A compound having a ketoxime ether structure and applications thereof

Abstract

The present application relates to the technical field of TLR2 antagonists, and particularly relates to a compound with a ketoxime ether structure and application thereof.The compound has a structure shown in formula I: or a pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4 and R5 are independently selected from any one of a hydrogen atom, a phenolic hydroxyl group, an amino group, a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C5 cycloalkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, an amide group, a sulfonamide group, an ester group, a cyano group, OCH2F, OCHF2, OCF3, SCF3 and N(CH3)2; ring A is one of a 6-14 membered aryl group and a 5-14 membered heteroaryl group; and R6 is any one of an ester group with 1-15 carbon atoms, an amide group, a sulfonamide group, an alkyl group, an alkoxy group, an oxazole, an isoxazole, a thiazole, an isothiazole, an oxadiazole, a thiadiazole, a substituted oxazole, a substituted isoxazole, a substituted thiazole, a substituted isothiazole, a substituted oxadiazole and a substituted thiadiazole.The compound can be used as a TLR2 antagonist.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of TLR2 antagonists, in particular to a compound with a ketoxime ether structure and its application. BACKGROUND

[0002] Pattern recognition receptors (PRRs) on innate immune cells in the human body can recognize foreign microorganisms such as bacteria, viruses and fungi, have completely different structural components from the human body, i.e. pathogen-associated molecular patterns (PAMPs), and then initiate innate immune responses. TLR-like receptors (TLRs) are the most important family of pattern recognition receptors, not only the portal of innate immune responses, but also the bridge connecting innate immunity and specific immunity.

[0003] Among the 13 subtypes of TLRs, TLR2 has the widest expression range. TLR2 is expressed on different types of cells such as innate immune cells, T cells, epithelial cells and endothelial cells. In addition, the unique heterodimerization ability of TLR2 makes it the member of the TLRs family that recognizes the most ligands. TLR2 is located on the cell surface and belongs to type I transmembrane protein, which can be divided into extracellular region, transmembrane region and intracellular region. Generally, TLR2 combines with TLR1 or TLR6 through the extracellular region to form TLR2 / TLR1 or TLR2 / TLR6 heterodimer, and then recognizes different PMAPs or DAMPs molecules, and then recruits adaptor protein MYD88 through the intracellular region to initiate immune signal transmission, activate downstream NF-κB pathway and MAPK pathway, promote the release of various cytokines, and accelerate the clearance of pathogens, thereby playing an anti-bacterial and anti-viral role. However, long-term or excessive activation of TLR2 can cause various inflammatory diseases, autoimmune diseases and neurodegenerative diseases. Therefore, the activation and inhibition of TLR2 signaling pathway must be strictly regulated.

[0004] Excessive activation of TLR2 is closely related to the occurrence and development of inflammatory diseases, autoimmune diseases and neuropsychiatric diseases, and TLR2 antagonists can block the binding of TLR2 to its ligand, inhibit the activation of downstream signaling pathways, and can be used for the treatment of the above diseases. After more than ten years of efforts, researchers have found many TLR2-targeted antagonists. The currently reported TLR2 antagonists can be divided into three categories, namely TLR2 orthostatic antagonists targeting the extracellular region of TLR2, TLR2 allosteric antagonists targeting the intracellular region of TLR2, and TLR2 antagonists with unclear action mode (Other TLR2 antagonists).

[0005] Although researchers have screened a variety of types of TLR2 antagonists by different methods such as high-throughput screening and virtual screening, unfortunately, none of the TLR2 antagonists has been approved for marketing so far. The existing TLR2 antagonists generally have the shortcomings of low activity, poor drug-likeness and poor physicochemical properties, and therefore, it is the main direction of future TLR2 antagonist research and development to find TLR2 antagonists with strong immunosuppressive activity and good drug-likeness. SUMMARY

[0006] In order to solve the problems of the existing TLR2 antagonists in activity and drugability, the present application provides a new compound with stronger activity and better drugability, which is more suitable for treating and / or preventing diseases caused by excessive activation of TLR2, and has great development value and research value.

[0007] To achieve the above-mentioned object, the present application provides the following solutions:

[0008] One of the technical solutions of the present application is a compound represented by formula I:

[0009] or a pharmaceutically acceptable salt, a cis-trans isomer, an enantiomer, a diastereomer, a tautomer, a racemate, a solvate and an N-oxide or an amino acid conjugate thereof;

[0010] In formula I, R1, R2, R3, R4 and R5 are independently selected from any one of hydrogen atom, phenolic hydroxyl, amino, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, amido, sulfonamido, ester, cyano, OCH2F, OCHF2, OCF3, SCF3 and N(CH3)2;

[0011] Ring A is one of substituted or unsubstituted phenyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl;

[0012] R6 is any one of ester, amido, sulfonamido, alkyl, alkoxy, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, substituted oxazole, substituted isoxazole, substituted thiazole, substituted isothiazole, substituted oxadiazole and substituted thiadiazole with 1-15 carbon atoms, and the substituent of the substituted group is selected from fluorine, chlorine, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 3-8Cycloalkylalkyl, 3-8 membered heterocyclic alkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocyclic alkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, amino C 1-6 Any one of the alkyl groups.

[0013] When ring A is substituted, it can be substituted at any position by one or more substituents;

[0014] The substituents of ring A are selected from: R6, fluorine, chlorine, Cl, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 3-8 Cycloalkylalkyl, 3-8 membered heterocyclic alkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocyclic alkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, amino C 1-6 Any one of the alkyl groups.

[0015] The second technical solution of the present invention is the use of the above-mentioned compound in the preparation of a drug for treating and / or preventing TLR2-mediated inflammatory diseases, autoimmune diseases or neurodegenerative diseases.

[0016] The third technical solution of the present invention is a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, its ester or its cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate, N-oxide or amino acid conjugate.

[0017] The fourth technical solution of the present invention is a pharmaceutical preparation comprising the above-mentioned compound or its pharmaceutically acceptable salt, ester or its cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate, N-oxide or amino acid conjugate, or the above-mentioned pharmaceutical composition, and a pharmaceutically acceptable carrier.

[0018] The present invention discloses the following technical effects:

[0019] This invention provides a novel compound with a ketoxime ether structure that exhibits antagonistic activity against Toll-like receptor 2 (TLR2) and can be used as a TLR2 antagonist to treat TLR2-mediated inflammatory diseases, autoimmune diseases, and neurodegenerative diseases. Detailed Implementation

[0020] The present application will now be described in detail with reference to a number of exemplary embodiments thereof, which description is not to be considered as a limitation of the application, but merely as being illustrative of certain aspects, features and embodiments thereof.

[0021] The first aspect of the present application provides a compound of Formula I:

[0022] or a pharmaceutically acceptable salt, cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate, N-oxide or amino acid conjugate thereof;

[0023] In Formula I, R1, R2, R3, R4, R5are independently selected from any one of hydrogen atom, phenolic hydroxyl, amino, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, amido, sulfonamido, ester, cyano, OCH2F, OCHF2, OCF3, SCF3, N(CH3)2;

[0024] Ring A is one of substituted or unsubstituted phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl;

[0025] R6is any one of ester, amido, sulfonamido, alkyl, alkoxy, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, substituted oxazole, substituted isoxazole, substituted thiazole, substituted isothiazole, substituted oxadiazole, substituted thiadiazole, substituted group is selected from: fluorine, chlorine, Cl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 3-8 cycloalkylalkyl, 3-8 membered heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 1-6 alkyl.

[0026] When ring A is substituted, it can be substituted at any position with one or more substituents;

[0027] The substituents of ring A are selected from: R6, fluorine, chlorine, Cl, C 1-6 alkyl, haloC 1-6 alkyl, C1-6 alkoxy, haloC 1-6 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 3-8 cycloalkylalkyl, 3-8 membered heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, amino C 1-6 any of the alkyl groups.

[0028] The present application does not make any particular limitation on the source of the raw materials for preparing the compound of Formula I, and commercially available products known to those skilled in the art can be used.

[0029] In some embodiments of the present application, the ring A is a furan ring, a thiophene ring, a benzene ring, a pyridine ring, or a pyridone ring.

[0030] The second aspect of the present application provides a use of the above-mentioned compound in the preparation of a medicament for treating and / or preventing inflammatory diseases (such as asthmatic airway inflammation, surgery-induced neuroinflammation and cognitive dysfunction, and osteoarthritis, etc.), autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, etc.), and neurodegenerative diseases (such as Parkinson's disease, Lewy body dementia, and Alzheimer's disease, etc.) mediated by TLR2.

[0031] The third aspect of the present application provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, or cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate, N-oxide, or amino acid conjugate thereof.

[0032] In some embodiments of the present application, the pharmaceutical composition is formulated for oral administration.

[0033] In some embodiments of the present application, the pharmaceutical composition is formulated for injection administration.

[0034] wherein the injection is intravenous, subcutaneous, intramuscular, intraperitoneal, intrathecal, intracranial, intratumoral, or peritumoral.

[0035] In some embodiments of the present application, the pharmaceutical composition is formulated for transenteral delivery.

[0036] In some embodiments of the present application, the pharmaceutical composition is formulated for controlled release in the small intestine or colon of a subject.

[0037] In some embodiments of the application, the pharmaceutical composition is formulated for delivery outside the systemic circulation of the subject.

[0038] In some embodiments of the application, the pharmaceutical composition is formulated for local or intravesical delivery.

[0039] In some embodiments of the application, the pharmaceutical composition is formulated for inhalation delivery.

[0040] A fourth aspect of the present application provides a pharmaceutical preparation comprising the above-mentioned compound or its pharmaceutically acceptable salt, ester or its cis-trans isomer, enantiomer, diastereoisomer, tautomer, racemate, solvate, N-oxide or amino acid conjugate, or the above-mentioned pharmaceutical composition, and a pharmaceutically acceptable carrier.

