Compound acting as voltage-gated sodium channel inhibitor and use thereof

Abstract

The present invention relates to a selective inhibitor of the voltage-gated sodium channel Nav1.8 and a use thereof in the preparation of related drugs. The drugs are used for treating diseases responsive to inhibition of the voltage-gated sodium channel Nav1.8, such as chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.

Description

Compounds as voltage-gated sodium channel inhibitors and their applications

[0001] This application claims the following priority:

[0002] CN202411858565.3, application date: 2024.12.13; CN202510331624.X, application date: 2025.03.19; CN202510776518.2, application date: 2025.06.10; CN202511109702.8, application date: 2025.08.07. Technical Field

[0003] This invention relates to the field of chemical and pharmaceutical technology, specifically to a compound and its application as a voltage-gated sodium channel inhibitor. Background Technology

[0004] Pain plays an indispensable protective role in the body's normal life activities. As a warning signal, it alerts the body to potential dangers. However, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of living beings.

[0005] Pain originates from nociceptors in the peripheral nervous system, which are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. These receptors convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted via afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium ion channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium ion channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and alleviate pain.

[0006] NaV1.8 is primarily expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglion (DRG). Small DRG neurons expressing NaV1.8 include pain receptors involved in pain signal transduction. NaV1.8 mediates large-amplitude action potentials in small neurons of the DRG, which are essential for rapid repetitive action potentials in pain receptors and spontaneous activity in damaged neurons. Knockdown of NaV1.8 in rats has been achieved using antisense DNA or small interfering RNA and has resulted in near-complete reversal of neuropathic pain in spinal nerve ligation and chronic compression injury models. Therefore, the NaV1.8 channel is considered a promising target for analgesics, potentially playing a role in indications where pain exceeds its usefulness, such as neuropathic pain, inflammatory pain, and postoperative / spontaneous pain. Furthermore, since NaV1.8 is primarily confined to neurons that sense pain, selective NaV1.8 inhibitors may avoid the adverse events commonly associated with non-selective NaV blockers.

[0007] Besides pain, NaV1.8 channels are also believed to be associated with multiple sclerosis (MS), arrhythmias, cough, and pruritus. MS is a primary inflammatory demyelinating disease of the central nervous system, and its exact pathogenesis remains to be elucidated. Normal Purkinje fibers in the cerebellum do not express NaV1.8 channels, but their expression is upregulated in MS patients. In the cardiovascular system, NaV1.8 has been shown to be expressed in cardiac nerves such as Purkinje fibers and is considered a potential therapeutic target for cardiovascular diseases such as arrhythmias. NaV1.8 is expressed in the cough-related vagus plexus; its phosphorylation level and expression increase during pathological coughing, participating in the cough reflex. In mammalian pruritus, histamine and other pruritogenic factors released by lymphocytes and mast cells can activate NaV1.8 channels; knocking out NaV1.8 in mice can effectively alleviate histamine- and endothelin-induced pruritus.

[0008] Currently, Suzetrigine, a selective inhibitor of NaV1.8 from VERTEX, has been approved for marketing. Developing other highly selective voltage-gated sodium channel NaV1.8 inhibitors is of great clinical significance. Summary of the Invention

[0009] This invention provides a compound, or a pharmaceutical composition thereof, which can act as a selective inhibitor of Nav1.8. The invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats diseases and / or conditions by inhibiting Nav1.8 through said compound. The invention further describes a method for synthesizing said compound. The compounds of this invention exhibit excellent biological activity and pharmacokinetic properties.

[0010] Specifically:

[0011] Disclosed are compounds having one of the following structures, or stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, deuterates, metabolites, pharmaceutically acceptable salts, or prodrugs having one of the following structures:

[0012] On one hand, the present invention relates to pharmaceutical compositions comprising the aforementioned compounds, or stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, mediators or combinations thereof.

[0013] On one hand, the use of the compound and pharmaceutical composition in the preparation of a medicament for treating diseases in which voltage-gated sodium channels NaV1.8 respond. These diseases include chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Chuck-Maley-Dus syndrome, incontinence, pathological cough, or arrhythmia.

[0014] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0015] Definitions and general terms

[0016] This invention will list in detail the relevant literature for the specific details provided, and the embodiments are accompanied by diagrams of structural and chemical formulas. This invention is intended to cover all options, variations, and equivalents that may be included within the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances. Many documents and similar substances distinguish or conflict with this application, including but not limited to the definitions of terms, usages of terms, described techniques, or the scope controlled as described in this application.

[0017] Unless otherwise stated, the following definitions will apply in this invention. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75th Ed, 1994. Furthermore, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all content incorporates these references.

[0018] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0019] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, geometric isomers, or conformational isomers, is within the scope of this invention.

[0020] Unless otherwise stated, the structural formulas and compounds described in this invention include all isomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, compounds of the present invention that are individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs are also within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0021] "Metabolic product" refers to the product obtained in vivo by the metabolism of a specific compound described in this invention or its pharmaceutically acceptable salt, analogue, or derivative, which exhibits similar activity to the compound of formula (I) in vivo or in vitro. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0022] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name the symbols for the plane polarization rotation of compounds. (-) or l indicates that the compound is levorotatory, while the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0023] The terms "tautomer" or "tautomerism form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons.

[0024] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, borate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and N+ (C 1-4 Salts of alkyl groups (4). This invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates.

[0025] In this invention, "hydrate" refers to an associative compound formed when the solvent molecules are water.

[0026] The term "solvent" in this invention refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0027] The “deuterated compounds” of this invention refer to compounds obtained by replacing one or more hydrogen atoms with deuterium in the compounds of this invention, in order to improve drug metabolism cycles, reduce the production of toxic metabolites or drug interactions, thereby reducing the dosage, improving safety and obtaining better therapeutic effects, etc.

[0028] In this invention, "ester" refers to an ester formed in vivo by a compound of formula (I) containing a hydroxyl group that is hydrolyzable. Such an ester is, for example, a pharmaceutically acceptable ester that, upon hydrolysis in a human or animal body, produces a parent alcohol. The groups of an ester of formula (I) containing a hydroxyl group that is hydrolyzable in vivo include, but are not limited to: phosphate group, acetoxymethoxy group, 2,2-dimethylpropionyloxymethoxy group, alkylyl group, benzoyl group, phenylacetyl group, alkoxycarbonyl group, dialkylcarbamoyl group, and N-(dialkylaminoethyl)-N-alkylcarbamoyl group, etc.

[0029] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), for example, by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

[0030] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound of this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0031] Unless otherwise stated herein or the context clearly indicates otherwise, the terms “an,” “a,” “the,” and similar terms used herein, as well as in the context of the invention (especially in the context of the claims), may be interpreted as including both the singular and the plural. Detailed Implementation

[0032] The present invention will now be described with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way.

[0033] Unless otherwise specified, the raw materials and reagents used in the following examples are all derived from commercially available or known synthetic routes.

[0034] The equipment and detection conditions are described below: ¹H NMR spectra were recorded using a Bruker 500MHz NMR spectrometer. ¹H NMR spectra were recorded using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0035] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate: 1 mL / min; mobile phase: 0%-95% (CH3CN) in a ratio of H2O containing 0.1% formic acid:CH3CN = 90:10), electrospray ionization (ESI) at 210 nm / 254 nm, and detection by DAD.

[0036] Compounds are named according to conventional naming principles in the field or using software; commercially available compounds are named according to the supplier's catalog.

[0037] Example 1

[0038] Step 1: Synthesis of compounds 1-3

[0039] Under a nitrogen atmosphere, compound 1-1 (2.83 g, 21.4 mmol) was added to a 30 mL toluene solution containing compound 1-2 (2.00 g, 14.3 mmol), DIAD (4.2 mL, 21.4 mmol), and triphenylphosphine (5.62 g, 21.41 mmol). The reaction mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was diluted with 100 mL of water and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain compound 1-3 (1.80 g, 6.73 mmol), a colorless oil, with a yield of 47.1%.

[0040] 1 H NMR (400MHz, CDCl3) δ = 9.06 (d, J = 2.8Hz, 1H), 8.37 (dd, J = 2.8, 9.0Hz, 1H), 6.89 (d, J = 9.0Hz, 1H), 4.57- 4.49(m,2H),4.49-4.41(m,1H),4.21-4.13(m,1H),3.92-3.83(m,1H),1.47(s,3H),1.43-1.38(m,3H).

[0041] Step 2: Synthesis of compounds 1-4

[0042] Under a nitrogen atmosphere, 10% Pd / C (100 mg, 0.09 mmol) was added to 20 mL of ethyl acetate containing compound 1-3 (500 mg, 1.97 mmol). The mixture was purged three times with hydrogen to a final pressure of 15 psi, and the reaction solution was stirred at 25 °C for 16 hours. After the reaction was complete, the solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 1-4 (450 mg, 1.97 mmol), a colorless oil, in 100% yield. The crude product was used directly in the next step.

[0043] 1 H NMR (400MHz, DMSO-d6) δ = 7.47 (d, J = 2.8Hz, 1H), 7.00 (dd, J = 2.8, 8.8Hz, 1H), 6.55 (d, J = 8.8Hz, 1H), 4.7 6(s,2H),4.39-4.29(m,1H),4.13-3.98(m,3H),3.69(dd,J=6.4,8.4Hz,1H),1.33(s,3H),1.28(s,3H);

[0044] LC-MS(ESI):[M+H] + =225.1.

[0045] Step 3: Synthesis of compounds 1-6

[0046] Under a nitrogen atmosphere, compounds 1-4 were added to 2 mL of dichloromethane solution containing compounds 1-5 (80 mg, 0.20 mmol) and triethylamine (0.1 mL, 1.00 mmol). The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain compounds 1-6 (22 mg, 0.03 mmol), a colorless oil, with a yield of 63.5%.

[0047] 1H NMR (400MHz, CDCl3) δ = 8.21 (s, 1H), 8.17 (d, J = 2.8Hz, 1H), 7.92 (dd, J = 2.8, 8.8Hz, 1H), 7.21-7.13 ( m,1H),7.03-6.92(m,1H),6.76(d,J=8.8Hz,1H),5.01(d,J=11.2Hz,1H),4.53-4.44(m,1H),4.40-4 .30(m,2H),4.26(dd,J=8.0,11.2Hz,1H),4.14(dd,J=6.8,8.4Hz,1H),3.85(dd,J=6.4,8.4Hz,1H), 2.88-2.78(m,1H),2.40(s,1H),1.70(s,3H),1.46(s,3H),1.40(s,3H),0.81(dd,J=2.0,7.6Hz,3H);

[0048] LC-MS(ESI):[M+H] + =587.2.

[0049] Step 4: Synthesis of Compound 1

[0050] Under a nitrogen atmosphere, trifluoroacetic acid (0.2 mL, 3.07 mmol) was added to a 2 mL solution of dichloromethane containing compound 1-6 (90 mg, 0.15 mmol), and the reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, saturated sodium bicarbonate was slowly added dropwise to the reaction solution to adjust the pH to 7. The aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reverse-phase chromatography (column: Waters Xbridge C18 150*25mm*5um; mobilephase: [A:H2O(10mM NH4HCO3); B:ACN]; B%: 40.00%-70.00%, 15.00min; flow rate: 25.00ml / min) to obtain compound 1 (43.6mg, 0.08mmol), a yellow oily substance, with a yield of 50.8% and a deuteration rate of 98.07%.

[0051] 1H NMR (400MHz, DMSO-d6) δ = 10.19 (s, 1H), 8.29 (s, 1H), 7.87 (dd, J = 2.8, 8.8Hz, 1H), 7.27-7.12 (m,2H),6.78(d,J=8.8Hz,1H),5.06(d,J=10.4Hz,1H),4.86(d,J=5.2Hz,1H),4.61(t,J=5.6H z,1H),4.34(s,1H),4.21(dd,J=4.2,10.8Hz,1H),4.08(dd,J=6.4,10.8Hz,1H),3.76(qd,J=5 .2,10.8Hz,1H),3.65(s,1H),3.41(t,J=5.6Hz,2H),2.89-2.77(m,1H),1.60(s,3H),0.73(br d,J=6.0Hz,3H);

[0052] LC-MS(ESI):[M+H] + =547.2.

[0053] Example 2

[0054] Step 1: Synthesis of Compound 2-2

[0055] Under a nitrogen atmosphere, di-tert-butyl dicarbonate (1.4 mL, 6.94 mmol) and triethylamine (1.2 mL, 8.68 mmol) were added to a 10 mL solution of dichloromethane containing compound 2-1 (500 mg, 2.89 mmol). The reaction was carried out at 25 °C for 16 hours. After the reaction was complete, 30 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Compound 2-2 (377 mg, 1.33 mmol), a white solid, was obtained by column chromatography (SiO2, PE:EA = 1:0 to 10:1), yielding a yield of 46.1%.

[0056] 1 H NMR (400MHz, DMSO-d6) δ = 9.72 (br s, 1H), 8.45 (d, J = 2.4Hz, 1H), 7.82 (dd, J = 2.4, 8.8Hz, 1H), 7.53 (d, J = 8.8Hz, 1H), 1.49-1.46 (m, 9H);

[0057] LC-MS(ESI):[M+H] + =274.9.

[0058] Step 2: Synthesis of compounds 2-4

[0059] Under a nitrogen atmosphere, compounds 2-3 (31.03 mg, 0.26 mmol), potassium carbonate (48.83 mg, 0.35 mmol), potassium iodide (3.36 mg, 0.02 mmol), and N,N-dimethylglycine (3.64 mg, 0.04 mmol) were added to 1 mL of N,N-dimethylformamide solution containing compound 2-2 (50 mg, 0.18 mmol). The reaction solution was heated to 120 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Compound 2-4 (50.0 mg, 0.24 mmol), a yellow viscous substance, was separated by column chromatography (SiO2, PE:EA = 1:1-0:1). This crude product was directly used as a feed for the next step.

[0060] LC-MS(ESI):[M+H] + =210.2.

[0061] Step 3: Synthesis of Compound 2

[0062] Under a nitrogen atmosphere, compounds 2-4 (42.10 mg, 0.20 mmol) and triethylamine (0.1 mL, 0.67 mmol) were added to a 1 mL solution of dichloromethane containing compound 2-5 (50 mg, 0.13 mmol). The reaction was carried out at 25 °C for 0.6 h. After the reaction was complete, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by reverse-phase chromatography (Waters Xbridge C18 150 × 25 mm × 5 μm column, aqueous phase-organic phase H2O (10 mM NH4HCO3)-acetonitrile, initial gradient 38.00, ending gradient 68.00, gradient time 15.00) to obtain compound 2 (5.56 mg, 0.01 mmol), a gray solid, yield: 7.3%.

