Compound with ketoxime ether structure and application thereof

Abstract

The invention relates to the technical field of TLR2 antagonists, in particular to a compound with a ketoxime ether structure and application thereof. The compound has a structure as shown in a formula I: # imgabs0 # or a pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4 and R5 are independently selected from any one of hydrogen atoms, phenolic hydroxyl groups, amino groups, halogen, C1-C4 alkyl groups, C1-C4 alkoxy groups, C3-C5 cycloalkyl groups, C2-C4 alkenyl groups, C2-C4 alkynyl groups, amide groups, sulfanilamide groups, ester groups, cyano groups, OCH2F, OCHF2, OCF3, SCF3 and N (CH3) 2; the 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 sulfanilamide group, an alkyl group, an alkoxy group, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, substituted oxazole, substituted isoxazole, substituted thiazole, substituted isothiazole, substituted oxadiazole and substituted thiadiazole. The compound can be used as a TLR2 antagonist.

Description

Technical Field

[0001] The present invention relates to the technical field of TLR2 antagonists, and in particular to a compound with a ketoximine ether structure and application thereof. Background Art

[0002] Pattern recognition receptors (PRRs) present on the innate immune cells in the human body can recognize foreign microorganisms such as bacteria, viruses and fungi, which have completely different structural components from those of the human body, namely pathogen-associated molecular patterns (PAMPs), thereby initiating innate immune responses. TLR-like receptors (TLRs) are the most important family of pattern recognition receptors. They are not only the gateway to the innate immune response, but also the bridge between 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 with the most ligand recognition in the TLRs family. TLR2 is located on the cell surface and belongs to type I transmembrane protein. It can be divided into three structures: extracellular region, transmembrane region, and intracellular region. Generally, TLR2 binds to TLR1 or TLR6 through the extracellular region to form TLR2 / TLR1 or TLR2 / TLR6 heterodimers, and then recognizes different PMAPs or DAMPs molecules in combination, and then recruits the adaptor protein MYD88 through the intracellular region to initiate the conduction of immune signals, activate the downstream NF-κB pathway and MAPK pathway, promote the release of various cytokines, and accelerate the clearance of pathogens, thereby exerting antibacterial and antiviral effects. 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] The excessive activation of TLR2 is closely related to the occurrence and development of inflammatory diseases, autoimmune diseases and neuropsychiatric diseases. TLR2 antagonists can block the binding of TLR2 to its ligands and inhibit the activation of downstream signaling pathways, and can be used to treat the above diseases. After more than ten years of efforts, researchers have discovered many antagonists targeting TLR2. Currently reported TLR2 antagonists can be divided into three categories, namely, orthostatic antagonists targeting the extracellular region of TLR2, allosteric antagonists targeting the intracellular region of TLR2, and other TLR2 antagonists with unclear modes of action.

[0005] Although researchers have obtained various types of TLR2 antagonists through high-throughput screening and virtual screening, unfortunately, no TLR2 antagonist has been approved for marketing so far. Existing TLR2 antagonists generally have the disadvantages of low activity, poor drug-like properties, and poor physical and chemical properties. Therefore, finding TLR2 antagonists with strong immunosuppressive activity and good drug-like properties is the main direction of future TLR2 antagonist research and development. Summary of the invention

[0006] In order to address the deficiencies of existing TLR2 antagonists in terms of activity and drugability, the present invention 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 and research value.

[0007] To achieve the above object, the present invention provides the following solutions:

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

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

[0010] In formula I, 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;

[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 an ester group, 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 having 1 to 15 carbon atoms, and the substituted group substituent 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 heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 1-6 Any one of the alkyl groups.

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

[0014] The substituent of ring A is 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 heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 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 inflammatory diseases, autoimmune diseases or neurodegenerative diseases mediated by TLR2.

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

[0017] A 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] The present invention provides a new compound with a ketoximine ether structure. The compound has a certain antagonistic activity to Toll-like receptor 2 (TLR2), and can be used as a TLR2 antagonist for treating TLR2-mediated inflammatory diseases, autoimmune diseases and neurodegenerative diseases. DETAILED DESCRIPTION

[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0021] The first aspect of the present invention provides a compound represented by formula I:

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

[0023] In formula I, 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;

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

[0025] R6 is any one of an ester group, 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 having 1 to 15 carbon atoms, and the substituted group substituent is selected from the group consisting of 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 heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 1-6 Any one of the alkyl groups.

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

[0027] The substituent of ring A is selected from: R6, fluorine, chlorine, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C1-6 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 heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 1-6 Any one of the alkyl groups.

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

[0029] In some embodiments of the present invention, 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 invention provides the use of the above-mentioned compound in the preparation of a drug for treating and / or preventing inflammatory diseases mediated by TLR2 (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.).

[0031] The third aspect of the present invention provides a pharmaceutical composition 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.

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

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

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

[0035] In some embodiments of the invention, the pharmaceutical composition is formulated for enteral delivery.