[0041] In some embodiments of the application, the dosage form is a tablet, a capsule, a powder, a pill, a granule, an oral liquid, an injection or an emulsion.

[0042] All parameters and the rest of the description in the embodiments of the present application, unless otherwise stated, are based on mass. The fillers used in column chromatography separation are silica gel if not specified. The experimental methods in the following examples, if not specified, are usually carried out under conventional conditions or under the conditions recommended by the manufacturer.

[0043] NMR used in the examples 1 The H spectrum analyzer is Bruker 600MHz NMR of Bruker Company in Switzerland and Oxford 400MHz NMR of China; the mass spectrum is determined by Agilent liquid chromatography-mass spectrometry system.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The methods and materials described herein are illustrative only and not intended to be limiting.

[0045] The present application is further illustrated by the following examples.

[0046] Example 1

[0047] Preparation of (E)-5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)furan-2-carboxylic acid ethyl ester. The synthesis steps are shown as follows.

[0048]

[0049] Step 1: Preparation of 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester

[0050] Ethyl 5-(((l,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylate (2000 mg, 6.35 mmol) and n-butylamine (464 mg, 6.35 mmol) were dissolved in anhydrous methanol under argon protection for 18 hours. After TLC monitoring of the end of the reaction, 6 mL of 4N hydrochloric acid methanol solution was added to the reaction system at 0°C and stirred for 0.5 h, and then dried at 25°C. The target compound (1111 mg, 79.2%) was obtained as a white solid after washing with methyl tert-butyl ether and filtration. 1 H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.60 (m, 4H), 7.13 (d, J = 3.5 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 5.20 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 315.0, found: 315.0.

[0051] Step 2: Preparation of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride

[0052] Ethyl 5-(((l,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylate (2000 mg, 6.35 mmol) and n-butylamine (464 mg, 6.35 mmol) were dissolved in anhydrous methanol under argon protection for 18 hours. After TLC monitoring of the end of the reaction, 6 mL of 4N hydrochloric acid methanol solution was added to the reaction system at 0°C and stirred for 0.5 h, and then dried at 25°C. The target compound (1111 mg, 79.2%) was obtained as a white solid after washing with methyl tert-butyl ether and filtration. 1 H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.60 (m, 4H), 7.13 (d, J = 3.5 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 5.20 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 315.0, found: 315.0.

[0053] Step 3: Preparation of ethyl (E)-5-((((l-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)furan-2-carboxylate

[0054] To a solution of 2,3,4-trihydroxyacetophenone (70 mg, 0.42 mmol) and ethyl 5-((aminoxy)methyl)furan-2-carboxylate hydrochloride (110 mg, 0.50 mmol) in methanol, the reaction was carried out at room temperature, and TLC was used to monitor the completion of the reaction. After the reaction was completed, the solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain the target compound as a light yellow solid (45 mg, 32.4%). 1 H NMR (400 MHz, Chloroform-d) δ 11.31 (s, 1H), 7.15 (d, J = 3.5 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.54 (s, 2H), 5.13 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 16 H 17 NO7: 336.1078, found: 336.1077.

[0055] Example 2

[0056] Preparation of (E)-ethyl 5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)thiophene-2-carboxylate. The synthesis steps are shown below.

[0057]

[0058] Step 1: Preparation of ethyl 5-formylthiophene-2-carboxylate

[0059] To a solution of 5-formyl-2-thiophenecarboxylic acid (5000 mg, 32.05 mmol), iodoethane (5998 mg, 38.46 mmol) and potassium carbonate (8847 mg, 64.11 mmol) in 30 mL of DMF, the reaction was carried out at 60 °C. After the reaction was completed, ethyl acetate was added, washed with saturated brine 3 times, and the solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain the target compound as a colorless liquid (3110 mg, 52.7%). 1 H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 7.83 (d, J = 3.9 Hz, 1H), 7.73 (d, J = 3.9 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] +m / z 184.0, found: 184.0.

[0060] Step 2: Preparation of ethyl 5-(hydroxymethyl)thiophene-2-carboxylate

[0061] Ethyl 5-formylthiophene-2-carboxylate (2990 mg, 16.25 mmol) was dissolved in anhydrous methanol, sodium borohydride (307 mg, 8.14 mmol) was added in portions at 0 °C, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed as monitored by TLC, the solvent was removed by rotary evaporation, the residue was dissolved in ethyl acetate, washed with saturated brine three times, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was purified by column chromatography on silica gel to give the target compound (2872 mg, 95.0%) as a yellowish liquid. 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 3.8 Hz, 1H), 6.91 (d, J = 3.9 Hz, 1H), 4.76 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.47 (s, 1H), 1.33 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 187.0, found: 187.0.

[0062] Step 3: Preparation of ethyl 5-(bromomethyl)thiophene-2-carboxylate

[0063] Ethyl 5-(hydroxymethyl)thiophene-2-carboxylate (2600 mg, 13.98 mmol) and triphenylphosphine (5038 mg, 15.38 mmol) were dissolved in anhydrous tetrahydrofuran, carbon tetrabromide (4028 mg, 15.38 mmol) was added in portions at 0 °C, and the reaction was allowed to proceed at room temperature for 12 h. After the reaction was completed as monitored by TLC, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the target compound (3104 mg, 89.5%) as a yellowish liquid. 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 3.8 Hz, 1H), 7.06 (d, J = 3.7 Hz, 1H), 4.66 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 248.9, found: 248.9.

[0064] Step 4: Preparation of ethyl 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)thiophene-2- carboxylate

[0065] The synthetic method of 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)thiophene-2- carboxylic acid ethyl ester was referenced to that of 5-(((1,3-dioxoisoindolin-2- yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. Light yellow solid (2017 mg, 53.9%). 1 H NMR (400 MHz, Chloroform-d) δ 7.86 - 7.71 (m, 4H), 7.68 (d, J = 3.8 Hz, 1H), 7.19 (d, J = 3.8 Hz, 1H), 5.35 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 332.1, found: 332.1.

[0066] Step 5: Preparation of 5-((aminooxy)methyl)thiophene-2-carboxylic acid ethyl ester hydrochloride

[0067] The synthetic method of 5-((aminooxy)methyl)thiophene-2-carboxylic acid ethyl ester hydrochloride was referenced to that of 5-((aminooxy)methyl)furan-2-carboxylic acid ethyl ester hydrochloride. White solid (994 mg, 77.2%). 1 H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J = 3.8 Hz, 1H), 7.29 (d, J = 3.8 Hz, 1H), 5.26 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 202.1, found: 202.1.

[0068] Step 6: Preparation of (E)-5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)thiophene-2-carboxylic acid ethyl ester

[0069] The synthetic method of (E)-5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)thiophene-2-carboxylic acid ethyl ester was referenced to that of Example 1. White solid (104 mg, 71.2%). 1H NMR(400MHz,Chloroform-d)δ11.29(s,1H),7.70(d,J=3.7Hz,1H),7.08(d,J=3.7Hz,1H),6.90(d,J=8.9Hz,1H ), 6.52 (d, J = 8.8Hz, 1H), 5.52 (s, 2H), 5.30 (s, 2H), 4.34 (q, J = 7.1Hz, 2H), 2.30 (s, 3H), 1.36 (t, J = 7.1Hz, 3H). ESI-HRMS[M+1] + calcd for C 16 H 17 NO6S:352.0849,found:352.0849.

[0070] Example 3

[0071] The preparation of ethyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylene)amino)oxy)methyl)benzoate is shown below via the following synthetic route.

[0072]

[0073] Step 1: Preparation of ethyl 3-formylbenzoate

[0074] Isophthalaldehyde (7000 mg, 52.23 mmol) and iodine (19888 mg, 78.35 mmol) were dissolved in ethanol, and potassium carbonate (14417 mg, 104.48 mmol) was added. The mixture was reacted at 60 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue obtained after concentration was dissolved in ethyl acetate, washed three times with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue obtained after concentration was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give the target compound (3752 mg, 40.4%) as a colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ10.09(s,1H),8.54(s,1H),8.31(d,J=7.8Hz,1H),8.09 (d, J=7.7Hz, 1H), 7.63 (t, J=7.7Hz, 1H), 4.43 (q, J=7.0Hz, 2H), 1.43 (t, J=7.1Hz, 3H). ESI-MS:calcd for[M+H] + m / z 179.1,found:179.1.

[0075] Step 2: Preparation of ethyl 3-(hydroxymethyl)benzoate

[0076] The synthesis method of 3-(hydroxymethyl)benzoic acid ethyl ester was referred to that of 5-(hydroxymethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (2624 mg, 72.0%). 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 4.76 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.82 (s, 1H), 1.40 (t, J = 7.2 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 181.1, found: 181.1.

[0077] Step 3: Preparation of 3-(bromomethyl)benzoic acid ethyl ester

[0078] The synthesis method of 3-(bromomethyl)benzoic acid ethyl ester was referred to that of 5-(bromomethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (1866 mg, 55.5%). 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 4.51 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 243.0, found: 243.0.

[0079] Step 4: Preparation of 3-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoic acid ethyl ester

[0080] The synthesis method of 3-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoic acid ethyl ester was referred to that of 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. White solid (2040 mg, 89.4%). 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.85 - 7.69 (m, 5H), 7.49 (t, J = 7.7 Hz, 1H), 5.26 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H]+ m / z 326.1 found:326.1.

[0081] Step 5: Preparation of ethyl 3-(aminooxy)methyl)benzoate hydrochloride

[0082] The synthesis method of ethyl 3-(aminooxy)methyl)benzoate hydrochloride refers to that of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1184 mg, 87.7%) 1 H NMR (400 MHz, DMSO-d6) d 11.21 (s, 3H), 8.03 - 7.94 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 5.14 (s, 2H), 4.33 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 196.1 found:196.1.