[0063] 1H NMR (400MHz, DMSO-d6) δ = 10.38 (s, 1H), 8.64-8.51 (m, 1H), 8.08-7.98 (m, 2H), 7.23 -7.08(m,2H),5.19(t,J=5.6Hz,1H),5.08(d,J=10.4Hz,1H),4.69(dd,J=4.0,6.2Hz ,1H),4.24(dd,J=7.6,10.4Hz,1H),4.14(t,J=9.6Hz,1H),3.97-3.90(m,4H),3.67 (m,1H),3.55(m,1H),2.76(quin,J=7.6Hz,1H),1.60(s,3H),0.72(d,J=6.0Hz,3H);

[0064] LC-MS(ESI):[M+H] + =546.2.

[0065] Step 4: Synthesis of Compound 2A and Compound 2B

[0066] Compound 2 (134 mg, 0.25 mmol) was separated by chirality (column: DAICL CHIRALPAK IM (250 mm * 30 mm, 10 μm), aqueous-organic phase: CO2-EtOH (0.1% NH3H2O), initial gradient: 35.00, final gradient: 35.00, gradient time: 2.30, flush gradient: 100.00, flow rate: 150.00 ml / min) to give compound 2A (first peak, 43.35 mg, 0.08 mmol, white solid, yield: 32.1%) and compound 2B (34.15 mg, 0.06 mmol, white solid, yield: 25.4%).

[0067] Compound 2A: 1 H NMR (400MHz, DMSO-d6) δ = 10.75 (s, 1H), 8.36 (d, J = 1.6Hz, 1H), 8.23 ​​(d, J = 5.6Hz, 1H), 7.48 -7.46(m,1H),7.22-7.16(m,1H),7.13-7.09(m,1H),5.20(t,J=5.6Hz,1H),5.09(d,J=10. 0Hz,1H),4.71-4.67(m,1H),4.27-4.23(m,1H),4.17-4.12(m,1H),3.97-3.93(m,4H),3.7 0-3.65(m,1H),3.58-3.54(m,1H),2.82-2.74(m,1H),1.60(s,3H),0.73(d,J=6.8Hz,3H);

[0068] LC-MS(ESI):[M+H] + =546.1.

[0069] Compound 2B: 1 H NMR (400MHz, DMSO-d6) δ = 10.76 (s, 1H), 8.35 (d, J = 1.6Hz, 1H), 8.23 ​​(d, J = 5.6Hz, 1H), 7.49 -7.47(m,1H),7.22-7.16(m,1H),7.13-7.09(m,1H),5.20(t,J=5.6Hz,1H),5.09(d,J=10. 0Hz,1H),4.72-4.67(m,1H),4.27-4.21(m,1H),4.18-4.13(m,1H),3.96-3.92(m,4H),3.6 9-3.65(m,1H),3.58-3.54(m,1H),2.82-2.74(m,1H),1.59(s,3H),0.73(d,J=6.4Hz,3H);

[0070] LC-MS(ESI):[M+H] + =546.2.

[0071] Example 3

[0072] Step 1: Synthesis of Compound 3-3

[0073] Compound 3-1 (200 mg, 0.54 mmol) was dissolved in dichloromethane (3 mL) and added dropwise to a solution of compound 3-2 (74.58 mg, 1.07 mmol) and triethylamine (0.2 mL, 1.61 mmol) in dichloromethane (3 mL). The mixture was stirred at 25 °C for 2 hours. Sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (2 × 5 mL). The extract was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (30% to 50% EtOAc in PE) to give compound 3-3 (180 mg, 0.49 mmol, 90.8%), a yellow oily substance, in 90.8% yield.

[0074] LC-MS(ESI):[M+H] + =370.0.

[0075] Step 2: Synthesis of compounds 3-5

[0076] Under a nitrogen atmosphere and at 0°C, compound 3-3 (150 mg, 0.41 mmol) was added to a solution of N,N-dimethylformamide (1 mL) containing compound 3-4 (94.52 mg, 0.61 mmol) and potassium carbonate (168.40 mg, 1.22 mmol). The mixture was heated to 25°C and stirred for 16 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by silica gel column chromatography (30% to 50% EtOAc in PE). The eluent was evaporated to dryness to give compound 3-5 (110 mg, 0.22 mmol, 53.7%) as a yellow solid, yield: 53.7%.

[0077] LC-MS(ESI):[M+H] + =505.0.

[0078] Step 3: Synthesis of Compound 3

[0079] Compounds 3-5 (100 mg, 0.20 mmol) were dissolved in ammonia-methanol solution (0.8 mL, 5.95 mmol) and reacted at 25 °C for 16 h. The mixture was purified by reversed-phase preparative chromatography (column: Phenomenex Luna C18 150*25 mm*10 μm, aqueous-organic phase, H₂O (0.225% FA)-ACN gradient, initial gradient 46.00, final gradient 66.00, gradient time 10.00, pause time, flush gradient 100.00, flush time 5.00, flow rate 25.00 mL / min). The solution was lyophilized to give compound 3 (44.01 mg, 0.09 mmol, 44.9%) as a white solid, yield 44.9%.

[0080] 1 H NMR (400MHz, DMSO-d6) δ = 12.67 (s, 1H), 8.48 (d, J = 5.6Hz, 1H), 8.09 (br s, 1H), 7.72 (br s,1H),7.53(d,J=2.4Hz,1H),7.29-7.06(m,3H),5.11(d,J=10.4Hz,1H),4.26-4.17(m,1H),3.94(s,3H),2.74(s,1H),1.62(s,3H),0.73(br d,J=6.4Hz,3H);

[0081] LC-MS(ESI):[M+H] + =490.1.

[0082] Example 4

[0083] Step 1: Synthesis of Compound 4-2

[0084] Under nitrogen protection, trimethyl sulfoxide (15.22 g, 69.15 mmol) and sodium hydride (2.77 g, 69.15 mmol) were added to 15 mL of dimethyl sulfoxide and stirred for 30 minutes. Then, a solution of compound 4-1 (15 g, 115.26 mmol) in dimethyl sulfoxide (15 mL) was slowly added dropwise to the above system, and the mixture was stirred overnight. Extraction was performed with water (300 mL) and methyl tert-butyl ether (150 mL), followed by separation and purification by silica gel column chromatography (PE:MTBE = 100:0–80:20) to give 4.67 g of a pale yellow oily liquid, yield: 28.1%.

[0085] 1 H NMR (400MHz, CDCl3) δ4.13 (dd, J=8.3, 6.4Hz, 1H), 3.99–3.82 (m, J=17.9, 10.2, 5.8Hz, 2H), 3.07–3.00 (m,J=6.3,3.8,2.7Hz,1H),2.90–2.81(m,1H),2.66(dd,J=4.9,2.6Hz,1H),1.46(s,3H),1.37(s,3H).

[0086] Step 2: Synthesis of Compound 4-3

[0087] Compound 4-2 (930 mg, 6.45 mmol) was dissolved in an ammonia-methanol solution (30 mL), purged with argon, and stirred at room temperature until the reaction was complete as monitored by TLC. The solution was concentrated under reduced pressure to give 1 g of a yellow oily liquid, yield: 96.2%. This was used directly in the next step.

[0088] LC-MS(ESI):[M+H] + =162.1.

[0089] Step 3: Synthesis of Compound 4-4

[0090] Compound 4-3 (100 mg, 0.62 mmol) was dissolved in tetrahydrofuran (4 mL), and after purging with argon, N,N'-carbonyldiimidazole (100 mg, 0.62 mmol) was added. The mixture was stirred overnight at 50 °C. Water (4 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography with DCM:MeOH = 100:0–90:10 as the eluent, yielding 80 mg of a yellow solid, yield: 68.9%.

[0091] 1H NMR (400MHz, DMSO-d6) δ7.55(s,1H),4.54(dt,J=8.9,5.9Hz,1H),4.22(dd,J=12.2,5.6Hz,1H),4.05(dd,J=8. 7,6.7Hz,1H),3.69(dd,J=8.7,5.4Hz,1H),3.54(t,J=8.9Hz,1H),3.30–3.20(m,1H),1.34(s,3H),1.28(s,3H);

[0092] LC-MS(ESI):[M+H] + =188.1.

[0093] Step 4: Synthesis of compounds 4-5

[0094] Compound 4-4 (440 mg, 2.35 mmol), [(6-bromopyridin-3-yl)amino]methane-2-methylpropyl-2-yl ester (642 mg, 2.35 mmol), cesium carbonate (1148 mg, 3.53 mmol), tris(dibenzylacetone)dipalladium (322 mg, 0.35 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (612 mg, 1.06 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL), and the mixture was purged with argon and stirred at 85 °C for 6 h. The mixture was filtered, and the filter cake was washed with DCM (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography with PE:EA = 100:0 to 50:50 as the eluent, yielding 420 mg of a pale yellow solid, yield: 47.1%.

[0095] 1 H NMR(400MHz, DMSO-d6)δ9.49(s,1H),8.39(s,1H),7.93(dd,J=24.3,8.7Hz,2H),4.77–4.66(m,1H),4.40(dt,J=7.0,4.8Hz,1H),4.1 7(t,J=9.6Hz,1H),4.08(dd,J=8.9,7.1Hz,1H),3.99(dd,J=10.3,5.6Hz,1H),3.81(dd,J=9.0,5.0Hz,1H),1.47(s,9H),1.27(s,6H);

[0096] LC-MS(ESI):[M+H] + =380.3.

[0097] Step 5: Synthesis of compounds 4-6

[0098] Compounds 4-5 (322 mg, 0.85 mmol) were dissolved in tetrabutylammonium fluoride (1 M in THF) (16.1 mL, 16.13 mmol) in THF (14 mL), and the mixture was purged with argon and stirred overnight at 50 °C. Ethyl acetate (40 mL) was added to the reaction mixture, and the organic phase was washed with water (20 mL × 5). After separation, the aqueous phase was extracted with ethyl acetate (40 mL × 2). The combined organic phases were purified by column chromatography with PE:EA = 90:10–34:66 as the eluent, yielding 168 mg of a pale yellow solid, yield: 70.9%.

[0099] 1 H NMR(400MHz, DMSO-d6)δ7.70(dd,J=5.8,2.6Hz,2H),7.04(dd,J=9.0,2.7Hz,1H),5.12(s,1H),4.73–4.61(m,1H),4.41–4.3 4(m,J=6.9,4.9Hz,1H),4.16–3.98(m,3H),3.93(dd,J=10.2,5.8Hz,1H),3.78(dd,J=8.9,5.1Hz,1H),1.28(d,J=4.6Hz,6H);

[0100] LC-MS(ESI):[M+H] + =280.2.

[0101] Step Six: Synthesis of Compounds 4-7

[0102] Compounds 4-6 (120 mg, 0.32 mmol) were dissolved in dichloromethane (3 mL), and triethylamine (0.1 mL, 0.97 mmol) and 3-(5-aminopyridin-2-yl)-5-((R)-2,2-dimethyl-1,3-dioxocyclopentan-4-yl)oxazolidin-2-one (107.91 mg, 0.39 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated sodium bicarbonate solution, extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to give 180 mg of a yellow oily product, with a yield of 90.8%.

[0103] LC-MS(ESI):[M+H] + =616.1.

[0104] Step 7: Synthesis of Compound 4

[0105] Compound 4-7 (150 mg, 0.24 mmol) was dissolved in DCM (1 mL), and PTSA (125.89 mg, 0.73 mmol) was added. The reaction was carried out at 25 °C for 16 h, and the crude product was concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25 mm*10 μm, aqueous-organic phase, H2O (0.225% FA)-ACN gradient, initial gradient 40.00, final gradient 70.00, gradient time 10.00, pause time, flush gradient 100.00, flush time 11.00, flow rate 25.00 mL / min). The fraction obtained was lyophilized to give 123.15 mg of white solid, yield: 87.4%.

[0106] 1 H NMR (400MHz, DMSO-d6) δ = 10.39 (s, 1H), 8.58 (s, 1H), 8.05 (d, J = 1.2Hz, 2H), 7.16 (br d,J=6.8Hz,2H),5.37(d,J=5.2Hz,1H),5.09(d,J=10.4Hz,1H),4.86-4.78(m,1H),4.72(br d,J=3.2Hz,1H),4.25(br d,J=2.4Hz,1H),4.14-4.04(m,2H),3.96(d,J=2.0Hz,3H),3.81-3.73(m,1H),3.43(br d,J=6.0Hz,2H),2.77(br t,J=7.6Hz,1H),1.61(s,3H),0.73(br d,J=6.0Hz,3H);

[0107] LC-MS(ESI):[M+H] + =576.1.

[0108] Example 5

[0109] Step 1: Synthesis of Compound 5-2

[0110] Under a nitrogen atmosphere, cesium carbonate (20.55 g, 63.08 mmol) and Pd(dppf)Cl2.CH2Cl2 (1.29 g, 1.58 mmol) were added to a mixed solution of 150 mL of 2-methyltetrahydrofuran and 15 mL of water containing compound 5-1 (5 g, 31.54 mmol) and potassium ethylenetrifluoroborate (5.07 g, 37.85 mmol). The reaction solution was heated to 90 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was added and cooled to room temperature. The mixture was concentrated, and 50 mL of water was added to dilute the residue. The residue was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reverse-phase preparation (0.1% FA) and silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 2 (2.21 g, 14.72 mmol), a pink solid, with a yield of 46.6%.

[0111] 1 H NMR (400MHz, CDCl3) δ = 9.39 (d, J = 2.4Hz, 1H), 8.44 (dd, J = 2.4, 8.4Hz, 1H), 7.48 (d, J = 8. 4Hz, 1H), 6.91 (dd, J=10.8, 17.6Hz, 1H), 6.46 (d, J=17.6Hz, 1H), 5.75 (d, J=10.8Hz, 1H).

[0112] Step 2: Synthesis of Compound 5-3

[0113] Under a nitrogen atmosphere, 4.3 mL of an aqueous solution of osmium tetroxide (0.1 mL, 0.25 mmol) was slowly added dropwise to a mixed solution of 4.3 mL of water and 16 mL of acetone containing N-methylmorpholine oxide (4353.92 mg, 37.17 mmol) and compound 5-2 (1860.00 mg, 12.39 mmol). After the addition was complete, the reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to 0 °C, quenched with 50 mL of saturated sodium sulfite aqueous solution, and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 mL × 15). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain compound 3 (1.16 g, 6.30 mmol), a pale yellow solid, with a yield of 50.8%.