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

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

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

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

[0040] The fourth aspect of the present invention provides a pharmaceutical preparation 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, or the above-mentioned pharmaceutical composition, and a pharmaceutically acceptable carrier.

[0041] In some embodiments of the present invention, the dosage form is a tablet, capsule, powder, pill, granule, oral solution, injection or emulsion.

[0042] All parameters and other descriptions in the examples of the present invention are based on mass unless otherwise specified. The fillers used for column chromatography separation are all silica gel unless otherwise specified. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0043] The nuclear magnetic resonance used in the examples 1 The H spectrum analyzer was a Bruker 600 MHz nuclear magnetic resonance instrument from Bruker, Switzerland, and a Zhongke Oxford 400 MHz nuclear magnetic resonance instrument; the mass spectrum was measured by an Agilent liquid chromatography-mass spectrometry system.

[0044] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The methods and materials described herein are for exemplary purposes only.

[0045] The present invention is further described below by way of examples.

[0046] Example 1

[0047] Preparation of (E)-ethyl 5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)furan-2-carboxylate. The synthetic steps are shown below.

[0048]

[0049] Step 1: Preparation of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate

[0050] 5-Chloromethyl-2-furancarboxylic acid ethyl ester (2300 mg, 12.23 mmol) and N-hydroxyphthalimide (2991 mg, 18.35 mmol) were dissolved in 20 mL of N,N-dimethylformamide (DMF), and N,N-diisopropylethylamine (3945 mg, 30.59 mmol) was added, and the mixture was reacted for 6 h under argon protection. After the reaction was completed as monitored by thin layer chromatography (TLC), water was added to the reaction solution until the solid was completely precipitated, and 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester was obtained after filtration, washing, and drying as a light yellow solid (2568 mg, yield 66.6%). 1 H NMR (400MHz, Chloroform-d) δ7.91–7.60 (m, 4H), 7.13 (d, J = 3.5Hz, 1H), 6.65 (d, J = 3.5Hz, 1H), 5.20 (s, 2H), 4.32 (q, J = 7.1Hz, 2H), 1.33 (t, J = 7.1Hz, 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-(((1,3-dioxoisoindol-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 and reacted for 18 hours under argon protection. After the reaction was completed by TLC monitoring, 6 mL of 4N hydrochloric acid methanol solution was added to the reaction system at 0°C and stirred for 0.5 h. After being spin-dried at 25°C, the target compound (1111 mg, 79.2%) was obtained by filtration as a white solid. 1 H NMR (400MHz, Methanol-d4) δ7.24 (d, J = 3.5 Hz, 1H), 6.82 (d, J = 3.5 Hz, 1H), 5.11 (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 186.1, found: 186.1.

[0053] Step 3: Preparation of ethyl (E)-5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)furan-2-carboxylate

[0054] 2,3,4-Trihydroxyacetophenone (70 mg, 0.42 mmol) and 5-((aminooxy)methyl)furan-2-carboxylic acid ethyl ester hydrochloride (110 mg, 0.50 mmol) were dissolved in methanol and reacted at room temperature. After the reaction was completed, the crude product was dried by spin drying 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 (400MHz, Chloroform-d) δ11.31(s,1H),7.15(d,J=3.5Hz,1H),6.89(d,J=8.8Hz,1H),6.54(d,J=3.4Hz,1H ), 6.51 (d, J = 8.8Hz, 1H), 5.54 (s, 2H), 5.13 (s, 2H), 4.37 (q, J = 7.1Hz, 2H), 2.27 (s, 3H), 1.38 (t, J = 7.1Hz, 3H). ESI-HRMS[M+1] + Calculate 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] 5-Formyl-2-thiophenecarboxylic acid (5000 mg, 32.05 mmol), iodoethane (5998 mg, 38.46 mmol) and potassium carbonate (8847 mg, 64.11 mmol) were dissolved in 30 mL DMF and reacted at 60° C. After the reaction was completed by TLC monitoring, ethyl acetate was added, washed with saturated brine 3 times, and dried 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 (400MHz, Chloroform-d) δ9.97 (s, 1H), 7.83 (d, J = 3.9Hz, 1H), 7.73 (d, J = 3.9Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 1.40 (t, J = 7.1Hz, 3H). ESI-MS:calcdfor[M+H] +m / z 184.0, found: 184.0.

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

[0061] Dissolve 5-formylthiophene-2-carboxylic acid ethyl ester (2990 mg, 16.25 mmol) in anhydrous methanol, add sodium borohydride (307 mg, 8.14 mmol) in batches at 0°C, and react at room temperature for 2 hours. After the reaction is completed, the solvent is dried by TLC monitoring, dissolved in ethyl acetate, washed with saturated brine three times, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration is chromatographed on a silica gel column to obtain the target compound (2872 mg, 95.0%) as a light yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ7.60 (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:calcdfor[M+H] + m / z 187.0, found: 187.0.