[0083] Step 6: Preparation of ethyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0084] The synthesis method of ethyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to that of Example 1. White solid (47 mg, 32.8%). 1 H NMR (400 MHz, Chloroform-d) d 11.40 (s, 1H), 8.08 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 5.48 (s, 2H), 5.21 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0085] ESI-HRMS [M+1] + calcd for C 18 H 19 NO6: 346.1285, found: 346.1286.

[0086] Example 4

[0087] (E)-4-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester was prepared according to the following synthetic route.

[0088]

[0089] Step 1: Preparation of ethyl 4-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate

[0090] The synthesis of ethyl 4-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate was referenced to the synthesis of ethyl 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylate. Light yellow solid (5610 mg, 93.2%). 1 HNMR (400 MHz, Chloroform-d) δ 8.05 (d, J = 8.1 Hz, 2H), 7.85 - 7.71 (m, 4H), 7.61 (d, J = 8.0 Hz, 2H), 5.26 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 326.1 found: 326.1.

[0091] Step 2: Preparation of ethyl 4-(aminooxy)methyl)benzoate hydrochloride

[0092] The synthesis of ethyl 4-(aminooxy)methyl)benzoate hydrochloride was referenced to the synthesis of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (820 mg, 96.2%). 1 H NMR (400 MHz, Methanol-d4) δ 8.10 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 5.14 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 196.1 found: 196.1.

[0093] Step 3: Preparation of (E)-4-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0094] The synthesis of (E)-4-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester was referenced to the synthesis of Example 1. White solid (103 mg, 50.2%).1 H NMR (600 MHz, Chloroform-d) δ 11.34 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 5.55 (s, 2H), 5.21 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 18 H 19 NO6: 346.1285, found: 346.1286.

[0095] Example 5

[0096] Preparation of (E)-3-((((l-(3,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester.

[0097]

[0098] The synthesis of (E)-3-((((l-(3,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester was performed according to the synthetic procedure of Example 1. Light green solid (41 mg, 47.7%). 1 H NMR (600 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.10 (s, 2H), 5.22 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0099] ESI-HRMS [M+1] + calcd for C 18 H 19 NO5: 330.1336, found: 330.1339.

[0100] Example 6

[0101] Preparation of (E)-3-((((l-(2,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0102]

[0103] The synthesis method of (E)-3-((((1-(2,4-dihydroxyphenyl)ethyl)amino)oxy)methyl)benzoic acid ethyl ester refers to the synthesis method of Example 1. Colorless liquid (36 mg, 75.0%). 1 H NMR (600 MHz, Chloroform-d) δ 11.29 (s, 1H), 8.08 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 6.38 (dd, J = 8.5, 2.7 Hz, 1H), 5.65 (s, 1H), 5.20 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 18 H 19 NO5: 330.1336, found: 330.1338.

[0104] Example 7

[0105] Preparation of (E)-3-((((1-(2,3-dihydroxyphenyl)ethyl)amino)oxy)methyl)benzoic acid ethyl ester

[0106]

[0107] The synthesis method of (E)-3-((((1-(2,3-dihydroxyphenyl)ethyl)amino)oxy)methyl)benzoic acid ethyl ester refers to the synthesis method of Example 1. White solid (75 mg, 61.5%). 1 H NMR (600 MHz, Chloroform-d) δ 11.27 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.96 (dd, J = 8.1, 1.5 Hz, 1H), 6.95–6.91 (m, 1H), 6.79 (t, J = 8.0 Hz, 1H), 5.70 (s, 1H), 5.25 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 18 H19 NO 5: 330.1336, found: 330.1337.

[0108] Example 8

[0109] Preparation of (E)-3-((((1-(4-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0110]

[0111] The synthesis of (E)-3-((((1-(3-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic method of Example 1. White solid (124 mg, 78.6%) 1 H NMR (600 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). ESI-HRMS [M + 1] + calcd for C 18 H 19 NO 4: 314.1387, found: 314.1390.

[0112] Example 9

[0113] Preparation of (E)-3-((((1-(3-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0114]

[0115] The synthesis of (E)-3-((((1-(3-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic method of Example 1. White solid (124 mg, 78.6%) 1H NMR (400 MHz, Chloroform-d) δ 11.01 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.93 (dd, J = 8.3, 1.3 Hz, 1H), 6.88 (ddd, J = 7.9, 7.3, 1.3 Hz, 1H), 5.25 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 18 H 19 NO4: 314.1387, found: 314.1387.

[0116] Example 10

[0117] Synthesis of (E)-3-((((l-(2-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0118]

[0119] Synthesis of (E)-3-((((l-(2-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic procedure of Example 1. White solid (106 mg, 99.1%) 1 H NMR (400 MHz, Chloroform-d) δ 11.01 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.93 (dd, J = 8.3, 1.3 Hz, 1H), 6.88 (ddd, J = 7.9, 7.3, 1.3 Hz, 1H), 5.25 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 18 H 19 NO4: 314.1387, found: 314.1387.

[0120] Example 11

[0121] Preparation of (E)-3-((((1-(4-hydroxy-3-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0122]

[0123] The synthesis of (E)-3-((((1-(4-hydroxy-3-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic method of Example 1. Colorless liquid (34 mg, 32.9%) 1 H NMR (600 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.81 (s, 1H), 5.26 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 2.25 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESI-HRMS [M + 1] + calcd for C 19 H 21 NO5: 344.1492, found: 344.1494.

[0124] Example 12

[0125] Preparation of (E)-3-((((1-(3-hydroxy-4-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0126]

[0127] The synthesis of (E)-3-((((1-(3-hydroxy-4-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic method of Example 1. Colorless liquid (56 mg, 54.4%) 1H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.4, 2.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.68 (s, 1H), 5.25 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 2.23 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 19 H 21 NO5: 344.1492, found: 344.1495.

[0128] Example 13

[0129] Preparation of (E)-3-((((1-(2-hydroxy-3-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0130]

[0131] The synthesis of (E)-3-((((1-(2-hydroxy-3-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester was performed according to the synthetic procedure of Example 1. White solid (50 mg, 34.7%) 1 H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.02 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.81 (t, J = 7.9 Hz, 1H), 5.29 (s, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 2.29 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). ESI-HRMS [M+1] + calcd for C 19 H 21 NO5: 344.1492, found: 344.1495.

[0132] Example 14

[0133] Preparation of (E)-3-((((1-(3-hydroxy-2-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0134]

[0135] Step 1: Synthesis of 3-acetyl-2-hydroxyphenyl acetate

[0136] 2,3-Dihydroxyacetophenone (600 mg, 3.95 mmol) was dissolved in 3 mL of pyridine, and acetic anhydride (442 mg, 4.34 mmol) was added dropwise at 0 °C, and the reaction was carried out at 70 °C. After the reaction was completed, 1 N hydrochloric acid solution was added to adjust PH = 2, and ethyl acetate was extracted three times, and the organic phase was combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound (891 mg, 87.4%) as a light yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 12.44 (s, 1H), 7.65 (dd, J = 8.1, 1.6 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 2.65 (s, 3H), 2.35 (s, 3H). ESI-MS: calcd for [M+H] + m / z 195.1 found: 195.1.

[0137] Step 2: Synthesis of 3-acetyl-2-methoxyphenyl acetate

[0138] 3-Acetyl-2-hydroxyphenyl acetate (400 mg, 2.06 mmol), methyl iodide (321 mg, 2.27 mmol), and potassium carbonate (426 mg, 3.09 mmol) were added to 3 mL of DMF, and the reaction was carried out at room temperature. After the reaction was completed, saturated brine was added, and ethyl acetate was extracted three times, and the organic phase was combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound (223 mg, 52.0%) as a colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 7.54 (dd, J = 7.7, 1.9 Hz, 1H), 7.23 (dd, J = 8.0, 1.8 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 3.85 (s, 3H), 2.63 (s, 3H), 2.37 (s, 3H). ESI-MS: calcd for [M+H] + m / z 209.1 found: 209.1.

[0139] Step 3: Synthesis of 1-(3-hydroxy-2-methoxyphenyl)ethan-1-one

[0140] 3-acetyl-2-methoxyphenyl acetate (194 mg, 0.93 mmol) and potassium carbonate (257 mg, 1.87 mmol) were dissolved in 4 mL of methanol and reacted at room temperature. After the reaction was completed, water was added for dilution, and ethyl acetate was extracted three times. The organic phase was combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain the target compound (141 mg, 91.0%) as a light yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.18 (dd, J = 7.6, 1.8 Hz, 1H), 7.13 (dd, J = 8.0, 1.9 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 5.88 (s, 1H), 3.84 (s, 3H), 2.63 (s, 3H). ESI-MS: calcd for [M+H] + m / z 167.1 found: 167.1.

[0141] Step 4: Synthesis of (E)-3-((((1-(3-hydroxy-2-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate The synthesis method of (E)-3-((((1-(3-hydroxy-2-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate was performed by reference to the synthesis method of Example 1. Colorless liquid (76 mg, 52.8%) 1 H NMR (600 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 4.6 Hz, 2H), 6.64 (t, J = 4.6 Hz, 1H), 5.23 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.64 (s, 3H), 2.17 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 19 H 21 NO5: 344.1492, found: 344.1496.

[0142] Example 15

[0143] Preparation of (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0144]

[0145] Step 1: Synthesis of methyl 3-(((l,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate

[0146] The synthesis of methyl 3-(((l,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate was referenced to the synthesis of ethyl 5-(((l,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2- carboxylate. White solid (3850 mg, 94.2%). 1 H NMR (600 MHz, Chloroform-d) δ 8.16 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.84 - 7.69 (m, 5H), 7.48 (t, J = 7.7 Hz, 1H), 5.24 (s, 2H), 3.91 (s, 3H). ESI-MS: calcd for [M+H] + m / z 312.1 found: 312.1.