[0114] 1H NMR (400MHz, DMSO-d6) δ = 9.29 (d, J = 2.4Hz, 1H), 8.58 (dd, J = 2.8, 8.8Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 5.7 6(d,J=5.2Hz,1H),4.79(t,J=6.0Hz,1H),4.72(q,J=5.2Hz,1H),3.78-3.69(m,1H),3.62-3.53(m,1H).

[0115] Step 3: Synthesis of Compound 5-4

[0116] Under a nitrogen atmosphere, p-toluenesulfonic acid (120 mg, 0.67 mmol) and 2,2-dimethoxypropane (2.1 mL, 16.70 mmol) were added to a mixed solution of 20 mL of 2-methyltetrahydrofuran and 20 mL of acetone containing compound 5-3 (1230.00 mg, 6.68 mmol). The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was complete, 10 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was diluted with 50 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 5-4 (1.40 g, 6.24 mmol), a white solid, with a yield of 93.5%.

[0117] 1 H NMR (400MHz, DMSO-d6) δ = 9.32 (d, J = 2.4Hz, 1H), 8.63 (dd, J = 2.4, 8.4Hz, 1H), 7.76 (d, J = 8.8Hz, 1H), 5.2 7(t,J=6.4Hz,1H),4.45(dd,J=7.2,8.4Hz,1H),3.91(dd,J=6.0,8.4Hz,1H),1.46(s,3H),1.43(s,3H);

[0118] LC-MS(ESI):[M+H] + =224.9.

[0119] Step 4: Synthesis of Compound 5-5

[0120] Under an argon atmosphere, 10% Pd / C (100 mg, 0.09 mmol) was added to 28 mL of ethyl acetate solution containing compound 5-4 (700 mg, 3.12 mmol). After three purgings with hydrogen, the reaction mixture was stirred at 25 °C for 6 hours under a hydrogen (15 psi) atmosphere. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 5-5 (590 mg, 3.04 mmol), a pale green oil, with a yield of 97.3%.

[0121] 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (d, J = 2.4Hz, 1H), 7.12 (d, J = 8.4Hz, 1H), 6.92 (dd, J = 2.8, 8.4Hz, 1H), 5.30 (s ,2H),4.92(t,J=6.8Hz,1H),4.21(dd,J=6.4,8.0Hz,1H),3.78(t,J=7.6Hz,1H),1.39(s,3H),1.36(s,3H);

[0122] LC-MS(ESI):[M+H] + =195.0.

[0123] Step 5: Synthesis of compounds 5-7

[0124] Under a nitrogen atmosphere, triethylamine (559.4 μL, 4.02 mmol) was added to 10 mL of dichloromethane solution containing compounds 5-6 (500 mg, 1.34 mmol) and 5-5 (260.56 mg, 1.34 mmol). The reaction solution was reacted at 25 °C for 1 hour. After the reaction was complete, 10 mL of water was added to dilute the reaction solution. The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 5-7 (590 mg, 1.11 mmol), a pale yellow oil, with a yield of 82.9%.

[0125] 1H NMR (400MHz, DMSO-d6) δ = 10.44 (s, 1H), 8.70 (dd, J = 2.4, 5.2Hz, 1H), 8.05 (ddd, J = 2.4 ,5.2,8.4Hz,1H),7.44(d,J=8.4Hz,1H),7.22-7.10(m,2H),5.17-4.99(m,2H),4.32( dd,J=6.8,8.0Hz,1H),4.23(dd,J=7.6,10.4Hz,1H),3.94(d,J=2.0Hz,3H),3.81(dd, J=6.8,8.0Hz,1H),2.79-2.72(m,1H),1.60(s,3H),1.41(s,3H),1.38(s,3H),0.73(br d,J=6.0Hz,3H);

[0126] LC-MS(ESI):[M+H] + =531.2.

[0127] Step Six: Synthesis of Compounds 5-8

[0128] Under a nitrogen atmosphere, TFA (0.4 mL, 5.28 mmol) was added to 4.5 mL of dichloromethane solution containing compound 5-7 (140 mg, 0.26 mmol). The reaction solution was reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by reverse-phase preparation (Waters Xbridge 150 × 25 mm × 5 μm, water (water(NH4HCO3)-ACN, 30%-60% over 25 min). Compound 5-8 (82 mg, 0.16 mmol), a white solid, was obtained, yield: 63.1%.

[0129] 1H NMR (400MHz, DMSO-d6) δ = 10.39 (s, 1H), 8.65 (d, J = 2.4Hz, 1H), 7.97 (dd, J = 2 .4,8.4Hz,1H),7.42(d,J=8.4Hz,1H),7.22-7.11(m,2H),5.44-5.26(m,1H), 5.08(d,J=10.4Hz,1H),4.72-4.59(m,1H),4.53(dd,J=4.0,6.4Hz,1H),4.2 3(dd,J=7.6,10.4Hz,1H),3.94(d,J=2.0Hz,3H),3.66-3.58(m,1H),3.43(br dd,J=6.8,10.4Hz,1H),2.82-2.71(m,1H),1.60(s,3H),0.73(br d,J=6.0Hz,3H);

[0130] LC-MS(ESI):[M+H] + =491.2;

[0131] Step 7: Synthesis of compounds 5-9

[0132] Under ice bath conditions, compound 5-8 (57 mg, 116.22 μmol) and dichloromethane (2 mL) were added to a 25 mL single-necked flask, followed by triethylamine (19.4 μL, 139.47 μmol), and then methanesulfonyl chloride (9.4 μL, 122.04 μmol). The mixture was stirred under ice bath conditions after the addition was complete. The solution was concentrated under reduced pressure, and DCM:MeOH (20:1) was purified by silica gel column chromatography to give a white solid compound (30 mg, 0.05 mmol, 45.4%).

[0133] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=2.3Hz,1H),8.39(s,1H),8.05(dd,J=8.5,2.5Hz,1H),7.30(d, J=8.5Hz,1H),7.02(ddd,J=8.1,5.5,2.1Hz,1H),6.83(td,J=9.2,7.4Hz,1H),4.99–4.92(m,2H) ,4.40(dd,J=10.7,3.9Hz,1H),4.32(dd,J=10.8,6.3Hz,1H),4.04(dd,J=11.0,8.0Hz,1H),3.94 (d,J=2.8Hz,3H),2.96(s,3H),2.69(p,J=7.7Hz,1H),1.62(d,J=1.2Hz,3H),0.77–0.64(m,3H);

[0134] LC-MS(ESI):[M+H] + =569.3.

[0135] Step 8: Synthesis of Compound 5

[0136] Oxymethane hydrochloride (3.21 mg, 0.09 mmol) was dissolved in methanol (2 mL), and NaOH (70.36 mg, 1.76 mmol) was added. The mixture was stirred for 10 min, and the methanol solution of methoxyamine was distilled off. Compound 5-9 (100 mg, 0.18 mmol) was added to the solution, and the reaction mixture was stirred at 80 °C for 16 h. The product was then purified by high performance liquid chromatography (Boston Green ODS 150*30 mm*5 μm, H₂O (0.225% FA)-ACN) and lyophilized to give 10.5 mg of a white solid product, with a yield of 11.5%.

[0137] 1 H NMR (400MHz, DMSO-d6) δ=10.41(s,1H),8.76-8.56(m,1H),8.11-7.92(m,1H),7.44(d,J=8.5Hz,1H),7.25-7.06(m,2H),6.85-6.31(m,1H),5.51(br d,J=4.1Hz,1H),5.10(d,J=10.3Hz,1H),4.80-4.62(m,1H),4.24(dd,J=7.6,10.3Hz,1H),3.95(d, J=2.0Hz,3H),3.40(s,3H),3.17(dd,J=3.6,13.0Hz,1H),2.84-2.70(m,2H),1.60(s,3H),0.73(br d,J=6.0Hz,3H);

[0138] LC-MS(ESI):[M+H] + =520.2.

[0139] Example 6

[0140] Step 1: Synthesis of compounds 5-8A and 5-8B

[0141] Compounds 5-8 were resolved by SFC (Column: DAICL CHIRALCEL OX (250×50mm×10um); Condition: CO2-EtOH (0.1% NH3H2O); B%: 15-15; Gradient Time (min): 5; 100%; B Hold Time (min): 0; Flow Rate (ml / min): 150), and then purified again by reverse phase (Atels Xbridge 150×25mm×5um, water (water(NH4HCO3)-ACN, 35%-65% over 25min)) to give: compound 5-8A (40.86mg, 0.08mmol), white solid, yield: 31.2%; compound 5-8B (41.28mg, 0.08mmol), grayish-white solid, yield: 31.9%.

[0142] Compound 5-8A:

[0143] 1 H NMR (400MHz, DMSO-d6) δ = 10.39 (s, 1H), 8.64 (d, J = 2.4Hz, 1H), 8.00 (dd, J = 2.4, 8.4Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.22-7.11 (m, 2H), 5.35 (br s,1H),5.08(d,J=10.4Hz,1H),4.65(br s,1H),4.53(dd,J=4.0,6.4Hz,1H),4.23(dd,J=7.6,10.4Hz,1H),3.94(d,J=2.0Hz,3H),3.66-3.58(m,1H),3.43(br dd,J=6.8,10.4Hz,1H),2.76(t,J=7.6Hz,1H),1.60(s,3H),0.73(br d,J=6.0Hz,3H);

[0144] LC-MS(ESI):[M+H] + =491.2.

[0145] Compound 5-8B:

[0146] 1H NMR (400MHz, DMSO-d6) δ=10.38(s,1H),8.66(d,J=2.0Hz,1H),7.97(dd,J=2.4,8.4Hz,1H ),7.42(d,J=8.4Hz,1H),7.21-7.12(m,2H),5.44-5.26(m,1H),5.08(d,J=10.4Hz,1H),4 .72-4.59(m,1H),4.53(dd,J=4.0,6.4Hz,1H),4.23(dd,J=7.6,10.4Hz,1H),3.94(d,J=2 .0Hz,3H),3.66-3.58(m,1H),3.47-3.42(m,1H),2.82-2.71(m,1H),1.60(s,3H),0.73(br d,J=5.6Hz,3H);

[0147] LC-MS(ESI): [M+H]+=491.2.

[0148] Step 2: Synthesis of Compound 6

[0149] Compound 5-8A and ultra-dry DCM (2 mL) were added to a 25 mL single-necked flask under ice bath conditions, followed by dropwise addition of boron tribromide (dichloromethane solution, 1 M) (76.6 mg, 305.85 μmol). After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 10 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (5 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase chromatography to obtain 16 mg of a white solid, with a yield of 32.9%.

[0150] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.65(s,1H),8.00(d,J=8.5Hz,1H),7.42(d,J=8.6Hz,1H),7.02(d,J=8.2Hz,1H),6.84(d,J=9.1Hz,1H),5.35 (s,1H),5.09(d,J=10.3Hz,1H),4.60(d,J=44.1Hz,2H),4.24(t,J=9.1Hz ,1H),3.61(s,2H),2.92–2.78(m,1H),1.59(s,3H),0.71(d,J=7.4Hz,3H);

[0151] LC-MS(ESI):[M+H] + =476.9.

[0152] Example 7

[0153] Step 1: Synthesis of Compound 7-2

[0154] Under a nitrogen atmosphere, compound 5-8 (1.35 g, 2.75 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 °C, and triethylamine (0.84 g, 8.26 mmol) was added. Methylsulfonyl chloride (0.41 g, 3.58 mmol) was added dropwise, and the mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (2 × 30 mL), washed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.40) to give compound 7-2 (167 mg, 0.35 mmol), a colorless oil, yield: 12.8%.

[0155] LC-MS(ESI):[M+H] + =473.1.

[0156] Step 2: Synthesis of Compound 7-3

[0157] Under a nitrogen atmosphere, compound 7-2 (117 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium methanethiol (35 mg, 0.50 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed successively with water (3 × 20 mL) and saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 7-3 (130 mg, 0.25 mmol), a pale yellow oil, with a yield of 100%.

[0158] LC-MS(ESI):[M+H] + =521.1.

[0159] Step 3: Synthesis of Compound 7-4

[0160] Under a nitrogen atmosphere, imidazole (102.02 mg, 1.5 mmol) was added to a tetrahydrofuran (5 mL) solution containing compound 7-3 (130 mg, 0.25 mmol), followed by the addition of TBSCl (112.93 mg, 0.75 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (2 × 30 mL), and the combined organic phases were washed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.45) to give compound 7-4 (137 mg, 0.22 mmol), a colorless oil, yield: 86.4%.

[0161] LC-MS(ESI):[M+H] + =635.2.

[0162] Step 4: Synthesis of Compounds 7-5

[0163] Compound 7-4 (127 mg, 0.20 mmol) was dissolved in methanol (5 mL), and diacetoxyiodobenzene (137 mg, 0.42 mmol) and ammonium acetate (25 mg, 0.32 mmol) were added sequentially. The mixture was reacted at 25 °C for 2 hours. The reaction was quenched with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (3 × 20 mL), and the combined organic phases were washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 15 / 1, Rf = 0.60) to give compound 7-5 (90 mg, 0.14 mmol), a colorless oil, yield: 67.6%.

[0164] LC-MS(ESI):[M+H] + =666.3.

[0165] Step 5: Synthesis of Compounds 7-6

[0166] Compound 7-5 (70 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (0.5 mL, 0.50 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed successively with water (3 × 20 mL) and saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase preparation (column: Watwers xbridge 150*25mm 10um, aqueous-organic phase: H2O(10mMNH4HCO3)-CAN, initial gradient: 32.00, final gradient: 62.00, gradient time: 15.00, flush gradient: 100.00, flush time: 2.00, flow rate: 25.00) to give compound 6 (30mg, 0.05mmol), a white solid, yield: 51.7%.

[0167] LC-MS(ESI):[M+H] + =552.1.

[0168] Step Six: Synthesis of Compound 7

[0169] Compounds 7-6 (30 mg, 0.05 mmol) were separated by chirality (column: DAICL CHIRALPAK AD (250 mm * 50 mm, 10 μm), aqueous-organic phase: CO2-EtOH, initial gradient: 20.00, final gradient: 20.00, gradient time: 8.50, flush gradient: 100.00, flow rate: 150.00 mL / min) to give compound 7 (28.1 mg, 0.05 mmol), a light pink solid, yield: 93.1%.

