyl groups further comprising one, two, three or four independent R ４１ may be substituted with The R ４１ is hydrogen, halogen, cyano group, nitro group, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ alkyl group, -C ０～２ Alkylene groups -OH, -O(C １～６ alkyl group), -O(halogen-substituted C １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -C ０～２ Alkylene group -N(C １～６ alkyl group) (C １～６ alkyl group), —C(O)C １～６ alkyl group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring further comprises one, two, three, or four independent R ３１ may be substituted with Or, R ３ , R ４ together with the atom directly connected thereto form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring, and the carbocyclic ring or heterocycloalkyl group further has one, two, three or four independent R ３１ may be substituted with, and the R ３１ is hydrogen, halogen, cyano group, nitro group, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ alkyl group, -C ０～２ Alkylene groups -OH, -O(C １～６ alkyl group), -O(halogen-substituted C １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -C ０～２ Alkylene group -N(C １～６ alkyl group) (C １～６ alkyl groups).

2. R １ 2. The compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of formula 3:

3. R ２１ , R ２２ , R ２９ are each independently hydrogen, deuterium, a cyano group, a methyl group, an ethyl group, —OH, a trifluoromethyl group, a cyclopropyl group, or —CH ２ OH, —NH ２ 2. The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

4. R ２３ , R ２４ together with the atom directly connected thereto form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; R ２５ , R ２６ together with the atom directly connected thereto form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; R ２７ , R ２８ The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that: together with the atom directly linked thereto, form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group.

5. R ２ 5. The compound according to claim 1, 3 or 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of formula 4:

6. R ３ is hydrogen, fluorine, methyl group, -CH ２ 2. The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of OH and methoxy.

7. R ４ is selected from the group consisting of a 6-membered nitrogen-containing heterocycle, a 7-membered nitrogen-containing bridged ring, an 8-membered nitrogen-containing bridged ring, a 9-membered nitrogen-containing heterospirocycle, and an 11-membered nitrogen-containing heterospirocycle, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1.

8. R ４ is selected from the group consisting of Formula 5, Among them, R ４１ 8. The compound according to claim 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that:

9. R ４ The compound of claim 8, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of formula 6:

10. R ３ , R ４ The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that:

11. R ３ , R ４ together with the atoms directly connected thereto form formula 7, R ３１ 11. The compound according to claim 10, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that:

12. R ３１ The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 11, wherein is selected from the group consisting of methyl groups.

13. 2. The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound according to formula 1 is any of the following compounds: 【Table 1】

14. 2. The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound according to formula 1 is selected from the group consisting of formula 8:

15. 15. Use of a compound according to any one of claims 1 to 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a WEE1-mediated disease.

16. The use according to claim 15, characterized in that the WEE1-mediated disease is one or more of diseases associated with inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

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