[0147] Step 2: Synthesis of methyl 3-((aminooxy)methyl)benzoate hydrochloride

[0148] The synthesis of methyl 3-((aminooxy)methyl)benzoate hydrochloride was referenced to the synthesis of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (2118 mg, 88.1%). 1 H NMR (600 MHz, Methanol-d4) δ 8.11 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 5.13 (s, 2H), 3.92 (s, 3H). ESI-MS: calcd for [M+H] + m / z 182.1 found: 182.1.

[0149] Step 3: Synthesis of methyl (E)-3-((((l-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0150] The synthesis of methyl (E)-3-((((l-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate was referenced to the synthesis of Example 1. White solid (27 mg, 81.2%) 1H NMR (400 MHz, Chloroform-d) δ 11.39 (s, 1H), 8.08 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 5.49 (s, 2H), 5.21 (s, 2H), 3.93 (s, 3H), 2.31 (s, 3H). ESI-HRMS [M + 1] + calcd for C 17 H 17 NO6: 332.1129, found: 332.1132.

[0151] Example 16

[0152] Preparation of propyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0153]

[0154] Step 1: Synthesis of propyl 3-formylbenzoate

[0155] The synthesis method of propyl 3-formylbenzoate was referenced to that of ethyl 3-formylbenzoate. White solid (3316 mg, 38.5%) 1 H NMR (600 MHz, Chloroform-d) δ 10.06 (s, 1H), 8.50 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 4.30 (t, J = 6.7 Hz, 2H), 1.79 (h, J = 7.2 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M + H] + m / z 193.1 found: 193.1.

[0156] Step 2: Synthesis of propyl 3-(hydroxymethyl)benzoate

[0157] The synthesis method of propyl 3-(hydroxymethyl)benzoate was referenced to that of ethyl 5-(hydroxymethyl)thiophene-2-carboxylate. Colorless liquid (2624 mg, 72.0%) 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 5.34 (t, J = 5.8 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 1.73 (h, J = 7.1 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H]+m / z 257.0 found: 257.0. + m / z 195.1, found: 195.1.

[0158] Step 3: Synthesis of propyl 3-(bromomethyl)benzoate

[0159] The synthesis method of propyl 3-(bromomethyl)benzoate was referenced to that of ethyl 5-(bromomethyl)thiophene-2-carboxylate. Colorless liquid (1917 mg, 63.5%) 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 4.52 (s, 2H), 4.29 (t, J = 6.7 Hz, 2H), 1.80 (h, J = 7.0 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H). ESI-MS: calcd for [M+H]+m / z 257.0 found: 257.0.

[0160] Step 4: Synthesis of propyl 3-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate

[0161] The synthesis method of propyl 3-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate was referenced to that of ethyl 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylate. White solid (1886 mg, 83.8%). 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 4.52 (s, 2H), 4.29 (t, J = 6.7 Hz, 2H), 1.80 (h, J = 7.0 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H). ESI-MS: calcd for [M+H]+m / z 257.0 found: 257.0. +m / z 340.1 found: 340.1.

[0162] Step 5: Synthesis of propyl 3-(aminooxy)methyl)benzoate hydrochloride

[0163] The synthesis method of propyl 3-(aminooxy)methyl)benzoate hydrochloride refers to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1159 mg, 94.3%). 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 5.10 (s, 2H), 4.30 (t, J = 6.6 Hz, 2H), 1.81 (h, J = 7.1 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 210.1 found: 210.1.

[0164] Step 6: Synthesis of propyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0165] The synthesis method of propyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. White solid (103 mg, 48.3%) 1 H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.28 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.27 (s, 2H), 4.24 (t, J = 6.6 Hz, 2H), 2.27 (s, 3H), 1.72 (h, J = 7.2 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). ESI-HRMS [M+1] + calcd for C 19 H 21 NO6: 360.1442, found: 360.1444.

[0166] Example 17

[0167] Preparation of (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethenyl)amino)oxy)methyl) butyl benzoate

[0168]

[0169] Step 1: Synthesis of butyl 3-formylbenzoate

[0170] Butyl 3-formylbenzoate (5000 mg, 22.62 mmol), iodobutane (7279 mg, 39.99 mmol) and potassium carbonate (9198 mg, 66.65 mmol) were added in DMF and reacted at 70 °C. After the reaction was completed, ethyl acetate was added, and then the organic phase was washed with saturated brine three times, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound (5919 mg, 86.1%) as a colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 4.37 (t, J = 6.6 Hz, 2H), 1.84 - 1.72 (m, 2H), 1.55 - 1.41 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 207.1 found: 207.1.

[0171] Step 2: Synthesis of butyl 3-(hydroxymethyl)benzoate

[0172] The synthesis method of butyl 3-(hydroxymethyl)benzoate was referred to the synthesis method of ethyl 5-(hydroxymethyl)thiophene-2-carboxylate. Colorless liquid (4785 mg, 94.8%). 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 4.76 (s, 2H), 4.33 (t, J = 6.6 Hz, 2H), 1.80 - 1.70 (m, 2H), 1.60 (s, 1H), 1.54 - 1.41 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 209.1 found: 209.1.

[0173] Step 3: Synthesis of butyl 3-(bromomethyl)benzoate

[0174] The synthesis of butyl 3-(bromomethyl)benzoate was referenced from the synthesis of ethyl 5-(bromomethyl)thiophene-2-carboxylate. Colorless liquid (3858 mg, 70.8%) 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 4.52 (s, 2H), 4.33 (t, J = 6.6 Hz, 2H), 1.76 (p, J = 6.9 Hz, 2H), 1.48 (h, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 271.0 found: 271.0.

[0175] Step 4: Synthesis of butyl 3-(((1,3-dioxoisoindolin-2- yl)oxy)methyl)benzoate

[0176] The synthesis of butyl 3-(((1,3-dioxoisoindolin-2- yl)oxy)methyl)benzoate was referenced from the synthesis of ethyl 5-(((1,3-dioxoisoindolin-2- yl)oxy)methyl)furan-2-carboxylate. White solid (2990 mg, 65.3%). 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.87 - 7.68 (m, 5H), 7.49 (t, J = 7.7 Hz, 1H), 5.25 (s, 2H), 4.32 (t, J = 6.6 Hz, 2H), 1.81 - 1.69 (m, 2H), 1.53 - 1.40 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 354.1 found: 354.1.

[0177] Step 5: Synthesis of butyl 3-(aminooxy)methyl)benzoate hydrochloride

[0178] The synthesis of butyl 3-(aminooxy)methyl)benzoate hydrochloride was referenced from the synthesis of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1699 mg, 92.6%) 1H NMR (400 MHz, Methanol-d4) δ 8.15 - 8.02 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 5.10 (s, 2H), 4.35 (t, J = 6.6 Hz, 2H), 1.86 - 1.69 (m, 2H), 1.57 - 1.42 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 234.1 found: 234.1.

[0179] Step 6: Synthesis of butyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0180] The synthesis method of (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate was referenced to the synthesis method of Example 1. White solid (76 mg, 68.6%) 1 H NMR (600 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.29 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.36 (d, J = 8.7 Hz, 1H), 5.28 (s, 2H), 4.28 (t, J = 6.5 Hz, 2H), 2.28 (s, 3H), 1.74 - 1.63 (m, 2H), 1.48 - 1.37 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). ESI-HRMS [M+1] + calcd for C 20 H 23 NO6: 374.1598, found: 374.1602.

[0181] Example 18

[0182] Preparation of pentyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0183]

[0184] Step 1: Synthesis of pentyl 3-formylbenzoate

[0185] 3-carboxybenzaldehyde (5000 mg, 33.32 mmol), bromopentane (6040 mg, 39.99 mmol) and potassium carbonate (9198 mg, 66.65 mmol) were added in DMF and reacted at 70 °C. After the reaction was completed, ethyl acetate was added, and then washed with saturated brine three times. The organic phase was combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound (5830 mg, 79.5%) as a colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.53 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 4.36 (t, J = 6.7 Hz, 2H), 1.80 (p, J = 6.9 Hz, 2H), 1.49 - 1.33 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 221.1 found: 221.1.

[0186] Step 2: Synthesis of 3-(hydroxymethyl)pentyl benzoate

[0187] The synthesis method of 3-(hydroxymethyl)pentyl benzoate was referred to that of 5-(hydroxymethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (3400 mg, 67.4%). 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 4.76 (s, 2H), 4.32 (t, J = 6.7 Hz, 2H), 1.77 (p, J = 6.8 Hz, 2H), 1.62 (s, 1H), 1.46 - 1.35 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 223.1 found: 223.1.

[0188] Step 3: Synthesis of 3-(bromomethyl)pentyl benzoate

[0189] The synthesis method of 3-(bromomethyl)pentyl benzoate was referred to that of 5-(bromomethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (3160 mg, 77.2%) 1H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 4.53 (s, 2H), 4.32 (t, J = 6.7 Hz, 2H), 1.78 (p, J = 6.8 Hz, 2H), 1.49 - 1.34 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 285.0 found: 285.0.

[0190] Step 4: Synthesis of pentyl 3-(((l,3-dioxoisoindolin-2- yl)oxy)methyl)benzoate

[0191] The synthesis of pentyl 3-(((l,3-dioxoisoindolin-2- yl)oxy)methyl)benzoate followed the procedure for the synthesis of ethyl 5-(((l,3-dioxoisoindolin-2- yl)oxy)methyl)furan-2-carboxylate. White solid (2930 mg, 75.6%) 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 4.53 (s, 2H), 4.32 (t, J = 6.7 Hz, 2H), 1.78 (p, J = 6.8 Hz, 2H), 1.49 - 1.34 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 268.1 found: 268.1.