[0170] 1H NMR (400MHz, DMSO-d6) δ = 10.45 (s, 1H), 8.70 (d, J = 2.0Hz, 1H), 8.08-8.05 (m, 1H), 7.5 1(d,J=8.4Hz,1H),7.19-7.16(m,2H),6.15-6.09(m,1H),5.12-5.01(m,2H),4.27-4. 22(m,1H),3.95(d,J=2.0Hz,3H),3.81-3.79(m,1H),3.48-3.37(m,1H),3.29-3.23(m ,1H),3.00(d,J=11.2Hz,3H),2.81-2.73(m,1H),1.61(s,3H),0.74(d,J=6.0Hz,3H);

[0171] LC-MS(ESI):[M+H] + =552.2.

[0172] Step 7: Synthesis of Compound 7A and Compound 7B

[0173] Compound 7 was resolved by SFC (column: DAICEL CHIRALPAK IG 250mm×30mm×5um; mobile phase: [A:CO2; B:IPA (0.1% NH3 H2O)]; B%: 30.00%-30.00%, 6.00min; flow rate: 60.00g / min) to obtain crude compound 7A (5mg, 83purity) and P2 (8mg, 60purity). Crude compound 7A was then prepared by prep-HPLC (column: Waters xbridge 150×25mm 10um; mobile phase: [A:H2O (10mM NH4HCO3); B:ACN]; B%: 42.00%-62.00%, 8.00min; flow rate: 25.00ml / min) to obtain compound 7A (2.6mg, 20.0%). The crude compound 7B was prepared by prep-HPLC (column: Waters xbridge 150×25mm 10um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 42.00%-62.00%, 8.00min; flow rate: 25.00ml / min) to obtain compound 7B (4.51mg, 34.0%).

[0174] Compound 7A: 1 H NMR (400MHz, DMSO-d6) δ = 10.44 (s, 1H), 8.69 (d, J = 2.4Hz, 1H), 8.06 (dd, J = 2.8 ,8.8Hz,1H),7.50(d,J=8.6Hz,1H),7.20-7.13(m,2H),6.09(d,J=5.0Hz,1H),5 .13-5.05(m,2H),4.24(dd,J=8.0,10.4Hz,1H),3.95(d,J=2.0Hz,3H),3.78(s ,1H),3.46-3.34(m,2H),2.97(s,3H),2.80-2.72(m,1H),1.60(s,3H),0.73(br d, J = 6.4 Hz, 3H);

[0175] LC-MS(ESI):[M+H] + =552.2.

[0176] Compound 7B: 1H NMR (400MHz, DMSO-d6) δ = 10.44 (s, 1H), 8.69 (d, J = 2.4Hz, 1H), 8.06 (dd, J = 2.4, 8.4Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 7.20-7.13 (m, 2H), 6.14 (d, J = 5.0 Hz,1H),5.09(d,J=10.4Hz,1H),5.02(ddd,J=2.8,5.0,7.6Hz,1H),4.24(dd,J=8.0,10.0Hz,1H),3.95(d,J=2.0Hz,3H),3.82-3.78(m,1H),3.46(br d,J=14.4Hz,1H),3.32-3.24(m,1H),3.00(s,3H),2.76(t,J=7.6Hz,1H),1.60(s,3H),0.73(br d,J=6.8Hz,3H);

[0177] LC-MS(ESI):[M+H] + =552.2.

[0178] Example 8

[0179] Step 1: Synthesis of Compound 8-2

[0180] Compound 8-1 (5.4 mL, 29.26 mmol), N,O-dimethylhydroxylamine hydrochloride (8.56 g, 87.78 mmol), DIEA (24.2 mL, 146.30 mmol), HATU (11.68 g, 30.72 mmol), and N,N-dimethylformamide (80 mL) were added sequentially to a 250 mL single-necked flask. After the addition was complete, the mixture was transferred to room temperature and stirred until the reaction was complete as monitored by TLC. Pure water and ethyl acetate were added, and the organic phase was separated. The organic phase was washed three times with saturated brine and concentrated under reduced pressure to give 8.2 g of a pale yellow, clear liquid, with a yield of 99.3%.

[0181] LC-MS(ESI):[M+H] + =283.2.

[0182] Step 2: Synthesis of Compound 8-3

[0183] Compound 8-2 (8.26 g, 29.26 mmol), imidazole (3.6 mL, 52.67 mmol), TBDMSCl (7.6 mL, 43.89 mmol), and tetrahydrofuran (80 mL) were added sequentially to a 250 mL single-necked flask. After addition, the mixture was transferred to room temperature and stirred overnight. Saturated brine was added, and the mixture was washed with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by wet silica gel column chromatography (PE:EA = 10:1-5:1) to obtain 9.08 g of a colorless oily product, with a yield of 78.3%.

[0184] 1 H NMR(400MHz, CDCl3)δ7.36–7.26(m,5H),5.63(d,J=8.8Hz,1H),5.19–4.99(m,2H),4.8 6–4.67(m,1H),3.92–3.77(m,2H),3.74(s,3H),3.20(s,3H),0.84(s,9H),0.00(s,6H);

[0185] LC-MS(ESI):[M+H] + =397.3.

[0186] Step 3: Synthesis of Compound 8-4

[0187] Under nitrogen protection at -78°C, 2-methylpropyl-2-yl [(6-bromopyridin-3-yl)amino]methane-2-methylprop-2-yl ester (4.13 g, 15.13 mmol) and THF (20 mL) were added to a 50 mL single-necked flask, followed by a 1.6 M n-butyllithium solution in n-hexane (1.78 g, 27.74 mmol), and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran (20 mL) containing compound 8-3 (5 g, 12.61 mmol) was slowly added to the system, and stirring was continued at room temperature for 1 hour after the addition was complete. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 6:1-1:1) to give 2 g of a yellow oily product, with a yield of 29.9%.

[0188] LC-MS(ESI):[M+H] + =530.3.

[0189] Step 4: Synthesis of Compound 8-5

[0190] Compound 8-4 (139 mg, 3.68 mmol) was added to a 50 mL single-necked flask under ice bath conditions, followed by 10 mL of methanol, and the mixture was transferred to room temperature and stirred until the reaction was complete as monitored by TLC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 2:1) to give 700 mg of a colorless oily product, with a yield of 46.5%.

[0191] 1 H NMR(400MHz, CDCl3)δ8.35(d,J=2.6Hz,1H),7.89(s,1H),7.33–7.23(m,8H),5.06(s,2H),4.9 7–4.92(m,1H),3.50–3.38(m,1H),2.20–2.17(m,2H),1.20(s,9H),0.83(s,9H),-0.00(s,6H);

[0192] LC-MS(ESI):[M+H] + =532.1.

[0193] Step 5: Synthesis of Compounds 8-6

[0194] At room temperature, compound 8-5 (700 mg, 1.32 mmol) and THF (10 mL) were added to a 50 mL single-necked flask, followed by sodium hydride (60%, dispersed in liquid paraffin) (41.1 mg, 1.71 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was then quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 1:1) to give compound 8-6 (88 mg, 15.8% yield, colorless oil) and compound 8-6' (137 mg, 24.6% yield, colorless transparent solid).

[0195] LC-MS(ESI):[M+H] + =424.1.

[0196] Step Six: Synthesis of Compounds 8-7

[0197] Under a nitrogen atmosphere, compound 8-6 (153 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL, 6.73 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 8-7 (116 mg, 0.36 mmol), a yellow oil, with a yield of 99.3%.

[0198] LC-MS(ESI):[M+H] + =324.2;

[0199] Step 7: Synthesis of Compound 8

[0200] Under a nitrogen atmosphere, 1-butylphosphine anhydride (183.04 mg, 0.25 mmol) was added to a solution of N,N-dimethylformamide (3 mL) containing compound 8-7 (75 mg, 0.23 mmol), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxybenzene)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (60 mg, 0.17 mmol), and DIPEA (65.67 mg, 0.51 mmol). The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction solution was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse pre-processing (column: Waters xbridge 150*25mm 10µm, aqueous-organic phase: H2O (10mM NH4HCO3)-CAN, initial gradient: 40.00, ending gradient: 70.00, gradient time: 9.00, flush gradient: 100.00, flush time: 2.00, flow rate: 25.00 mL / min) to obtain the product (30.4 mg, 0.05 mmol), a white solid, yield: 32.0%.

[0201] 1 H NMR (400MHz, DMSO-d6) δ = 10.51 (s, 1H), 8.58 (d, J = 2.4Hz, 1H), 8.12-8.09 (m, 1 H),7.83(s,1H),7.41(d,J=8.4Hz,1H),7.19-7.15(m,2H),5.27(d,J=4.8Hz,1H ),5.12-5.08(m,2H),4.27-4.22(m,1H),3.95(d,J=2.0Hz,3H),3.79-3.77(m, 1H),3.52-3.48(m,2H),2.79-2.75(m,1H),1.61(s,3H),0.73(d,J=5.6Hz,3H);

[0202] LC-MS(ESI):[M+H] + =546.2.

[0203] Example 9

[0204] Step 1: Synthesis of Compound 9-2

[0205] Under ice bath and nitrogen protection, 9-1 (1600 mg, 7.14 mmol), hydrazine hydrate (0.4 mL, 8.56 mmol), THF (40 mL), and rhodium on carbon (11 mg, 0.02 mmol) were added to a 25 mL two-necked flask. After addition, stirring continued under ice bath conditions until the reaction was complete as monitored by TLC. The black insoluble matter was removed by filtration, the solution was concentrated under reduced pressure, and purified by wet loading onto silica gel column chromatography at a PE:EA ratio of 10:1–1:1, yielding 1400 mg of a yellow-green oily product (93.3% yield).

[0206] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,2H),8.08(d,J=2.5Hz,1H),7.30(d,J=8.4Hz,1H),7.22(dd,J=8.4,2.6Hz,1H ),5.01(t,J=6.8Hz,1H),4.28(dd,J=8.1,6.5Hz,1H),3.82(dd,J=8.1,7.1Hz,1H),1.42(s,3H),1.38(s,3H);

[0207] LC-MS(ESI):[M+H] + =211.1.

[0208] Step 2: Synthesis of Compound 9-3

[0209] Add (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxybenzene)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxyl chloride (500 mg, 1.34 mmol), compound 9-2 (500 mg, 2.38 mmol), dichloromethane (10 mL), and triethylamine (0.7 mL, 5.37 mmol) to a 25 mL single-necked flask. Stir overnight at room temperature. Wash three times with saturated brine, separate the organic phase, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (PE:EA = 4:1-1:1) to give 700 mg of a yellow oily product (98.4% yield).

[0210] 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.81(s,1H),8.04(d,J=8.7Hz,1H),7.52(d,J= 8.6Hz,1H),7.25–7.00(m,2H),5.64(d,J=8.8Hz,1H),5.11(t,J=6.7Hz,1H),4.30(d,J =8.5Hz,1H),3.95(d,J=2.1Hz,3H),3.84(dd,J=8.3,6.5Hz,1H),2.80(t,J=7.7Hz,1H) ,2.22(t,J=7.3Hz,1H),1.58(s,3H),1.43(s,3H),1.40(s,3H),0.77(d,J=7.2Hz,3H);

[0211] LC-MS(ESI):[M+H] + =547.1.

[0212] Step 3: Synthesis of Compound 9

[0213] Compound 9-3 (350 mg, 0.64 mmol), dichloromethane (2 mL), and dioxane hydrochloride solution (1 mL, 3.66 mmol) were added to a 25 mL single-necked flask. The mixture was stirred at room temperature until the reaction was complete as monitored by TLC. Saturated sodium bicarbonate was added to adjust the pH to neutral, followed by extraction three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reversed-phase preparative chromatography to give 200 mg of a white solid, with a yield of 61%.

[0214] 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.74(s,1H),8.02–7.89(m,1H),7.49(d,J=8.7Hz ,1H),7.20–7.08(m,2H),5.64(d,J=8.9Hz,1H),5.48–5.38(m,1H),4.68(t,J=5.9Hz,1H ),4.57(d,J=5.6Hz,1H),4.31(d,J=8.5Hz,1H),3.95(d,J=2.1Hz,3H),3.65(dt,J=10.5 ,5.1Hz,1H),3.46(dt,J=10.7,6.1Hz,1H),2.84–2.77(m,1H),1.57(s,3H),0.76(s,3H);

[0215] LC-MS(ESI):[M+H] + =507.1.

[0216] Example 10

[0217] Step 1: Synthesis of Compound 10-2

[0218] Under a nitrogen atmosphere, DABCO (0.74 g, 6.57 mmol) was added to a mixed solution of dioxane (10 mL) and water (10 mL) containing compound 10⁻¹ (1 g, 6.57 mmol) and methyl propionate (1.6 mL, 17.66 mmol). The reaction mixture was stirred at 25 °C for 36 hours. After the reaction was complete, 50 mL of dichloromethane was added to the reaction mixture, and the mixture was filtered. 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with 30 g of silica gel to obtain a crude product. The crude product, after being mixed with silica gel, was slurried with 50 mL of ethyl acetate, filtered, and the filtrate was concentrated to obtain pure compound 10⁻² (1.4 g, 6.13 mmol), a yellow oily substance, with a yield of 93.2%.

[0219] LC-MS(ESI):[M+H] + =239.1.

[0220] Step 2: Synthesis of Compound 10⁻³

[0221] Under a nitrogen atmosphere and at -78°C, DIBAL-H (5.7 mL, 5.67 mmol) was added dropwise to a solution of compound 10⁻² (900 mg, 3.78 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at -78°C for 1 hour. At low temperature, 5 g of an aqueous solution of potassium sodium tartrate (20 mL) was slowly added dropwise to the reaction mixture. After returning to room temperature, dichloromethane (20 mL) was added, and the combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (PE / EA = 10 / 1 - 0 / 1) to give compound 10⁻³ (130 mg, 0.51 mmol), a yellow solid, yield: 13.6%.

[0222] LC-MS(ESI):[M+H] + =211.1.

[0223] Step 3: Synthesis of compound 10⁻⁴

[0224] Under a nitrogen atmosphere, benzaldehyde (0.2 mL, 1.86 mmol) was added to a toluene (2 mL) solution containing compound 10⁻³ (130 mg, 0.62 mmol) and p-toluenesulfonic acid (10.65 mg, 0.06 mmol). The reaction mixture was stirred at 110 °C for 2 hours. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase preparation (Phenomenex Luna C18 column 150*25mm*10um, aqueous phase-organic phase, H2O (0.1% NH3·H2O)-ACN start gradient, 50.00, end gradient, 60.00, gradient time, 10.00, pause time, flush gradient, 100.00, flush time, 5.00, flow rate, 25.00), and lyophilized to give compound 10⁻⁴ (100 mg, 0.21 mmol), a brown oil, yield: 34.1%.

[0225] LC-MS(ESI):[M+H] + =299.1.