[0192] Step 5: Synthesis of pentyl 3-(aminooxy)methyl)benzoate hydrochloride

[0193] The synthesis of pentyl 3-(aminooxy)methyl)benzoate hydrochloride followed the procedure for the synthesis of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1730 mg, 86.1%). 1H NMR (400 MHz, Methanol-d4) δ 8.13 - 8.02 (m, 2H), 7.69 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 5.10 (s, 2H), 4.34 (t, J = 6.6 Hz, 2H), 1.87 - 1.69 (m, 2H), 1.48 - 1.33 (m, 4H), 0.96 (t, J = 6.7 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 238.1 found: 238.1.

[0194] Step 6: Synthesis of pentyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0195] The synthesis of pentyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate followed the synthetic procedure of Example 1. Off-white solid (150 mg, 65.2%) 1 H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.28 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.27 (s, 2H), 4.26 (t, J = 6.5 Hz, 2H), 2.27 (s, 3H), 1.75 - 1.64 (m, 2H), 1.41 - 1.28 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). ESI-HRMS [M+1]+ calcd for C 21 H 25 NO6: 388.1755, found: 388.1757.

[0196] Example 19

[0197] Preparation of (E)-3-((((1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0198]

[0199] The synthesis of (E)-3-((((1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic procedure of Example 1. Colorless liquid (53 mg, 66.3%)1 H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.47 - 7.41 (m, 3H), 7.33 (d, J = 2.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 5.24 (s, 2H), 4.83 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.43 - 1.37 (m, 4H). ESI-HRMS [M+1] + calcd for C 19 H 21 NO5: 344.1492, found: 344.1491.

[0200] Example 20

[0201] Preparation of (E)-3-((((1-(4-hydroxy-3-(methylsulfonamido)phenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0202]

[0203] Step 1: Synthesis of 1-(4-(benzyloxy)-3-nitrophenyl)ethan-1-one

[0204] 4'-hydroxy-3'-nitroacetophenone (3000 mg, 16.57 mmol), benzyl bromide (4253 mg, 24.86 mmol) and potassium carbonate (6861 mg, 49.72 mmol) were added into 20 mL of DMF and reacted at room temperature. After the reaction was completed, it was diluted with 50 mL of ethyl acetate, washed with saturated brine three times, dried over anhydrous magnesium sulfate and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound (3800 mg, 84.6%) as a light yellow solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.47 - 7.41 (m, 3H), 7.33 (d, J = 2.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 5.24 (s, 2H), 4.83 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.43 - 1.37 (m, 4H). ESI-HRMS [M+1] + m / z 272.1 found:272.1.

[0205] Step 2: Synthesis of 1-(3-amino-4-(benzyloxy)phenyl)ethan-1-one

[0206] 1-(4-(benzyloxy)-3-nitrophenyl)ethan-1-one (3000 mg, 11.06 mmol) and 4,4'- bipyridine (8.64 mg, 0.05 mmol) were dissolved in 15 mL of anhydrous DMF, and tetrahydroxyboron (2976 mg, 33.20 mmol) was added portionwise at 0 °C, and the reaction was allowed to proceed at room temperature. After the reaction was completed, it was diluted with saturated brine, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to column chromatography on silica gel (dichloromethane:methanol = 50:1) to obtain the target compound (2390 mg, 89.6%) as a yellow solid. 1 HNMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.48 - 7.32 (m, 5H), 7.06 (d, J = 8.6 Hz, 1H), 6.82 (s, 1H), 5.19 (s, 2H), 2.97 (s, 3H), 2.57 (s, 3H). ESI-MS: calcd for [M+H] + m / z 242.1 found: 242.1.

[0207] Step 3: Synthesis of N-(5-acetyl-2-(benzyloxy)phenyl)methanesulfonamide

[0208] 1-(3-amino-4-(benzyloxy)phenyl)ethan-1-one (1500 mg, 6.22 mmol) and pyridine (1229 mg, 15.56 mmol) were dissolved in 10 mL of anhydrous dichloromethane. After the addition of methylsulfonyl chloride (855 mg, 7.47 mmol) was completed dropwise at 0 °C, the reaction was allowed to proceed at room temperature. After the reaction was completed, it was acidified with 1 N hydrochloric acid, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine twice, dried over anhydrous sodium sulfate, and concentrated. The residue obtained after concentration was subjected to column chromatography on silica gel (dichloromethane:methanol = 50:1) to obtain the target compound (1880 mg, 94.7%) as a yellow solid. 1 HNMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.48 - 7.32 (m, 5H), 7.06 (d, J = 8.6 Hz, 1H), 6.82 (s, 1H), 5.19 (s, 2H), 2.97 (s, 3H), 2.57 (s, 3H). ESI-MS: calcd for [M+H] + m / z 320.1 found: 320.1.

[0209] Step 4: Synthesis of N-(5-acetyl-2-hydroxyphenyl)methanesulfonamide

[0210] N-(5-acetyl-2-(benzyloxy)phenyl)methanesulfonamide (1200 mg, 3.76 mmol), 10% palladium on carbon (120 mg, 0.11 mmol) and ammonium formate (710 mg, 11.28 mmol) were dissolved in 15 mL of methanol and refluxed at 110 °C. After the reaction was completed, it was filtered and concentrated. The residue obtained after concentration was purified by column chromatography on silica gel (dichloromethane:methanol = 20:1) to obtain the target compound (570 mg, 66.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.99 (s, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.4, 2.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 2.97 (s, 3H), 2.47 (s, 3H). ESI-MS: calcd for [M+H] + m / z 230.0 found: 230.0.

[0211] Step 5: Synthesis of (E)-3-((((1-(4-hydroxy-3-(methylsulfonamido)phenyl)ethylidene)amino)oxy)methyl)benzoate

[0212] The synthesis of (E)-3-((((1-(4-hydroxy-3-(methylsulfonamido)phenyl)ethylidene)amino)oxy)methyl)benzoate was performed according to the synthetic method of Example 1. White solid (43 mg, 20.3%) 1 H NMR (600 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.39 - 7.31 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 5.23 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.99 (s, 3H), 2.21 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESI-HRMS [M+1] + calcd for C 19 H 22 N2O6S: 407.1271, found: 407.1274.

[0213] Example 21

[0214] Preparation of (E)-3-((((1-(3-carbamoyl-4-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester

[0215]

[0216] The synthesis of (E)-3-((((1-(3-carbamoyl-4-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid ethyl ester followed the synthetic procedure of Reference Example 1. White solid (28 mg, 14.7%) 1 H NMR (600 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.55 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.75 (dd, J = 8.8, 2.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.26 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). ESI-HRMS [M + 1] + calcd for C 19 H 20 N2O5: 357.1445, found: 357.1447.

[0217] Example 22

[0218] Preparation of (E)-1-(3,4-dihydroxyphenyl)ethan-1-one O-(3-(3-methyl-1,2,4-oxadiazol-5- yl)benzyl)oxime

[0219]

[0220] Step 1: Synthesis of methyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate

[0221] Isophthalic acid monomethyl ester (5400 mg, 30.00 mmol) was dissolved in 40 mL of anhydrous dichloromethane, and then 1 drop of DMF was added. The mixture was stirred at 60 °C after the addition of thionyl chloride (10703 mg, 90.00 mmol). After the reaction was completed, the solvent was removed by rotary evaporation to obtain a solid. The solid was dissolved in 30 mL of anhydrous dioxane, and then (Z)-N'-hydroxyisobutyrimidamide (2886 mg, 39.00 mmol) and N,N-diisopropylethylamine (7740 mg, 60.00 mmol) were added sequentially. After stirring at room temperature for 30 min, the mixture was stirred at 110 °C for 3 h. After the reaction was completed, 50 mL of ethyl acetate was added, and the mixture was washed with saturated brine three times. The mixture was dried over anhydrous magnesium sulfate and concentrated. The residue obtained after concentration was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1) to obtain the target compound (3570 mg, 54.6%) as a white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 3.97 (s, 3H), 2.50 (s, 3H). ESI-MS: calcd for [M+H] + m / z 219.1 found: 219.1.

[0222] Step 2: Synthesis of (3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanol

[0223] Methyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate (2940 mg, 13.48 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and then 26 mL of a 1.5 M DIBAL-H solution in toluene was added dropwise at 0 °C. After the dropwise addition was completed, the mixture was stirred at room temperature for 36 h. After the reaction was completed, 20 mL of a saturated ammonium chloride solution at 0 °C was added, and the mixture was extracted with ethyl acetate three times. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue obtained after concentration was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) to obtain the target compound as a white solid (2420 mg, 94.4%). 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 4.79 (d, J = 5.8 Hz, 2H), 2.47 (s, 3H), 2.02 (t, J = 5.9 Hz, 1H). ESI-MS: calcd for [M+H] + m / z 191.1 found: 191.1.

[0224] Step 3: Synthesis of 5-(3-(bromomethyl)phenyl)-3-methyl-l,2,4-oxadiazole

[0225] The synthesis of 5-(3-(bromomethyl)phenyl)-3-methyl-l,2,4-oxadiazole was referenced from the synthesis of ethyl 5-(bromomethyl)thiophene-2-carboxylate. White solid (1845 mg, 92.8%) 1 H NMR (600 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 4.52 (s, 2H), 2.47 (s, 3H). ESI-MS: calcd for [M+H] + m / z 253.0 found: 253.0.

[0226] Step 4: Synthesis of 2-((3-(3-methyl-l,2,4-oxadiazol-5-yl)benzyl)oxy)isoindole-l,3-dione

[0227] The synthesis of 2-((3-(3-methyl-l,2,4-oxadiazol-5-yl)benzyl)oxy)isoindole-l,3-dione was referenced from the synthesis of ethyl 5-(((l,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (1820 mg, 91.3%) 1 H NMR (600 MHz, Chloroform-d) δ 8.26 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.86 - 7.70 (m, 5H), 7.58 (t, J = 7.8 Hz, 1H), 5.28 (s, 2H), 2.47 (s, 3H). ESI-MS: calcd for [M+H] + m / z 336.1 found: 336.1.

[0228] Step 5: Synthesis of O-(3-(3-methyl-l,2,4-oxadiazol-5-yl)benzyl)hydroxylamine hydrochloride

[0229] The synthesis of O-(3-(3-methyl-l,2,4-oxadiazol-5-yl)benzyl)hydroxylamine hydrochloride was referenced from the synthesis of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (596 mg, 69.5%). 1HNMR (600 MHz, DMSO-d6) δ 11.21 (s, 3H), 8.13 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 5.18 (s, 2H), 2.43 (s, 3H). ESI-MS: calcd for [M+H] + m / z 206.1 found: 206.1.

[0230] Step 6: Synthesis of (E)-1-(3,4-dihydroxyphenyl)ethan-1-one O-(3-(3-methyl-1,2,4- oxadiazol-5-yl)benzyl) oxime The synthesis of (E)-1-(3,4-dihydroxyphenyl)ethan-1-one O-(3-(3-methyl-1,2,4- oxadiazol-5-yl)benzyl) oxime was performed according to the synthetic procedure of Reference Example 1. White solid (32 mg, 13.4%) 1 H NMR (600 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.05 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.3, 2.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 5.27 (s, 2H), 2.42 (s, 3H), 2.18 (s, 3H). ESI-HRMS [M+1] + calcd for C 18 H 17 N3O4: 340.1292, found: 340.1294.

[0231] Example 23

[0232] Preparation of (E)-1-(3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4- oxadiazol-3-yl)benzyl) oxime

[0233]

[0234] Step 1: Synthesis of (Z)-3-(N'-hydroxyformamidino)benzoic acid methyl ester

[0235] 3-cyanobenzoic acid methyl ester (8000 mg, 49.67 mmol), hydroxylamine hydrochloride (5253 mg, 74.51 mmol) and triethylamine (8042 mg, 79.47 mmol) were added into 100 mL of ethanol successively, and reacted at room temperature for 12 h. After the reaction, the solvent was evaporated to obtain a solid, 30 mL of water and 30 mL of ethyl acetate were added to dissolve the solid, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain the product as a white solid (9600 mg, 99.0%). 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.30 (s, 1H), 8.06 - 7.78 (m, 2H), 7.54 (t, J = 7.8 Hz, 1H), 5.96 (s, 2H), 3.87 (s, 3H). ESI-MS: calcd for [M+H] + m / z 195.1 found: 195.1.

[0236] Step 2: Synthesis of methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate

[0237] (Z)-3-(N'-hydroxyaminocarbonylamino)benzoic acid methyl ester (2500 mg, 12.88 mmol) and acetic anhydride (2631 mg, 25.77 mmol) were dissolved in 20 mL of acetic acid, and reacted at 118 °C. After the reaction, the solvent was evaporated, water and ethyl acetate were added, washed with saturated sodium bicarbonate solution until no bubbles were generated, then washed with saturated brine, dried, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound as a white solid (4706 mg, 76.1%) 1 H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 3.95 (s, 3H), 2.68 (s, 3H). ESI-MS: calcd for [M+H] + m / z 219.1 found: 219.1.

[0238] Step 3: Synthesis of (3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)methanol

[0239] Methyl 3-(5-methyl-l,2,4-oxadiazol-3-yl)benzoate (4000 mg, 18.34 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran, 3.67 mL of 2.5 M LiAlH4tetrahydrofuran solution was added dropwise at 0 °C, and the reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed, IN hydrochloric acid was added, and ethyl acetate was extracted three times. The organic phase was combined, dried, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain the target compound as a white solid (3128 mg, 89.8%) 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H), 2.66 (s, 3H), 1.92 (t, J = 6.0 Hz, 1H). ESI-MS: calcd for [M+H]+m / z 191.1 found: 191.1.

[0240] Step 4: Synthesis of 3-(3-(bromomethyl)phenyl)-5-methyl-l,2,4-oxadiazole

[0241] (3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)methanol (3000 mg, 15.78 mmol) and PPh3(5689 mg, 17.36 mol) were dissolved in 20 mL of anhydrous tetrahydrofuran. CBr4(4548 mg, 17.36 mmol) was added portionwise at 0 °C, and the reaction was allowed to proceed at room temperature for 12 h. After the reaction was completed, it was filtered, and the filtrate was concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain the target compound as a white solid (2693 mg, 67.7%) 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 4.54 (s, 2H), 2.67 (s, 3H). ESI-MS: calcd for [M+H] + m / z 253.0 found: 253.0.

[0242] Step 5: Synthesis of 2-((3-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-l,3-dione

[0243] The synthesis of 2-((3-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-l,3-dione was referenced from the synthesis of ethyl 5-(((l,3-dioxoisoindolin-2-yl)oxy)methyl)furan-2-carboxylate. White solid (2903 mg, 91.0%) 1 HNMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.86 - 7.68 (m, 5H), 7.52 (t, J = 7.7 Hz, 1H), 5.27 (s, 2H), 2.66 (s, 3H). ESI-MS: calcd for [M+H]+m / z 336.1 found: 336.1.

[0244] Step 6: Synthesis of O-(3-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride

[0245] The synthesis of O-(3-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride was referenced from the synthesis of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1593 mg, 88.5%). 1 HNMR (400 MHz, Methanol-d4) δ 8.20 - 8.05 (m, 2H), 7.81 - 7.51 (m, 2H), 5.12 (s, 2H), 2.66 (s, 3H). ESI-MS: calcd for [M+H] + m / z 206.1 found: 206.1.

[0246] Step 7: Synthesis of (E)-l-(3,4-dihydroxyphenyl)ethan-l-one O-(3-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)oxime

[0247] The synthesis of (E)-l-(3,4-dihydroxyphenyl)ethan-l-one O-(3-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)oxime was referenced from the synthesis of Example 1. Light yellow solid (73 mg, 54.9%) 1H NMR (600 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.04 (s, 1H), 8.01 (s, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.10 (d, J = 2.2 Hz, 1H), 6.93 (dd, J = 8.2, 2.2 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 2.67 (s, 3H), 2.16 (s, 3H). ESI-HRMS [M+1] + C 18 H 17 N3O4: 340.1292, found: 340.1291.

[0248] Example 24

[0249] Preparation of (E)-1-(3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-ethyl-1,2,4-oxadiazol-3- yl)benzyl)oxime

[0250]

[0251] The procedure for the synthesis of (Z)-3-(N'-hydroxyformamidino)benzoic acid methyl ester is outlined in Example 23

[0252] Step 2: Synthesis of 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester

[0253] The procedure for the synthesis of 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester is referenced to the procedure for the synthesis of 3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoic acid methyl ester. White solid (4729 mg, 74.8%) 1 H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.27 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 3.95 (s, 3H), 3.00 (q, J = 7.6 Hz, 2H), 1.47 (t, J = 7.6 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 233.1 found: 233.1.

[0254] Step 3: Synthesis of (3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)methanol

[0255] The synthesis method of (3-(5-ethyl-l,2,4-oxadiazol-3-yl)phenyl)methanol was referenced to the synthesis method of (3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)methanol. White solid (3312 mg, 81.4%) 1 H NMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 4.78 (s, 2H), 2.98 (q, J = 7.6 Hz, 2H), 1.81 (s, 1H), 1.46 (t, J = 7.6 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 205.1 found: 205.1.

[0256] Step 4: Synthesis of 3-(3-(bromomethyl)phenyl)-5-ethyl-l,2,4-oxadiazole

[0257] The synthesis method of 3-(3-(bromomethyl)phenyl)-5-ethyl-l,2,4-oxadiazole was referenced to the synthesis method of 3-(3-(bromomethyl)phenyl)-5-methyl-l,2,4-oxadiazole. White solid (3169 mg, 76.0%) 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 4.54 (s, 2H), 2.99 (q, J = 7.6 Hz, 2H), 1.46 (t, J = 7.6 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 267.0 found: 267.0.

[0258] Step 5: Synthesis of 2-((3-(5-ethyl-l,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-l,3-dione

[0259] The synthesis method of 2-((3-(5-ethyl-l,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-l,3-dione was referenced to the synthesis method of 5-(((l,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. White solid (3580 mg, 90.9%) 1HNMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.87 - 7.70 (m, 5H), 7.52 (t, J = 7.7 Hz, 1H), 5.27 (s, 2H), 2.98 (q, J = 7.6 Hz, 2H), 1.45 (t, J = 7.6 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 350.1 found: 350.1.

[0260] Step 6: Synthesis of O-(3-(5-ethyl-l,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride

[0261] The synthesis of O-(3-(5-ethyl-l,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride was referenced to the synthesis of 5-((aminooxy)methyl)furan-2-carboxylic acid ethyl ester hydrochloride. White solid (2067 mg, 83.2%) 1 H NMR (400 MHz, DMSO-d6) δ 8.11 - 7.95 (m, 2H), 7.65 - 7.61 (m, 2H), 5.13 (s, 2H), 3.03 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 220.1 found: 220.1.

[0262] Step 7: Synthesis of (E)-l-(3,4-dihydroxyphenyl)ethan-l-one O-(3-(5-ethyl-l,2,4-oxadiazol-3- yl)benzyl)oxime

[0263] The synthesis of (E)-l-(3,4-dihydroxyphenyl)ethan-l-one O-(3-(5-ethyl-l,2,4-oxadiazol-3- yl)benzyl)oxime was referenced to the synthesis of Example 1. Colorless liquid (82 mg, 89.1%) 1H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.3, 2.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.85 (s, 1H), 5.61 (s, 1H), 5.24 (s, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.20 (s, 3H), 1.46 (t, J = 7.6 Hz, 3H). ESI-HRMS [M+1] + calcd for C 19 H 19 N3O4: 354.1448, found: 354.1448.