[0226] Step 4: Synthesis of Compound 10-5

[0227] Compound 10-4 (50 mg, 0.17 mmol) was dissolved in DMF (1 mL), followed by the addition of 4-(pyridin-4-yl)pyridine (2.62 mg, 0.02 mmol) and tetrahydroxydiboron (60.11 mg, 0.67 mmol). The reaction was carried out at 25 °C for 1 h. The solution was concentrated under reduced pressure and purified by reverse-phase chromatography (Phenomenex Luna C18 column, 150*25 mm*10 μm; aqueous-organic phase; H2O (0.225% FA)-ACN gradient: initial gradient 48.00, final gradient 78.00, gradient time 10.00, pause time, flush gradient 100.00, flush time 5.00, flow rate 25.00). The product fraction was lyophilized to give compound 10-5 (35 mg, 0.13 mmol), a white solid, yield: 77.8%.

[0228] LC-MS (ESI): [M+Na] + =291.0.

[0229] Step 5: Synthesis of Compound 10-7

[0230] Compound 10⁻⁵ (30 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL) and added dropwise to a dichloromethane solution of compound 10⁻⁶ (50 mg, 0.33 mmol) and triethylamine (0.1 mL, 0.56 mmol). The mixture was stirred at 20 °C for 16 hours. After dilution with 20 mL of water, the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried, filtered, and concentrated. Reversed-phase column purification (Phenomenex Luna C18 150*25mm*10um column, aqueous-organic phase, H2O (0.225% FA)-ACN, initial gradient 48.00, ending gradient 78.00, gradient time 10.00, pause time, flush gradient 100.00, flush time 5.00, flow rate 25.00 ml / min), the obtained fraction was lyophilized to give compound 10⁻⁷ (50 mg, 0.08 mmol), a yellow solid, yield: 33.7%.

[0231] LC-MS(ESI):[M+H] + =605.2.

[0232] Step Six: Synthesis of Compound 10

[0233] Compound 10-7 (30 mg, 0.05 mmol) was dissolved in acetonitrile (0.2 mL), and PPTS (62.35 mg, 0.25 mmol) was added. The reaction was carried out at 25 °C for 4 h. The solution was concentrated under reduced pressure and purified by reverse-phase chromatography (Phenomenex Luna C18 column 150*25 mm*10 μm, aqueous-organic phase, H2O (0.225% FA)-ACN gradient, initial gradient 48.00, final gradient 78.00, gradient time 10.00, pause time, flush gradient 100.00, flush time 5.00, flow rate 25.00). The solution was lyophilized to give Example 10 (30 mg, 0.06 mmol), a yellow solid, yield: 112.4%. Further separation was performed using SFC (column: DAIICEL CHIRALPAK IK (250mm*25mm, 10um); mobile phase: [A: CO2; B: IPA (0.1% NH3H2O)]; B%: 25.00%-25.00%, 3.80 min; flow rate: 55.00 g / min). After purification, the product was lyophilized to obtain Example 10A (9.61 mg, 0.02 mmol), an off-white solid with a yield of 28.0%; and Example 10B (17.46 mg, 0.03 mmol), a yellow solid with a yield of 59.1%.

[0234] Compound 10A:

[0235] 1 H NMR (400MHz, DMSO-d6) δ = 10.40 (s, 1H), 8.65 (d, J = 2.4Hz, 1H), 7.99 (dd, J = 2.4, 8.8Hz, 1H), 7.40 (d, J = 8.4Hz, 1H), 7.22-7.07 (m, 2 H),5.60(d,J=4.4Hz,1H),5.11-5.00(m,4H),4.72(t,J=5.6Hz,1H),4.24(dd,J=7.6,10.4Hz,1H),3.95(d,J=2.0Hz,3H),3.87(br d,J=2.8Hz,1H),3.79(br d,J=4.8Hz,1H),2.76(t,J=7.2Hz,1H),1.60(s,3H),0.73(br d,J=6.4Hz,3H);

[0236] LC-MS(ESI):[M+H] + =517.1.

[0237] Compound 10B:

[0238] 1 H NMR (400MHz, DMSO-d6) δ = 10.40 (s, 1H), 8.64 (d, J = 2.4Hz, 1H), 8.01 (dd, J = 2.4, 8.4Hz, 1H), 7.40 (d, J = 8.4Hz, 1H), 7.15 (br d,J=6.4Hz,2H),5.60(d,J=4.4Hz,1H),5.18-4.97(m,4H),4.71(t,J=5.6Hz,1H),4.24(dd,J=7.2,10.4 Hz,1H),3.95(d,J=2.0Hz,3H),3.92-3.84(m,1H),3.82-3.72(m,1H),2.76(s,1H),1.60(s,3H),0.73(br d, J = 6.0 Hz, 3H);

[0239] LC-MS(ESI):[M+H] + =517.1.

[0240] Example 11

[0241] Step 1: Synthesis of Compound 11-2

[0242] Compounds 5-9 (150 mg, 0.26 mmol) were dissolved in ammonia-methanol solution (0.3 mL, 1.76 mmol), and the reaction mixture was reacted at 60 °C for 16 h. Water (1 mL) was added, followed by extraction with dichloromethane (2 mL x 2). The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20% MeOH in EtOAc) yielded compound 2 (120 mg, 0.25 mmol, 92.9%) as a yellow solid, yield: 92.9%.

[0243] LC-MS(ESI):[M+H] + =490.1.

[0244] Step 2: Synthesis of Compound 11-4

[0245] Under a nitrogen atmosphere, compounds 11-2 (120 mg, 0.25 mmol) and 11-3 (43.13 mg, 0.29 mmol) were dissolved in acetonitrile (5 mL), and triethylamine (0.1 mL, 0.74 mmol) was added. The reaction was carried out at 60 °C for 16 h. 20 mL of water was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase preparation (Phenomenex Luna C18 150*25mm*10um column, aqueous phase-organic phase, H2O (0.225% FA)-ACN start gradient, 48.00, end gradient, 78.00, gradient time, 10.00, pause time, flush gradient, 100.00, flush time, 5.00, flow rate, 25.00), and lyophilized to give 50 mg of compound 11-4 as a yellow solid, yield: 38.4%.

[0246] LC-MS(ESI):[M+H] + =532.1.

[0247] Step 3: Synthesis of Compound 11

[0248] Compound 11-4 (50 mg, 0.09 mmol) was purified by SFC. The sample was purified by rotary evaporation of the main peak obtained by (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 50.00%-50.00%, 3.60 min; flow rate: 75.00 g / min), and then lyophilized with acetonitrile and water to obtain Example 11 (31.43 mg, 0.06 mmol), a white solid, yield: 61.0%.

[0249] 1 H NMR (400MHz, DMSO-d6) δ = 10.73-10.46 (m, 1H), 8.73 (d, J = 2.0Hz, 1H), 8.46 (s, 1H), 8.07 (dd, J = 2.4, 8. 6Hz,1H),7.89-7.52(m,3H),7.50(d,J=8.4Hz,1H),7.24-7.09(m,2H),5.13(d,J=10.4Hz,1H),4.70(br dd,J=3.6,6.8Hz,1H),4.24(dd,J=7.6,10.4Hz,1H),3.95(d,J=2.0Hz,3H),3.47(br dd,J=3.2,13.2Hz,1H),3.38-3.36(m,1H),3.33-3.27(m,1H),2.77(br t,J=7.6Hz,1H),1.60(s,3H),0.73(br d,J=6.4Hz,3H);

[0250] LC-MS(ESI):[M+H] + =532.1.

[0251] Example 12

[0252] Step 1: Synthesis of Compound 12-2

[0253] Compound 12-1 (10 g, 36.61 mmol), methyl 3-mercaptopropionate (4.1 mL, 36.61 mmol), tris(dibenzylacetone)dipalladium (0.1 g, 0.11 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.1 g, 0.17 mmol), and potassium carbonate (10 g, 72.36 mmol) were added to dioxane (100 mL), purged three times with nitrogen, and stirred at 100 °C for 4 hours. The reaction mixture was diluted with ethyl acetate (200 mL), filtered, and evaporated to dryness. The residue was dissolved in ethyl acetate (300 mL), washed successively with water (100 mL x 2) and saturated brine (100 mL x 1), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness to obtain the crude product, and purified by silica gel column chromatography to obtain compound 12-2.

[0254] LC-MS(ESI):[M+H] + =313.0.

[0255] Step 2: Synthesis of Compound 12-3

[0256] Compound 12-2 (5 g, 16.01 mmol) was dissolved in methanol (50 mL), and sodium methoxide (1.73 g, 32.01 mmol) was slowly added. The mixture was stirred at room temperature for 13 hours. Ethyl acetate (300 mL) was added to the reaction solution, and the mixture was washed successively with water (100 mL x 1) and saturated brine (100 mL x 2). The organic phase was filtered, and the crude product was evaporated to dryness. Compound 12-3 was purified by silica gel column chromatography.

[0257] LC-MS(ESI):[M+H] + =226.0.

[0258] Step 3: Synthesis of Compound 12-4

[0259] Compound 12-3 (500 mg, 2.21 mmol), sodium difluorochloroacetate (500 mg, 3.28 mmol), and cesium carbonate (1.5 g, 4.60 mmol) were added to acetonitrile (30 mL), heated to 70 °C, and stirred for 2 hours. The reaction solution was directly filtered, and the filtrate was purified by high-performance liquid chromatography to obtain compound 12-4.

[0260] LC-MS(ESI):[M+H] + =277.1.

[0261] Step 4: Synthesis of Compound 12-5

[0262] Compound 12-4 (170 mg, 0.62 mmol) was dissolved in anhydrous dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL, 6.73 mmol) was added. The mixture was stirred at 20 °C for 1 hour. The reaction solution was directly evaporated to dryness. The residue was dissolved in ethyl acetate (200 mL), washed successively with saturated sodium bicarbonate aqueous solution (80 mL x 2) and saturated brine (80 mL x 1), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solution was evaporated to dryness to give compound 12-5.

[0263] LC-MS(ESI):[M+H] + =177.1.

[0264] Step 5: Synthesis of Compounds 12-7

[0265] Compound 12-5 (100 mg, 0.57 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (180 mg, 0.64 mmol), and N-methylimidazole (130 mg, 1.58 mmol) were dissolved in acetonitrile (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product, which was purified by high performance liquid chromatography to obtain compound 12-6.

[0266] LC-MS(ESI):[M+H] + =513.2.0.

[0267] Step Six: Synthesis of Compounds 12A and 12B

[0268] Compound 12-7 (160 mg, 0.31 mmol), diacetyliodobenzene (260 mg, 0.80 mmol) and ammonium carbonate (150 mg, 0.86 mmol) were mixed in anhydrous methanol (5 mL) and the mixture was stirred at 50 °C for 12 hours. The reaction solution was filtered, the filtrate was concentrated, and the concentrate was separated twice by preparative high-performance liquid chromatography (HPLC) (Column: Phenomenex luna C18 150×25mm×10um, Mobile phase: A: H2O (0.225% FA); B: CAN, Gradient: B from 45.00% to 75.00% in 10.00 min, Flow rate: 25.00 ml / min) and (Column: Phenomenex Mobile phase: A: H2O (10mM NH4HCO3); B: CAN; Gradient: B from 48.00% to 78.00% in 10.00 min, Flow rate: 25.00 ml / min) to obtain a mixture 12 of compounds 12A and 12B. Mixture 12 was separated into two single isomers by a preparative SFC (column: DAICEL CHIRALCEL OX (250mm×30mm, 10um); mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 15.00%-15.00%; Gradient Time (min): 3.50min; flow rate: 150.00ml / min).

[0269] Compound 12A (retention time = 1.291 min; SFC analysis method: Column: CHIRALCEL OX-3 (50 mm × 4.6 mm ID, 3 μm); mobile phase: [A: CO2; B: EtOH (0.05% DEA)]; Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 ml / min):

[0270] 1H NMR(400MHz,DMSO-d6)δ=10.95(br s,1H),8.73-8.50(m,2H),8.02-7.80(m,1H),7.36-6.91(m,3H),5.83(s,1H),5.13(d,J=10.0Hz,1H),4.2 6(dd,J=8.0,10.0Hz,1H),3.95(d,J=2.0Hz,3H),2.78(t,J=7.6Hz,1H),1.61(s,3H),0.73(d,J=6.0Hz,3H)

[0271] LC-MS(ESI):[M+H] + =544.1.

[0272] Compound 12B (retention time = 1.431 min; SFC analytical method: Column: CHIRALCEL OX-3 (50 mm × 4.6 mm ID, 3 μm); mobile phase: [A: CO2; B: EtOH (0.05% DEA)]; Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 ml / min):

[0273] 1 H NMR (400MHz, DMSO-d6) δ = 10.96 (s, 1H), 8.66 (d, J = 5.6Hz, 1H), 8.56 (s, 1H), 7.95 (d, J = 5.2Hz, 1H), 7.36-6.98 (m, 3H), 5.83 (s, 1H), 5 .14(d,J=10.4Hz,1H),4.26(dd,J=8.0,9.6Hz,1H),3.95(d,J=2.0Hz,3H),2.77(d,J=7.6Hz,1H),1.61(s,3H),0.73(d,J=6.0Hz,3H)

[0274] LC-MS(ESI):[M+H] + =544.1.

[0275] Example 13

[0276] Step 1: Synthesis of Compound 13-3

[0277] Under a nitrogen atmosphere, compounds 13-1 (250 mg, 0.44 mmol) and 13-2 (71 mg, 0.53 mmol) were dissolved in anhydrous ethanol (5 mL), and potassium carbonate (183 mg, 1.32 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (50 mL). The residue was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.20) to give compound 3 (113 mg, 0.19 mmol), a pale yellow oil, in 42.4% yield.

[0278] LC-MS(ESI):[M+H] + =606.3;

[0279] Step 2: Synthesis of Compound 13-4

[0280] Under a nitrogen atmosphere, 1.5 mL of hydrochloric acid aqueous solution (1.5 mmol, 1 mol / L) was added to 5 mL of ethanol solution containing compound 13-3 (100 mg, 0.17 mmol). The reaction mixture was stirred at 25 °C for 36 hours. After the reaction was complete, the reaction mixture was concentrated. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150*25 mm*10 μm, aqueous-organic phase: H2O (0.2% FA)-CAN, initial gradient: 28.00, final gradient: 58.00, gradient time: 10.00, flush gradient: 100.00, flush time: 3.00, flow rate: 25.00 mL / min) to obtain compound 13-4 (50 mg, 0.1 mmol), a pale yellow solid, with a yield of 59.9%.

[0281] LC-MS(ESI):[M+H] + =506.2.

[0282] Step 3: Synthesis of Compound 13

[0283] Under a nitrogen atmosphere, compounds 13-4 (120 mg, 0.24 mmol) and 13-5 (69.60 mg, 0.47 mmol) were dissolved in acetonitrile (5 mL), and DIEA (153.43 mg, 1.19 mmol) was added. The mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase preparative chromatography (column: Waters xbridge 150*25 mm 10 μm, aqueous-organic phase: H2O (10 mM NH4HCO3)-CAN, needle number: 2, initial gradient: 32.00, final gradient: 62.00, gradient time: 15.00, flush gradient: 100.00, flush time: 2.00, flow rate: 25.00 mL / min) to obtain compound 13 (20 mg, 0.04 mmol), a white solid, yield: 12.8%.

[0284] LC-MS(ESI):[M+H] + =548.2.

[0285] Step 4: Synthesis of Compound 13A and Compound 13B

[0286] Compound 13 (20 mg, 0.04 mmol) was separated by chirality (column: DAICL CHIRALPAK AD (250 mm * 30 mm, 10 μm), aqueous-organic phase: CO2-EtOH (0.1% NH3H2O), number of needles: 50, initial gradient: 30.00, final gradient: 30.00, gradient time: 5.20, flush gradient: 100.00, flow rate: 60.00) to give compound 13A (6.88 mg, 0.01 mmol, white solid, yield: 34.4%) and APH04332 (6.48 mg, 0.01 mmol, white solid, yield: 32.4%).

[0287] Compound 13A: 1H NMR (400MHz, DMSO-d6) δ = 10.38 (s, 1H), 8.63 (d, J = 2.4Hz, 1H), 7.96-7.94 (m, 1H), 7.35 ( d,J=8.4Hz,1H),7.19-7.15(m,2H),5.42-5.27(m,1H),5.10-5.08(m,1H),4.85-4.81(m, 1H),4.60-4.58(m,1H),4.53-4.32(m,1H),4.25-4.21(m,1H),3.95(d,J=2.4Hz,3H),3.6 4-3.61(m,1H),3.55-3.52(m,1H),2.80-2.73(m,1H),1.60(s,3H),0.73(d,J=6.0Hz,3H)

[0288] LC-MS(ESI):[M+H] + =548.3.

[0289] Compound 13B: 1 H NMR (400MHz, DMSO-d6) δ = 10.37 (s, 1H), 8.66 (d, J = 2.4Hz, 1H), 7.95-7.92 (m, 1H), 7.36 (d,J=8.8Hz,1H),7.19-7.15(m,2H),5.61-5.34(m,1H),5.10-5.08(m,1H),4.89-4.86 (m,1H),4.61-4.58(m,1H),4.25-4.21(m,1H),3.95(d,J=2.0Hz,3H),3.64-3.61(m,1H ),3.58-3.53(m,1H),2.78-2.74(m,1H),1.60(s,3H),1.24(s,2H),0.74-0.73(m,3H);

[0290] LC-MS(ESI):[M+H] + =548.2.

[0291] Example 14

[0292] Step 1: Synthesis of Compound 14-2

[0293] Compounds 5-8 (250 mg, 0.51 mmol) were dissolved in THF (3 mL) and carbonyl diimidazole (107.45 mg, 0.66 mmol) were added. The reaction was carried out at 25 °C for 1 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure to give compound 2 (250 mg, 0.43 mmol), a white solid. The crude product was used directly in the next step. Yield: 83.9%.

[0294] LC-MS(ESI):[M+H] + =585.1.

[0295] Step 2: Synthesis of Compound 14

[0296] Compound 14-2 (250 mg, 0.43 mmol) was dissolved in THF (3 mL), and ammonia (1.6 mL, 12.83 mmol) was added. The reaction was carried out at 20 °C for 4 h. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Phenomenex Luna C18 column 150*25 mm*10 μm, aqueous-organic phase, H2O (0.225% FA)-ACN gradient, initial gradient 48.00, final gradient 78.00, gradient time 10.00, pause time, flush gradient 100.00, flush time 5.00, flow rate 25.00) to give compound 14 (60 mg, 0.11 mmol), a yellow solid, yield: 26.3%.

[0297] LC-MS(ESI):[M+H] + =534.2.

[0298] Step 3: Synthesis of Compound 14A and Compound 14B

[0299] Compound 14 (60 mg, 0.11 mmol) was analyzed via SFC column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [A: CO2; B: IPA (0.1% NH4+)] 3·[H2O]; B%: 40.00%-40.00%, 2.50 min; flow rate: 70.00 g / min. The two peaks obtained after purification were evaporated to dryness, and acetonitrile and water were added, and then freeze-dried to obtain compound 14A (13.86 mg, 0.03 mmol), a white solid, yield: 22.6%; and compound 14B (16.72 mg, 0.03 mmol), a white solid, yield: 27.5%.

[0300] Compound 14A: 1 H NMR (400MHz, DMSO-d6) δ = 10.44 (s, 1H), 8.68 (s, 1H), 8.06 (dd, J = 1.6, 8.4Hz, 1H), 7 .48(d,J=8.4Hz,1H),7.23-6.99(m,2H),6.63-6.23(m,2H),5.78-5.39(m,1H),5.1 0(d,J=10.4Hz,1H),4.73(dd,J=4.4,6.4Hz,1H),4.39-4.14(m,2H),4.00(dd,J=7. 2,11.2Hz,1H),3.95(d,J=2.0Hz,3H),2.77(t,J=7.6Hz,1H),1.61(s,3H),0.73(br d, J = 6.4 Hz, 3H);

[0301] LC-MS(ESI):[M+H] + =534.2.

[0302] Compound 14B: 1 H NMR (400MHz, DMSO-d6) δ = 10.49 (s, 1H), 8.76 (d, J = 2.3Hz, 1H), 8.09 (dd, J = 2.4, 8.4Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.22 (br d,J=7.2Hz,2H),6.66-6.32(m,2H),6.00-5.43(m,1H),5.16(d,J=10.4Hz,1H),4.78(dd,J=4.4,6.4Hz,1H),4.4 5-4.18(m,2H),4.06(dd,J=7.2,11.2Hz,1H),4.01(d,J=2.0Hz,3H),2.82(t,J=7.6Hz,1H),1.66(s,3H),0.79(br d,J=6.4Hz,3H);

[0303] LC-MS(ESI):[M+H] + =534.1.

[0304] Example 15

[0305] Step 1: Synthesis of Compound 15-3

[0306] Compound 15-1 (0.5 g, 1.41 mmol), compound 15-2 (0.2 g, 1.66 mmol), TCFH (0.48 g, 1.69 mmol), and 1-methylimidazole (0.2 mL, 2.51 mmol) were dissolved in MeCN (10 mL), and the mixture was stirred at room temperature for 12 hours. Monitoring showed that the starting materials had reacted completely and product was formed. The reaction solution was concentrated and evaporated to dryness to obtain a crude product. The product was purified by silica gel chromatography in 612 mg, 95% yield.

[0307] LC-MS(ESI):[M+H] + =457.1.

[0308] Step 2: Synthesis of Compound 15-4

[0309] Compound 15-3 (222 mg, 0.49 mmol) was dissolved in THF (8 mL) and water (2 mL), then sodium periodate (110 mg, 0.51 mmol) was added. After stirring for 1 minute, potassium osmium tetroxide (22 mg, 0.06 mmol) was added. After the addition was complete, the reaction mixture was heated to 50 °C and stirred for 12 hours. Ethyl acetate (200 mL) was added, followed by washing with water (100 mL) and saturated brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative TLC to obtain 173 mg of the product, yield: 77.6%.

[0310] LC-MS(ESI):[M+H] + =459.1.

[0311] Step 3: Synthesis of Compound 15-5

[0312] Compound 15-4 (100 mg, 0.22 mmol), zinc iodide (100 mg, 0.31 mmol), and trimethylcyanosilane (30 mg, 0.30 mmol) were dissolved in ultra-dry tetrahydrofuran (3 mL), and then heated at 70 °C with stirring for two hours. The reactants reacted completely, and a product was formed. The reaction solution was cooled to room temperature and then used directly in the next step.

[0313] LC-MS(ESI):[M+H] + =486.1.

[0314] Step 4: Synthesis of Compound 15

[0315] Hydroxylamine aqueous solution (1 mL, 32.64 mmol) was added directly to the reaction solution from the previous step, and then stirred at room temperature for 2 hours. The mixture was filtered, purified by high-performance liquid chromatography (HPLC), and lyophilized to give 28 mg of a white solid; yield: 25.6%.

[0316] LC-MS(ESI):[M+H] + =519.2.

[0317] Step 5: Synthesis of Compound 15A and Compound 15B

[0318] Compound 15 was prepared and purified by SFC, Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um), Mobile phase: A for CO2 and B for IPA (0.1% NH3H2O), Gradient: B% = 24.00% isocrine mode, Flow rate: 150.00g / min, Monitor wavelength: 220 & 254nm, Column temperature: 40℃, System back pressure: 100bar. Two peaks were obtained, and then lyophilized to obtain two white solid products: Compound 15A, Peak 1: 7.38mg, Compound 15B, Peak 2: 7.34mg.

[0319] Compound 15A: 1 H NMR (400MHz, DMSO-d6) δ = 10.41 (s, 1H), 9.06 (s, 1H), 8.65 (m, 1H), 8.02 (m, 1H), 7.50 (m, 1H), 7.20-7.12 (m, 2H), 5.8 9(m,1H),5.16(s,2H),5.10(m,1H),4.94(m,1H),4.24(m,1H),3.95(m,3H),2.77(m,1H),1.61(s,3H),0.73(m,3H);

[0320] LC-MS(ESI):[M+H] + =519.2.

[0321] Compound 15B: 1H NMR (400MHz, DMSO-d6)δ=10.48(s,1H),9.12(s,1H),8.72(s,1H),8.10-8.03(m,1H),7.56(m,1H),7.27-7.19(m,2H), 5.95(m,1H),5.22(s,2H),5.16(m,1H),4.99(m,1H),4.30(m,1H),4.01(s,3H),2.83(m,1H),1.66(s,3H),0.79(m,3H);

[0322] LC-MS(ESI):[M+H] + =519.2.

[0323] Example 16

[0324] Step 1: Synthesis of Compound 16-2

[0325] Compound 16-1 (278 mg, 0.59 mmol) was dissolved in acetonitrile (6 mL), and trimethylcyanosilane (0.15 mL, 1.12 mmol) was added. Then, a tetrabutylammonium fluoride solution in tetrahydrofuran (1 mol / L, 0.77 mL, 0.77 mmol) was added dropwise. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 1 / 2, Rf = 0.3) to give compound 16-2 (130 mg, 0.26 mmol), a yellow solid, yield: 44.2%.

[0326] LC-MS(ESI):[M+H] + =500.2.

[0327] Step 2: Synthesis of Compound 16-3

[0328] Compound 16-2 (120 mg, 0.24 mmol) and imidazole (98 mg, 1.44 mmol) were dissolved in tetrahydrofuran (5 mL), and TBSCl (109 mg, 0.72 mmol) was added. The reaction mixture was stirred at 30 °C for 24 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, Rf = 0.4) to give compound 16-3 (160 mg, 0.20 mmol), a yellow oil, yield: 82.2%.

[0329] LC-MS(ESI):[M+H] + =614.4.

[0330] Step 3: Synthesis of Compound 16-4

[0331] Compound 16-3 (140 mg, 0.23 mmol) was dissolved in toluene (5 mL) and methanol (1 mL). Acetyl chloride (90 mg, 1.14 mmol) was added at 0 °C, and the reaction mixture was stirred at 30 °C for 2 hours. A methanol solution of amine (0.33 mL, 2.28 mmol) was then added at 0 °C, and the reaction mixture was stirred at 30 °C for 2 hours. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to give compound 16-4 (140 mg, 0.22 mmol), a yellow solid, in 97.3% yield.

[0332] LC-MS(ESI):[M+H] + =631.3.

[0333] Step 4: Synthesis of Compound 16

[0334] Under a nitrogen atmosphere, compound 16-4 (140 mg, 0.22 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol / L, 1.11 mL, 1.11 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (2 × 30 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse-phase preparation (chromatographic column: Phenomenex Luna C18 150*25mm*10um, aqueous phase-organic phase: H2O (0.225% FA)-CAN, needle number: 3, initial gradient: 22.00, ending gradient: 42.00, gradient time: 10.00, flush gradient: 100.00, flush time: 4.00, flow rate: 25.00 mL / min) to obtain compound 16 (30 mg, 0.06 mmol), a white solid, yield: 26.2%.

[0335] LC-MS(ESI):[M+H] + =517.3.

[0336] Step 5: Synthesis of Compound 16A and Compound 16B

[0337] Compound 16 (30 mg, 0.06 mmol) was separated by chirality (column: DAICL CHIRALPAK IM (250 mm * 30 mm, 10 μm), aqueous-organic phase: CO2-MeOH (0.2% NH3H2O), initial gradient: 40.00, final gradient: 40.00, gradient time: 3.20, flush gradient: 100.00, flow rate: 150.00 ml / min) to give compound 16A (11.27 mg, 0.02 mmol, yellow solid, yield: 35.8%) and compound 16B (12.63 mg, 0.02 mmol, yellow solid, yield: 41.8%).

[0338] Compound 16A: 1H NMR (400MHz, DMSO-d6) δ = 8.70 (d, J = 2.4Hz, 1H), 8.02-7.99 (m, 1H), 7.47 (d, J=8.4Hz,1H),7.19-7.16(m,3H),5.10(d,J=10.0Hz,1H),4.86-4.83(m,1H) ,4.27-4.22(m,1H),3.95(d,J=2.0Hz,3H),2.79-2.75(m,1H),2.59-2.57(m ,1H),2.55-2.54(m,1H),2.34-2.32(m,1H),1.61(s,3H),0.75-0.73(m,3H);

[0339] LC-MS(ESI):[M+H] + =517.2.

[0340] Compound 16B: 1 H NMR (400MHz, DMSO-d6) δ = 10.62-10.51 (m, 1H), 8.73 (d, J = 2.4Hz, 1H), 8.46 (s, 1H) ),8.09-8.06(m,1H),7.49(d,J=8.4Hz,1H),7.19-7.16(m,2H),5.13(d,J=10.4H z,1H),5.01-4.97(m,1H),4.27-4.23(m,1H),3.96(d,J=2.0Hz,3H),2.91-2.87( m,1H),2.79-2.75(m,1H),2.60-2.54(m,2H),1.61(s,3H),0.74(d,J=6.4Hz,3H);

[0341] LC-MS(ESI):[M+H] + =517.2.