[0264] Example 25. Preparation of (E)-1-(3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- propyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0265]

[0266] The procedure for the synthesis of (Z)-3-(N'-hydroxyformamidino)benzoic acid methyl ester is outlined in Example 23

[0267] Step 2: Synthesis of 3-(5-propyl-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester

[0268] (Z)-3-(N'-hydroxyformamidino)benzoic acid methyl ester (3500 mg, 18.04 mmol) and butyryl chloride (2305 mg, 21.64 mmol) were added to 30 mL of dry dioxane, followed by dropwise addition of N,N-diisopropylethylamine (4652 mg, 36.07 mmol). After 30 min at room temperature, the reaction was heated at 110 °C for 8 h. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue obtained after concentration was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1) to give the target compound as a light yellow liquid (4032 mg, 88.4%) 1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.27 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 3.95 (s, 3H), 2.94 (t, J = 7.5 Hz, 2H), 1.93 (h, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 247.1 found: 247.1.

[0269] Step 3: Synthesis of (3-(5-propyl-l,2,4-oxadiazol-3-yl)phenyl)methanol

[0270] The synthesis of (3-(5-propyl-l,2,4-oxadiazol-3-yl)phenyl)methanol was performed according to the synthesis of (3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)methanol. Colorless liquid (2522 mg, 79.1%) 1 H NMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 4.77 (s, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.08 - 1.86 (m, 3H), 1.06 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 219.1 found: 219.1.

[0271] Step 4: Synthesis of 3-(3-(bromomethyl)phenyl)-5-propyl-l,2,4-oxadiazole

[0272] The synthesis of 3-(3-(bromomethyl)phenyl)-5-propyl-l,2,4-oxadiazole was performed according to the synthesis of 3-(3-(bromomethyl)phenyl)-5-methyl-l,2,4-oxadiazole. Colorless liquid (2569 mg, 85.1%) 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 4.54 (s, 2H), 2.94 (t, J = 7.5 Hz, 2H), 1.92 (h, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H]+ m / z 281.1 found: 281.1.

[0273] Step 5: Synthesis of 2-((3-(5-propyl-l,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-l,3-dione

[0274] The synthesis method of 2-((3-(5-propyl-l,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-l,3-dione refers to the synthesis method of ethyl 5-(((l,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (2757 mg, 83.6%) 1 HNMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.88 - 7.67 (m, 5H), 7.52 (t, J = 7.7 Hz, 1H), 5.27 (s, 2H), 2.92 (t, J = 7.5 Hz, 2H), 1.91 (h, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 364.1 found: 364.1.

[0275] Step 6: Synthesis of O-(3-(5-propyl-l,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride

[0276] The synthesis method of O-(3-(5-propyl-l,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride refers to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1471 mg, 82.7%) 1 HNMR (400 MHz, DMSO-d6) δ 8.12 - 8.01 (m, 2H), 7.68 - 7.60 (m, 2H), 5.11 (s, 2H), 2.99 (t, J = 7.4 Hz, 2H), 1.82 (h, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 234.1 found: 234.1.

[0277] Step 7: Synthesis of (E)-l-(3,4-dihydroxyphenyl)ethan-l-one O-(3-(5-propyl-l,2,4-oxadiazol-3-yl)benzyl)oxime

[0278] The synthesis of (E)-l-(3,4-dihydroxyphenyl)ethan-l-one O-(3-(5- propyl-l,2,4-oxadiazol-3-yl)benzyl)oxime was performed according to the synthetic procedure of Reference Example 1. Colorless liquid (74 mg, 77.1%) 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.3, 2.0 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.86 (s, 1H), 5.71 (s, 1H), 5.24 (s, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.20 (s, 3H),

[0279] 1.91 (h, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). ESI-HRMS [M+1] + calcd for C 20 H 21 N3O4: 368.1605, found: 368.1602.

[0280] Example 26

[0281] Preparation of (E)-l-(3-fluoro-4,5-dihydroxyphenyl)ethan-l-one O-(3-(5-methyl-l,2,4- oxadiazol-3-yl)benzyl)oxime

[0282]

[0283] Step 1: Synthesis of 3-fluoro-4-hydroxy-5-methoxybenzoic acid

[0284] 3-Fluoro-4-hydroxy-5-methoxybenzaldehyde (1000 mg, 5.88 mmol) was dissolved in 10 mL of dioxane, then aminosulfonic acid (1254 mg, 12.94 mmol) and 1 mL of water were added. Sodium chlorite (1170 mg, 12.94 mmol) was added at 0 °C and after stirring for 30 min, the reaction was quenched with aqueous sodium bisulfite solution, extracted with ethyl acetate three times, the organic phase was combined, washed with saturated brine once, dried over anhydrous magnesium sulfate, and concentrated to give the target product as a white solid (856 mg, 78.4%). 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.12 (s, 1H), 7.43 - 7.19 (m, 2H), 3.86 (s, 3H). ESI-MS: calcd for [M-H] - m / z 185.0 found: 185.0.

[0285] Step 2: Synthesis of 3-fluoro-4-hydroxy-N, 5-dimethoxy-N-methylbenzamide

[0286] 3-Fluoro-4-hydroxy-5-methoxybenzoic acid (1500 mg, 8.06 mmol), dimethylamine hydrochloride (1642 mg, 16.93 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2318 mg, 12.09 mmol) and 1-hydroxybenzotriazole (326 mg, 2.42 mmol) were dissolved in 25 mL of dry dichloromethane, and after the addition of triethylamine (3257 mg, 32.25 mmol) the reaction was refluxed for 8 h. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with dichloromethane three times, the organic phases were combined, washed with IN hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (dichloromethane:methanol = 15:1) to give the target compound as a light yellow solid (758 mg, 41.0%) 1 H NMR (400 MHz, Chloroform-d) δ 7.26 (dd, J = 10.8, 1.8 Hz, 1H), 7.17 (t, J = 1.5 Hz, 1H), 5.80 (s, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H). ESI-MS: calcd for [M+H] + m / z 230.1 found: 230.1.

[0287] Step 3: Synthesis of l-(3-fluoro-4-hydroxy-5-methoxyphenyl)ethan-l-one

[0288] 3-Fluoro-4-hydroxy-N, 5-dimethoxy-N-methylbenzamide (500 mg, 2.18 mmol) was dissolved in 10 mL of dry tetrahydrofuran, and 10.9 mL of 1M methylmagnesium bromide tetrahydrofuran solution was added dropwise at 0°C, and the reaction was carried out at room temperature for 8 h. After the reaction was completed, ice water was added, the pH was adjusted to 2 with IN dilute hydrochloric acid, and the organic phase was extracted with ethyl acetate three times, dried over anhydrous magnesium sulfate and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (dichloromethane:methanol = 20:1) to give the target compound as a white solid (317 mg, 79.0%) 1H NMR (400 MHz, Chloroform-d) δ 7.41 - 7.34 (m, 2H), 5.87 (d, J = 1.6 Hz, 1H), 3.98 (s, 3H), 2.55 (s, 3H). ESI-MS: calcd for [M+H] + m / z 185.1 found: 185.1.

[0289] Step 4: Synthesis of (E)-1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl) oxime

[0290] 1-(3-Fluoro-4-hydroxy-5-methoxyphenyl)ethan-1-one (300 mg, 1.63 mmol) was dissolved in 5 mL of anhydrous dichloromethane, protected by nitrogen, and 9.78 mL of 1M BBr3dichloromethane solution was added dropwise at -78°C. After stirring for 15 min, the reaction was warmed to 0°C. After the reaction was completed, ice water was added for dilution, and saturated brine was added. The organic phase was extracted with ethyl acetate three times, combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the target compound as a white solid (226 mg, 81.6%) 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.94 (s, 1H), 7.27 (dd, J = 11.2, 2.1 Hz, 1H), 7.23 - 7.18 (m, 1H), 2.45 (s, 3H). ESI-MS: calcd for [M+H] + m / z 171.0 found: 171.0.

[0291] Step 5: Synthesis of (E)-1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl) oxime

[0292] The synthesis method of (E)-1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl) oxime was performed according to the synthesis method of Example 1. Gray solid (83 mg, 79.8%) 1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 1.5 Hz, 1H), 6.98 (dd, J = 11.2, 2.0 Hz, 1H), 5.71 (s, 1H), 5.51 (s, 1H), 5.25 (s, 2H), 2.67 (s, 3H), 2.18 (s, 3H). ESI-HRMS [M+1] + calcd for C 18 H 16 FN3O4: 358.1198, found: 358.1198.

[0293] Example 27

[0294] Preparation of (E)-1-(3-chloro-4,5-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl) oxime

[0295]

[0296] Step 1: Synthesis of 3-chloro-4-hydroxy-N,5-dimethoxy-N-methylbenzamide

[0297] The synthesis method of 3-chloro-4-hydroxy-N,5-dimethoxy-N-methylbenzamide refers to that of 3-fluoro-4-hydroxy-N,5-dimethoxy-N-methylbenzamide. White solid (2282 mg, 62.7%) 1 H NMR (400 MHz, Chloroform-d) δ 7.46 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 6.14 (s, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H). ESI-MS: calcd for [M+H] + m / z 246.1 found: 246.1.

[0298] Step 2: Synthesis of 1-(3-chloro-4-hydroxy-5-methoxyphenyl)ethan-1-one

[0299] The synthesis method of 1-(3-chloro-4-hydroxy-5-methoxyphenyl)ethan-1-one refers to that of 1-(3-fluoro-4-hydroxy-5-methoxyphenyl)ethan-1-one. White solid (711 mg, 62.3%) 1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 6.30 (s, 1H), 3.97 (s, 3H), 2.56 (s, 3H). ESI-MS: calcd for [M+H] + m / z 201.0 found: 201.0.