[0342] Example 17

[0343] Step 1: Synthesis of Compound 17

[0344] Under nitrogen protection at room temperature, triphenylphosphine dichloride (287.28 mg, 0.86 mmol) and ultra-dry chloroform (5 mL) were added to a 25 mL two-necked flask, followed by triethylamine (0.2 mL, 1.29 mmol), and the mixture was stirred for 10 minutes. Compound 17-1 (180.5 mg, 0.86 mmol) was then added to the system, and the mixture was stirred in an ice bath for 20 minutes. Compound 11-2 (211 mg, 0.43 mmol) was then added to the system, and the ice bath was removed. The mixture was stirred overnight at room temperature. After stirring was stopped, the mixture was washed with saturated brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 700 mg of crude compound 17.

[0345] LC-MS(ESI):[M+H] + =585.1.

[0346] Step 2: Synthesis of Compound 17A

[0347] Compound 17 (700 mg, 1.24 mmol) was prepared by reverse chromatography (column: Phenomenex Luna C18 150*25 mm*10 μm, aqueous-organic phase: H2O (0.225% FA)-CAN, needle number: 7, initial gradient: 25.00, final gradient: 55.00, gradient time: 10.00, flush gradient: 100.00, flush time: 3.00, flow rate: 25.00) to give compound 2 (30 mg, 0.05 mmol), a white solid, yield: 4.3%. Compound 17A (21.67 mg, 0.04 mmol) was obtained as a white solid with a yield of 71.5% by chiral separation {column: DAICL CHIRALPAK IM (250 mm * 30 mm, 10 μm), aqueous-organic phase: CO2-MeOH (0.2% NH3H2O), initial gradient: 30.00, final gradient: 30.00, gradient time: 2.90, flush gradient: 100.00, flow rate: 150.00 ml / min}.

[0348] 1H NMR (400MHz, DMSO-d6) δ=10.42(s,1H),8.67(d,J=2.0Hz,1H),8.05-8.03(m,1H),7.45(d,J= 8.4Hz,1H),7.22-7.13(m,2H),6.34-6.25(m,1H),5.67-5.61(m,1H),5.10(d,J=10.4Hz,1H), 4.63-4.59(m,1H),4.27-4.22(m,1H),3.95(d,J=2.0Hz,3H),3.41-3.38(m,1H),3.30-3.28(m ,1H),3.08-3.03(m,1H),2.81(s,3H),2.79-2.75(m,1H),1.61(s,3H),0.73(d,J=6.4Hz,3H);

[0349] LC-MS(ESI):[M+H] + =567.2.

[0350] Example 18

[0351] Step 1: Synthesis of Compound 18-2

[0352] Compound 18-1 (500 mg, 1.22 mmol) and iodine (396.70 mg, 2.45 mmol) were dissolved in THF (5 mL) and ammonium hydroxide (2.50 mL). The reaction mixture was stirred at 30 °C for 4 hours. After the reaction was complete, the reaction mixture was extracted with 30 mL of water and ethyl acetate (2 × 30 mL). The combined organic phases were washed with sodium sulfite aqueous solution (30 mL), then with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily crude product. The crude product was purified by silica gel chromatography (SiO2, PE:EA = 1:0 to 10:1), and concentrated under reduced pressure to obtain a colorless oil 2 (400 mg, 0.99 mmol, 80.6%).

[0353] 1 H NMR: (400MHz, CDCl3) δ = 7.45 (q, J = 8.4Hz, 1H), 7.24 (br dd,J=4.8,9.6Hz,1H),4.82(d,J=9.0Hz,1H),4.15(t,J=8.8Hz,1H),2.91(q,J=7.6Hz,1H),1.66(d,J=0.8Hz,3H),1.39(s,9H),0.87-0.81(m,3H).

[0354] Step 2: Synthesis of Compound 18-3

[0355] Compound 18-2 was dissolved in DCM (5 mL), and TFA (1 mL) was added. The reaction was carried out at 20 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a brownish oily crude product 18-3 (350 mg, 0.90 mmol, 91.4%).

[0356] LC-MS(ESI):[M+H] + =348.0.

[0357] Step 3: Synthesis of Compound 18-5

[0358] Compound 18-3 (330 mg, 0.94 mmol) and compound 4 (275.28 mg, 1.42 mmol) were dissolved in acetonitrile (5 mL), and (TCFH)N,N,N',N'-tetramethylchloromethanemididine hexafluorophosphate (397.66 mg, 1.42 mmol) and 1-methylimidazole (0.2 mL, 2.83 mmol) were added. The reaction mixture was reacted at 20 °C for 16 hours. After the reaction was complete, the reaction solution was extracted with 20 mL of water and ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (SiO2, PE:EA = 5:1 to 2:1), and concentrated under reduced pressure to give a pale yellow oil 18-5 (490 mg, 0.93 mmol, 98.7%).

[0359] LC-MS(ESI):[M+H] + =526.3.

[0360] Step 4: Synthesis of Compound 18

[0361] Compound 18-5 (400 mg, 0.76 mmol) was dissolved in DCM (10 mL), and TFA (10 mL) was added. The mixture was stirred at 35 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (100 mL) and concentrated directly under reduced pressure to obtain a brownish-yellow oily crude product. The crude product was purified by silica gel chromatography (SiO2, PE:EA = 1:1 to 0:1) to obtain a white solid powder compound 18 (310 mg, 0.64 mmol, 83.9%).

[0362] LC-MS(ESI):[M+H] + =486.1.

[0363] Step 5: Synthesis of Compound 18A

[0364] Compound 18 was resolved by SFC (column: DAICEL CHIRALCEL OX (250mm×30mm, 10um); mobile phase: [A: CO2; B: IPA (0.1% NH3H2O)]; B%: 35.00%-35.00%, 2.30 min; flow rate: 150.00 ml / min) to obtain compound 18A (179.21 mg, 0.37 mmol, 57.2%).

[0365] 1 H NMR: (400MHz, DMSO-d6) δ = 10.34 (s, 1H), 8.65 (d, J = 2.4Hz, 1H), 8.00 (dd, J = 2.5, 8.4Hz, 1H), 7.95-7.87 (m, 1H), 7.49 (br dd,J=3.4,8.8Hz,1H),7.42(d,J=8.4Hz,1H),5.34(d,J=4.8Hz,1H),5.25(d,J=9.2Hz,1H),4.64(t,J=5.6Hz,1H),4.54(td,J=4.4,6.8Hz,1 H),4.28(t,J=8.4Hz,1H),3.62(ddd,J=4.0,6.0,10.8Hz,1H),3.43(td,J=6.4,11.2Hz,1H),2.90(quin,J=7.2Hz,1H),1.62(s,3H),0.79(br d,J=6.4Hz,3H);

[0366] LC-MS(ESI):[M+H] + =486.1.

[0367] Example 19

[0368] Synthesis of Compound 19

[0369] Compound 16-2 was resolved by SFC (column: DAICEL CHIRALCEL OX (250mm×30mm, 10um); mobile phase: [A: CO2; B: MeOH (0.1% NH3H2O)]; B%: 15.00%-15.00%, 2.30 min; flow rate: 150.00 ml / min) to obtain compound 19, a white powder (47.35 mg, 0.09 mmol, 39.2%).

[0370] 1H NMR: (400MHz, DMSO-d6) δ = 10.45 (s, 1H), 8.70 (d, J = 2.4Hz, 1H), 8.07 (dd, J = 2.4, 8.8Hz, 1H), 7.51 (d, J = 8.8Hz, 1H), 7.19-7.13 (m, 2H), 6.16 (d, J =5.0Hz,1H),5.10(d,J=10.0Hz,1H),4.89-4.84(m,1H),4.28-4.20(m,1 H),3.95(d,J=2.0Hz,3H),3.02-2.95(m,1H),2.92-2.86(m,1H),2.76(br t,J=7.2Hz,1H),1.60(s,3H),0.73(br d, J = 6.4 Hz, 3H);

[0371] 19 F NMR: (377MHz, DMSO-d6) δ = -73.36 (br s, 3F), -138.17 (br d, J = 20.2Hz, 1F), -154.98 (br d, J = 20.2Hz, 1F);

[0372] LC-MS(ESI):[M+H] + =500.1.

[0373] Examples 20 and 21

[0374] Step 1: Synthesis of Compound 20-1

[0375] Compound 18-2 (1.1 g, 2.71 mmol) was dissolved in DMSO (10 mL), and ammonium carbonate (1.43 g, 8.14 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (SiO2, PE:EA = 15:1–10:1) to give compound 20-1 (405 mg, 1.06 mmol, 36.6%).

[0376] 1 H NMR: 1H NMR (400MHz, DMSO-d6) δ = 7.30 (dd, J = 8.4, 11.2Hz, 1H), 6.66 (dd, J = 4.4, 8.4Hz, 1H), 6.24 (s, 2H), 4.93 (d, J = 10.4 Hz,1H),3.95(dd,J=7.6,10.4Hz,1H),2.71(quin,J=7.2Hz,1H),1.52(s,3H),1.28(s,9H),0.74(d,J=6.0Hz,3H).

[0377] Step 2: Synthesis of Compounds 20-2 and 21-2

[0378] Compound 20-1 (405 mg, 1.01 mmol) was dissolved in acetonitrile (10 mL), and cuprous chloride (299 mg, 3.02 mmol), anhydrous copper chloride (474 ​​mg, 3.52 mmol), and tert-butyl nitrite (415 mg, 4.03 mmol) were added sequentially. The mixture was stirred at 25 °C for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid crude product. The crude product was purified by silica gel chromatography (SiO2, PE:EA = 15:1 to 10:1) to give a mixture of compounds 20-2 and 21-2.

[0379] Step 3: Synthesis of Compounds 20-3 and 21-3

[0380] A mixture of compounds 20-2 and 21-2 (360 mg) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a mixture of compounds 20-3 and 21-3.

[0381] Compound 20-3: LC-MS (ESI): [MH] - =363.9;

[0382] Compound 21-3: LC-MS (ESI): [MH] - =330.1.

[0383] Step 4: Synthesis of Compounds 20-4 and 21-4

[0384] A synthetic mixture (350 mg) of compounds 20-3 and 21-3 was dissolved in acetonitrile (5 mL), and methyl 4-aminopyridine-2-carboxylate (291.23 mg, 1.91 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (402.79 mg, 1.44 mmol), and N-methylimidazolium (0.4 mL, 4.79 mmol) were added. The mixture was reacted at 25 °C for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown crude product. The crude product was purified by silica gel chromatography (SiO2, PE:EA = 2:1 to 1:1) to give a mixture of compounds 20-4 and 21-4.

[0385] Compound 20-4: LC-MS (ESI): [M+H] + =500.1;

[0386] Compound 21-4: LC-MS (ESI): [M+H] + =466.2.

[0387] Step 5: Synthesis of Compounds 20 and 21

[0388] A mixture (100 mg) of compounds 20-4 and 21-4 was dissolved in ammonia-methanol solution (6 mol / L, 3 mL) and reacted at 40 °C for 2.5 h. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150×25mm×10um; mobile phase: [A: H2O (0.225% FA); B: ACN]; B%: 46.00%-76.00%, 10.00 min; flow rate: 25.00 mL / min) to obtain compounds 20 and 21.

[0389] Compound 20:

[0390] LC-MS(ESI):Ret.Time:0.827min,[M+H] + =485.1;

[0391] 1H NMR: (400MHz, DMSO-d6) δ = 10.66 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.31 (d, J = 2.0Hz, 1H), 8.08 (br s,1H),7.91-7.83(m,2H),7.68(dd,J=4.4,8.8Hz,1H),7.63(br d,J=2.0Hz,1H),5.28(d,J=9.2Hz,1H),4.35(t,J=8.4Hz,1H),2.93(t,J=7.6Hz,1H),1.63(s,3H),0.79(br d,J=7.2Hz,3H).

[0392] Compound 21:

[0393] LC-MS(ESI):Ret.Time:0.788min,[M+H] + =451.1,[M+H] + ;

[0394] 1 H NMR: (400MHz, DMSO-d6) δ = 10.70 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.29 (d, J = 2.0Hz, 1H), 8.07 (s, 1H), 7.92 (dd, J = 2.4, 8.4Hz, 1H), 7.85 (dd, J = 2.0, 5.6Hz ,1H),7.70-7.65(m,2H),7.63(d,J=2.0Hz,1H),5.26(d,J=9.2Hz,1H),4.36 (t,J=8.4Hz,1H),2.91(t,J=7.6Hz,1H),1.63(s,3H),0.76(d,J=6.4Hz,3H).

[0395] Example 22

[0396] Step 1: Synthesis of Compound 22-2

[0397] Compound 5-8A (500 mg, 1.02 mmol) was dissolved in THF (5 mL), and carbonyl diimidazole (0.5 mL, 4.22 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 22-2 (1.3 g, 2.22 mmol, 79.0%).

[0398] LC-MS(ESI):[M+H] + =585.3.

[0399] Step 2: Synthesis of Compound 22-3

[0400] Compound 22-2 (1.5 g, 2.57 mmol) was dissolved in THF (6 mL), and ammonia (8.6 mL, 66.72 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water, extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (column: Phenomenex Luna C18 150*40mm*15um, aqueous-organic phase: H2O (0.225% FA)-CAN, needle number: 2, initial gradient: 40.00, final gradient: 70.00, gradient time: 15.00, flush gradient: 100.00, flush time: 5.00, flow rate: 60.00) to obtain compound 22-3 (260 mg, 0.49 mmol, 21.9%).

[0401] LC-MS(ESI):[M+H] + =534.3.

[0402] Step 3: Synthesis of compound 22-4

[0403] Compound 22-3 (200 mg, 0.37 mmol) was dissolved in DCM (1 mL). AlCl3 (1.12 mmol, 149.3 mg) and dodecyl mercaptan (0.1 mL, 0.37 mmol) were added to the reaction solution, and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness to obtain the crude product, which was then separated by high performance liquid chromatography (HCl system) to obtain 60 mg of compound 22-4.

[0404] LC-MS(ESI):[M+H] + =520.0.

[0405] Step 4: Synthesis of Compound 22

[0406] Compound 22-4 (50 mg, 0.10 mmol), CD3I (20.93 mg, 0.14 mmol), and K2CO3 (13.30 mg, 0.10 mmol) were dissolved in DMF (1 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (50 mL), then extracted with EA (50 mL × 2), and the organic phases were combined, dried, filtered, and evaporated to dryness to obtain 60 mg of crude product. The crude product was purified by high performance liquid chromatography (FA: water: acetonitrile gradient elution fraction) and lyophilized to obtain compound 22 (5.51 mg, 0.01 mmol, 10.7%).