[0300] Step 3: Synthesis of 1-(3-chloro-4,5-dihydroxyphenyl)ethan-1-one

[0301] The synthesis method of 1-(3-chloro-4,5-dihydroxyphenyl)ethan-1-one refers to the synthesis method of 1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one. White solid (257 mg, 79.1%) 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 2H), 7.47 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 2.46 (s, 3H). ESI-MS: calcd for [M+H] + m / z 187.0 found: 187.0.

[0302] Step 4: Synthesis of (E)-1-(3-chloro-4,5-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0303] The synthesis method of (E)-1-(3-chloro-4,5-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Light yellow solid (67 mg, 83.8%) 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.18 (s, 2H), 5.73 (s, 2H), 5.25 (s, 2H), 2.66 (s, 3H), 2.19 (s, 3H). ESI-HRMS [M+1] + calcd for C 18 H 16 ClN3O4: 374.0902, found: 374.0905.

[0304] Example 28

[0305] Preparation of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl) oxime

[0306]

[0307] Step 1: Synthesis of 1-(2-fluoro-3,4-dimethoxyphenyl)ethan-1-one

[0308] AlCl3(999 mg, 7.49 mmol) was dissolved in 10 mL of anhydrous dichloromethane at -20 °C, and then acetyl chloride (678 mg, 8.65 mmol) and 1-fluoro-2,3- dimethoxybenzene (900 mg, 5.77 mmol) were added dropwise. After the addition was completed, the reaction was warmed to room temperature for 5 h. After the reaction was completed, it was poured into ice water, extracted with dichloromethane three times, and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain the target compound as a white solid (1036 mg, 90.7%) 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J = 9.0, 8.0 Hz, 1H), 6.76 (dd, J = 8.9, 1.5 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.60 (d, J = 5.2 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 199.1 found: 199.1.

[0309] Step 2: Synthesis of 1-(2-fluoro-3,4-dihydroxyphenyl)ethan-1-one

[0310] The synthesis method of 1-(2-fluoro-3,4-dimethoxyphenyl)ethan-1-one was referred to the synthesis method of 1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one. White solid (66 mg, 15.4%) 1 H NMR (400 MHz, DMSO-d6) δ 7.21 (t, J = 8.4 Hz, 1H), 6.70 (dd, J = 8.7, 1.4 Hz, 1H), 2.50 (d, J = 4.6 Hz, 3H). ESI-MS: calcd for [M+H] + m / z 171.0 found: 171.0.

[0311] Step 3: Synthesis of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl) oxime

[0312] The synthesis method of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime was referred to the synthesis method of Example 1. Yellowish solid (51 mg, 60.8%) 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.83 (t, J = 8.3 Hz, 1H), 6.64 - 6.55 (m, 1H), 5.81 (s, 2H), 5.27 (s, 2H), 2.67 (s, 3H), 2.24 (d, J = 2.2 Hz, 3H). ESI-HRMS [M+1] + calcd for C 18 H 16 FN3O4: 358.1198, found: 358.1201.

[0313] Example 29

[0314] Preparation of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4- oxadiazol-3-yl)benzyl)oxime

[0315]

[0316] Step 1: Synthesis of 2-chloro-N,3,4-trimethoxy-N-methylbenzamide

[0317] 2-chloro-3,4-dimethoxybenzoic acid (2000 mg, 9.26 mmol), hydroxylamine hydrochloride (943 mg, 9.75 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2307 mg, 12.04 mmol), 1-hydroxybenzotriazole (1626 mg, 12.04 mmol) and N-methylmorpholine (4963 mg, 49.07 mmol) were dissolved in 25 mL of anhydrous dichloromethane and reacted at room temperature for 8 h. After the reaction was completed, water was added for dilution, dichloromethane was extracted 3 times, the organic phase was combined, washed with 1 N HCl (aq) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the target compound as a yellowish solid (1173 mg, 48.9%) 1H NMR (400 MHz, Chloroform-d) δ 7.06 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.51 (s, 3H), 3.32 (s, 3H). ESI-MS: calcd for [M+H] + m / z 260.1 found: 260.1.

[0318] Step 2: Synthesis of 1-(2-chloro-3,4-dimethoxyphenyl)ethan-1-one

[0319] The synthesis method of 1-(2-chloro-3,4-dimethoxyphenyl)ethan-1-one refers to the synthesis method of 1-(3-fluoro-4-hydroxy-5-methoxyphenyl)ethan-1-one. White solid (730 mg, 87.9%) 1 H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.64 (s, 3H). ESI-MS: calcd for [M+H] + m / z 215.0 found: 215.0.

[0320] Step 3: Synthesis of 1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one

[0321] The synthesis method of 1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one refers to the synthesis method of 1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one. Yellow solid (129 mg, 29.7%) 1 H NMR (400 MHz, Methanol-d4) δ 7.17 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 2.56 (s, 3H). ESI-MS: calcd for [M+H] + m / z 187.0 found: 187.0.

[0322] Step 4: Synthesis of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0323] The synthesis method of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Pale yellow solid (26 mg, 14.3%)1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 6.74 (s, 2H), 5.95 (s, 1H), 5.87 (s, 1H), 5.28 (s, 2H), 2.67 (s, 3H), 2.23 (s, 3H). ESI-HRMS [M+l] + calcd for C 18 H 16 ClN3O4: 374.0902, found: 374.0906.

[0324] Example 30

[0325] Preparation of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- ethyl-1,2,4-oxadiazol-3-yl)benzyl) oxime

[0326]

[0327] The synthesis of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- ethyl-1,2,4-oxadiazol-3-yl)benzyl) oxime followed the synthetic procedure of Example 1. Yellow solid (39 mg, 60.0%) 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.83 (t, J = 8.3 Hz, 1H), 6.61 (dd, J = 8.6, 1.6 Hz, 1H), 5.88 (s, 2H), 5.27 (s, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.24 (d, J = 2.3 Hz, 3H), 1.46 (t, J = 7.6 Hz, 3H). ESI-HRMS [M+l] + calcd for C 19 H 18 FN3O4: 372.1354, found: 372.1354.

[0328] Example 31

[0329] Preparation of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- ethyl-1,2,4-oxadiazol-3-yl)benzyl) oxime

[0330]

[0331] The synthesis of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- ethyl-1,2,4-oxadiazol-3-yl)benzyl) oxime followed the synthetic method of Reference Example 1. Off-white solid (46 mg, 50.5%) 1 H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 6.78 (s, 2H), 5.81 (s, 1H), 5.73 (s, 1H), 5.28 (s, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.24 (s, 3H), 1.46 (t, J = 7.7 Hz, 3H). ESI-HRMS [M+1] + Caled for C 19 H 18 ClN3O4: 388.1059, found: 388.1060.

[0332] Example 32

[0333] Preparation of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- propyl-1,2,4-oxadiazol-3-yl)benzyl) oxime

[0334]

[0335] The synthesis of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5- ethyl-1,2,4-oxadiazol-3-yl)benzyl) oxime followed the synthetic method of Reference Example 1. Off-white solid (46 mg, 50.5%) 1 H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 6.78 (s, 2H), 5.81 (s, 1H), 5.73 (s, 1H), 5.28 (s, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.24 (s, 3H), 1.46 (t, J = 7.7 Hz, 3H). ESI-HRMS [M+1] + Caled for C20 H 20 FN3O4: 386.1511, found: 386.1514.

[0336] Example 33

[0337] Preparation of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl) oxime

[0338]

[0339] The synthesis method of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethan-1-one O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl) oxime refers to the synthesis method of Example 1. Light yellow solid (68 mg, 79.1%) 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 6.78 (s, 2H), 5.81 (s, 1H), 5.68 (s, 1H), 5.28 (s, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.92 (h, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H). ESI-HRMS [M+1] + calcd for C 20 H 20 ClN3O4: 402.1215, found: 402.1219.

[0340] Inhibition activity of the compounds prepared in Examples 1-33 on TNF-α produced by RAW264.7 cells induced by Pam3CSK4 was detected (ELISA method):

[0341] RAW264.7 (mouse macrophage) in logarithmic growth phase was diluted to 4 x 10 5The compounds were diluted to a final concentration of 100 μM in 96-well plates (100 μL / well), and then the gradient dilution of the compounds (50 μL / well) and DMEM medium (30 μL / well) were added, and incubated at 37 °C in 5% CO2 for 2 h, and then the TLR2 / 1 ligand Pam3CSK4 (10 ng / ml, 20 μL / well) was added. In addition, a blank control group (100 μL of DMEM medium containing 10% fetal bovine serum and 100 μL of RAW264.7 cells) and a stimulation control group (80 μL of DMEM medium containing 10% fetal bovine serum, 100 μL of RAW264.7 cells and 20 μL of Pam3CSK4) were set. Incubated at 37 °C in 5% CO2 for 24 h, and the supernatant was collected. The tumor necrosis factor-α (TNF-α) in the cell culture supernatant was detected by ELISA, and the OD value was detected by a microplate reader. The IC50 values of the compounds were obtained by fitting the concentration of the compounds and the inhibition rate of the cytokines by Graphpad prism 8.0.1 software. 50 .

[0342] Table 1 Antagonistic activity of the compounds prepared in Examples 1-33 and positive drugs on TLR2 / 1

[0343]

[0344]

[0345]

[0346]

[0347] The results show that the IC50 values of some of the compounds in the examples in RAW264.7 cells are better than that of the positive compound CUCPT-22 (34.96 ± 1.98 μM). 50

[0348] The above-described examples only describe the preferred modes of the present application, and do not limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements to the technical solutions of the present application made by those of ordinary skill in the art shall fall within the scope of protection determined by the claims of the present application.​

Claims

1. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof; the compounds of Formula I are specifically selected from the group consisting of:

2. Use of a compound of claim 1 in the preparation of a TLR2 antagonist.

3. A pharmaceutical composition, characterized by, a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical preparation, characterized by, a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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