[0407] 1 H NMR (400MHz, DMSO-d6) δ = 10.42 (s, 1H), 8.67 (d, J = 2.4Hz, 1H), 8.06-8.04 (m, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.19-7.15 (m, 2H), 6.45-6.40 (m, 2H) ,5.62(d,J=5.2Hz,1H),5.11-5.08(m,1H),4.72-4.71(m,1H),4.27-4. 17(m,2H),4.02-3.99(m,1H),2.81-2.73(m,1H),1.60(s,3H),0.73(br d,J=6.9Hz,3H);

[0408] 19 F NMR (376MHz, DMSO-d6) δ = -73.38 (br s, 3F), -138.21 (br s, 1F), -155.07 (br d, J = 20.0Hz, 1F);

[0409] LC-MS(ESI):[M+H] + =537.2.

[0410] Experimental Example 1: Manual Patch-Clamp Method for Detection of the Compound of the Present Invention on Voltage-Gated Sodium Channel Na V 1.8% inhibitory activity

[0411] Cell culture and passage: Stable expression of human Na V 1.8 cm CHO cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum and 10 μg / mL blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin. The cell culture temperature was 37°C and the carbon dioxide concentration was 5%. During cell passage, the old medium was removed and the cells were washed once with PBS, then 0.25% Trypsin-EDTA solution was added and incubated at 37°C. When cells detached from the bottom of the dish, an appropriate amount of preheated (37°C) complete medium was added. After the cells were dispersed from the bottom of the dish, they were transferred to sterile centrifuge tubes, centrifuged at 1000 rpm for 5 min to collect the cells, and then seeded into 6 cm cell culture dishes (2.5 × 10⁸ cm²). 5 1 cell / culture dish, 5 mL culture medium, for expansion or maintenance culture. To maintain cell electrophysiological activity, cell density should not be lower than 80%.

[0412] Before patch-clamp testing, stable expression of human Na V 1.8 CHO cells were isolated and counted by adding 0.25% Trypsin-EDTA solution. 6.5 × 10⁸ cells were then counted.3 Cells were attached to coverslips and cultured in 24-well plates (final volume 500 μL). Detection was performed 18 hours later.

[0413] Compound sample preparation: The test compound was prepared into a 100 mM stock solution using dimethyl sulfoxide (DMSO), and then diluted to different concentrations using extracellular fluid containing 100 nM tetrodotoxin (TTX) (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH). The concentration of DMSO in each working solution was 0.1%. The test compound working solutions were sonicated for 20 min before testing.

[0414] Patch-clamp testing: During patch-clamp operation, the capillary glass tube is first drawn into a recording electrode using a microelectrode puller. Then, the electrode, filled with intracellular fluid (50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA, pH adjusted to 7.2 with CsOH), is placed into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to bring the recording electrode into contact with the cell, and negative pressure is applied to aspirate and form a GΩ seal. Fast capacitance compensation is then performed, followed by continued negative pressure to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and relevant parameters are recorded. Leakage compensation is not applied.

[0415] Once the sodium current recorded in whole cells stabilized, drug administration began. Each drug concentration was administered for 5 minutes (or until the current stabilized) before moving to the next concentration. A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound were perfused sequentially from low to high concentration through the recording bath using gravity perfusion, with fluid exchange performed using a peristaltic pump during recording. The current detected in each cell in the compound-free solution served as its control group. Each concentration was independently measured twice. All electrophysiological experiments were performed at room temperature. Specifically, two concentrations were set for each test compound (for initial screening) or five concentrations (for IC50 calculation). 50 (Value). The effect of the test compound on Na+ was determined by calculating the relative percentage of the peak current generated by cells treated with the test compound to the peak current generated by cells in the control group. V Inhibitory activity of 1,8-sodium channels.

[0416] Whole-cell patch-clamp recording of Na V1.8 Voltage stimulation protocol for sodium current: After whole-cell sealing, the cell voltage was clamped at -120 mV. The voltage was first stepped from -130 mV to -10 mV in 10 mV increments, held for 5 s, and then a 0 mV depolarization pulse was applied to obtain the half-inactivation voltage (Vhalf). The resting state and half-inactivated state of sodium current were detected using a dual-pulse mode. First, a depolarization pulse (TP1) was applied to 0 mV for 50 ms to detect the resting sodium current. Then, the voltage was adjusted to Vhalf, held for 5 s, then restored to -120 mV, held for 20 ms, and a second depolarization pulse (TP2) was applied to 0 mV for 50 ms to detect the half-inactivated sodium current. Finally, the voltage was restored to the clamped voltage of -120 mV. Data were collected every 20 ms to observe the effect of the drug on the peak sodium current in the two different states.

[0417] Example compound for Na V The inhibitory activity of channel 1.8 was determined by the above experiments, and the inhibition rate and IC50 at a concentration of 10 nM were measured. 50 See Tables 1 and 2. (Where 5-8A is...) )

[0418] Table 1. Inhibitory activity (inhibition rate) of the compounds in the examples against NaV1.8 channels.

[0419] Table 2. Inhibitory activity of the compounds in the examples against NaV1.8 channels (IC50, 1000 mg / L). 50 )

[0420] Experimental results show that the compounds in the embodiments of the present invention have a positive effect on Na. V Both 1 and 8 showed good inhibitory effects.

[0421] Experimental Example 2: In vivo pharmacokinetic studies were conducted on rats via single intravenous injection or oral gavage.

[0422] Experimental Methods: Six male rats weighing 180–260 g were divided into two groups. All animals were fasted overnight. One group received a single oral dose of 10 mg / kg, while the other group received a single intravenous dose of 1 mg / kg via tail vein. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. Plasma samples were pretreated and then analyzed by LC / MS / MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining the drug concentration-time curve. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin software. The experimental results are shown in the table below.

[0423] Table 3. Rat pharmacokinetic parameters of compounds in the embodiments of the present invention

[0424] Experimental results show that the compounds in the embodiments of the present invention are well absorbed orally in rats, and have high exposure levels and bioavailability.

[0425] Experimental Example 3: In vivo pharmacokinetic studies were conducted on mice by single intravenous injection or oral gavage administration.

[0426] Experimental Methods: Six male C57BL / 6 mice (20-30g each) were randomly divided into two groups. One group received a single intravenous dose of 1 mg / kg via tail vein, while the other group received a single oral dose of 30 mg / kg. Both groups were allowed free access to food. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. After pretreatment, plasma samples were analyzed by LC / MS / MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining the drug concentration-time curve. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin software. The experimental results are shown in the table below.

[0427] Table 4. Pharmacokinetic parameters of compounds in the embodiments of the present invention in mice.

[0428] Experimental results show that the compounds in the embodiments of the present invention have high exposure levels, low clearance rates, and long half-lives in mice, demonstrating pharmacokinetic advantages.

[0429] Experiment Example 4: In vivo pharmacokinetic studies were conducted on monkeys via single intravenous injection or oral gavage.

[0430] Six male cynomolgus macaques weighing 2–6 kg were randomly divided into two groups: one group received a single intravenous dose of 1 mg / kg, and the other group received a single oral dose of 2 mg / kg. Animals in the intravenous dose group were allowed free access to food, while animals in the oral dose group were fasted overnight and resumed eating 4 hours after administration. Blood samples were collected from the intravenous dose group at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration, and from the oral dose group at the same times. Plasma samples were pretreated and then analyzed by LC / MS / MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples to obtain drug concentration-time curves. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin software. The experimental results are shown in the table below.

[0431] Table 5. Pharmacokinetic parameters of compounds in the embodiments of the present invention in monkeys.

[0432] Experimental Example 5: Plasma protein binding rate of the compounds of the present invention.

[0433] Experimental methods:

[0434] This experiment used a balanced dialysis apparatus to study the plasma protein binding rate of the compounds. Mouse, dog, and human plasma samples containing 5 μM of the analyte were equilibrated at 37°C for 6 hours in a balanced dialysis apparatus. Ketoconazole was used as a positive control. After incubation, 50 μL samples from the buffer chamber and plasma sample chamber were taken respectively. 50 μL of blank plasma was added to the buffer sample, and an equal volume (50 μL) of blank buffer solution was added to the plasma sample. Then, 400 μL of quencher (containing internal standard) was added to precipitate the protein. The concentration of the analyte was analyzed using LC-MS / MS. The free percentage in plasma was calculated based on the concentrations of the buffer and plasma samples. Plasma protein binding rate was calculated using the following formula: Plasma free fraction (f... u,p = (peak area ratio of buffer chamber / peak area ratio of plasma chamber), where "peak area ratio" is the ratio of the peak area response of the analyte to the internal standard.

[0435] The experimental results are shown in the table below:

[0436] Table 6. Plasma free fractions of compounds from different species in the embodiments of the present invention

[0437] Experiment Example 6: Pharmacological Test of a Mouse Model of Postoperative Pain

[0438] 1. Experimental Objective

[0439] The analgesic effect of the disclosed compound in a mouse plantar incision pain model was evaluated using a mechanical hyperalgesia test.

[0440] 2. Experimental reagents

[0441] Compounds 14A, 22, and 5-8A were added sequentially with 10% DMSO, 10% solubilol, and 80% saline, and vortexed until clear.

[0442] 3. Experimental Materials and Methods

[0443] 3.1 Species, strain, age, and sex of laboratory animals

[0444] C57 BL / 6J mice, 6-8 weeks old, male.

[0445] 3.2 Grouping of experimental animals

[0446] After acclimatization, C57 BL / 6J mice were grouped as follows:

[0447] 3.3 Experimental Methods

[0448] Foot incision pain modeling: Animals were anesthetized with isoflurane, and the toes were squeezed to confirm complete anesthesia before surgery. Ophthalmic ointment was applied to the animal's eyes to prevent corneal dryness. The left foot sole was disinfected three times with povidone-iodine and 70% ethanol, and surgery began after the skin had dried. A longitudinal incision of approximately 5 mm was made, starting 2 mm from the heel and moving towards the toes. After cutting the skin, the flexor digitorum brevis muscle was lifted and subjected to longitudinal blunt trauma. The wound was sutured and disinfected. After the animal was fully awake (able to move freely), it was returned to its cage. Ten animals that did not undergo mouse incision pain surgery were used as... Comparison.

[0449] Mechanoresonance Hypersensitivity Test: One day after modeling, mechanoresonance hypersensitivity tests were performed on the left hind paw of all model mice at 1 hour, 3 hours, and 6 hours after drug administration. Mice were placed individually in plexiglass boxes with a mesh bottom to ensure the mouse's foot could be tested. Mice were allowed 15 minutes to acclimatize before testing. After acclimatization, test fibers were applied to the center of the sole of the mouse's left hind paw. The test fibers included eight test intensities: 2.36 (0.02 g), 2.44 (0.04 g), 2.83 (0.07 g), 3.22 (0.16 g), 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), and 4.17 (1.4 g). During testing, the test fiber was pressed vertically against the skin and force was applied to bend the fiber for 6–8 seconds, with 5-second intervals between tests. Rapid withdrawal of the paw during testing was recorded as a pain response. Withdrawal of the paw when the test fiber left the skin was also recorded as a pain response. If the animal moves or walks without a pain response, the test should be repeated. The test should begin with 3.22 (0.16g). If the animal shows a pain response, the next test should use a test fiber with a lower strength; if the animal does not show a pain response, the next test should use a test fiber with a higher strength. The maximum strength of the test fiber is 4.17 (1.4g). Test results are recorded in the table below: X for pain response, O for no pain response.

[0450] Mechanosensitive hypersensitivity is expressed as the withdrawal threshold (PWT) in mouse behavioral tests, and is calculated using the following formula:

[0451] 50% reaction threshold (g) = (10 (Xf+kδ) ) / 10,000

[0452] Xf = Final test fiber value used in the test

[0453] k = table value (Chaplan et al. 1994, page 62)

[0454] δ = mean difference

[0455] 3.4 Data Analysis

[0456] After the data was aggregated and statistically analyzed, Prism (Graph pad software, Inc.) software was used to analyze the data, and one-way ANOVA was used to test the data.

[0457] 4. Results

[0458] The analgesic efficacy of the drug in the mouse plantar incision pain model is shown in the table below: Note: Data represent Mean ± SEM, *vs solvent control, ***P<0.001.

[0459] 5. Conclusion

[0460] At different time points after administration, compounds 14A and 22 both showed significant analgesic effects in a mouse plantar incision pain model, and the efficacy of Example 22 was dose-dependent, with better analgesic effects than the control 5-8A.

[0461] Experimental Example 7: Pharmacodynamic Test of a Mouse Acetic Acid Writhing Model

[0462] 1. Experimental Objective

[0463] The analgesic effect of the compounds disclosed herein was evaluated using a mouse acetic acid writhing model.

[0464] 2. Experimental reagents

[0465] Compounds 14A, 5-8A, 18A, and 19 were added sequentially with 5% DMSO, 15% solubilol, and 85% saline, and vortexed until clear.

[0466] 3. Experimental Materials and Methods

[0467] 3.1 Species, strain, age, and sex of laboratory animals

[0468] CD-1 mice, 7-8 weeks old, male.

[0469] 3.2 Grouping of experimental animals

[0470] After acclimatization, CD-1 mice were grouped as follows:

[0471] 3.3 Experimental Methods

[0472] Animals were placed in an observation room for 30 minutes to acclimatize. Subsequently, each experimental animal group was administered the corresponding compound by gavage. One hour after administration, a 0.6% acetic acid solution was injected intraperitoneally, and the number of writhing movements of the mice within 30 minutes was observed and recorded. A positive reaction was defined as the mouse exhibiting abdominal concavity, anterior abdominal wall pressed tightly against the cage floor, hip twitching, and hind limb extension.

[0473] 3.4 Data Analysis

[0474] After the data was aggregated and statistically analyzed, Prism (Graph pad software, Inc.) software was used to analyze the data, and one-way ANOVA was used to test the data.

[0475] 4. Results

[0476] The number of writhing responses in each group of mice is shown in the table below: Note: Data represent Mean±SEM, *vs solvent control group, **P<0.01, ***P<0.001.

[0477] 5. Conclusion

[0478] Compounds 14A, 18A, and 19 all exhibited significant analgesic effects in a mouse acetic acid writhing model, and were superior to the control compounds 5-8A.

[0479] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

Claims

1. A compound having one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, deuterated product, metabolite, pharmaceutically acceptable salt, or prodrug having one of the following structures:

2. A pharmaceutical composition comprising the compound of claim 1; wherein the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

3. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating diseases in which voltage-gated sodium channels NaV1.8 are inhibited.

4. The use according to claim 3, wherein the disease is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Chuck-Maley-Dus syndrome, incontinence, pathological cough, or arrhythmia.

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