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

[0063] Dissolve 5-(Hydroxymethyl)thiophene-2-carboxylic acid ethyl ester (2600 mg, 13.98 mmol) and triphenylphosphine (5038 mg, 15.38 mmol) in anhydrous tetrahydrofuran, add carbon tetrabromide (4028 mg, 15.38 mmol) in batches at 0°C, react at room temperature for 12 h, filter after the reaction is completed under TLC monitoring, and concentrate the filtrate under reduced pressure. Silica gel column chromatography gives the target compound (3104 mg, 89.5%) as a light yellow liquid. 1 HNMR (400MHz, Chloroform-d) δ7.61 (d, J = 3.8Hz, 1H), 7.06 (d, J = 3.7Hz, 1H), 4.66 (s, 2H), 4.32 (q, J = 7.1Hz, 2H), 1.35 (t, J = 7.1Hz, 3H). ESI-MS:calcd for[M+H] + m / z 248.9, found: 248.9.

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

[0065] The synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)thiophene-2-carboxylate was referred to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. Pale yellow solid (2017 mg, 53.9%). 1 H NMR (400MHz, Chloroform-d) δ7.86–7.71 (m, 4H), 7.68 (d, J = 3.8Hz, 1H), 7.19 (d, J = 3.8Hz, 1H), 5.35 (s, 2H), 4.33 (q, J = 7.1Hz, 2H), 1.36 (t, J = 7.1Hz, 3H). ESI-MS:calcd for[M+H] + m / z 332.1, found: 332.1.

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

[0067] The synthesis method of ethyl 5-((aminooxy)methyl)thiophene-2-carboxylate hydrochloride was referred to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (994 mg, 77.2%). 1 H NMR (400MHz, Methanol-d4) δ7.74 (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 ethyl (E)-5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)thiophene-2-carboxylate

[0069] The synthesis method of (E)-ethyl 5-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)thiophene-2-carboxylate refers to the synthesis method 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] + Calculate 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)ethylidene)amino)oxy)methyl)benzoate, the synthetic route is shown below.

[0072]

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

[0074] Dissolve isophthalaldehyde (7000 mg, 52.23 mmol) and iodine (19888 mg, 78.35 mmol) in ethanol, add potassium carbonate (14417 mg, 104.48 mmol), and react at 60°C for 12 hours. After the reaction is completed, concentrate under reduced pressure, dissolve the residue obtained after concentration in ethyl acetate, wash three times with saturated brine, dry over anhydrous magnesium sulfate, and concentrate. The residue obtained after concentration is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain 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 ethyl 3-(hydroxymethyl)benzoate is based on the synthesis method of ethyl 5-(hydroxymethyl)thiophene-2-carboxylate. Colorless liquid (2624 mg, 72.0%). 1 H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.98(d,J=7.6Hz,1H),7.57(d,J=7.4Hz,1H),7. 44(t,J=7.7Hz,1H), 4.76(s,2H), 4.38(q,J=7.1Hz,2H), 1.82(s,1H), 1.40(t,J=7.2Hz,3H). ESI-MS:calcd for[M+H] + m / z 181.1, found: 181.1.

[0077] Step 3: Preparation of ethyl 3-(bromomethyl)benzoate

[0078] The synthesis method of ethyl 3-(bromomethyl)benzoate refers to the synthesis method of ethyl 5-(bromomethyl)thiophene-2-carboxylate. Colorless liquid (1866 mg, 55.5%). 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.97(d,J=7.6Hz,1H),7.57(d,J=7.5Hz,1 H), 7.41 (t, J = 7.7Hz, 1H), 4.51 (s, 2H), 4.38 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.1Hz, 3H). ESI-MS:calcd for[M+H] + m / z 243.0, found: 243.0.

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

[0080] The synthesis method of ethyl 3-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate refers to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (2040 mg, 89.4%). 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),8.07(d,J=7.8Hz,1H),7.85–7.69(m,5H ), 7.49 (t, J = 7.7Hz, 1H), 5.26 (s, 2H), 4.38 (q, J = 7.1Hz, 2H), 1.40 (t, J = 7.1Hz, 3H). ESI-MS:calcdfor[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 the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1184 mg, 87.7%) 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 3H), 8.03–7.94 (m, 2H), 7.70 (d, J = 7.6Hz, 1H), 7.58(t,J=7.6Hz,1H), 5.14(s,2H), 4.33(q,J=7.0Hz,2H), 1.33(t,J=7.2Hz,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 the synthesis in Example 1. White solid (47 mg, 32.8%). 1 H NMR (400MHz, Chloroform-d) δ11.40(s,1H),8.08(s,1H),8.02(d,J=7.8Hz,1H),7.59(d,J=7.5Hz,1H),7.46(t,J=7.7Hz,1H),6. 89(d,J=8.9Hz,1H),6.50(d,J=8.8Hz,1H),5.48(s,2H),5.21(s,2H),4.39(q,J=7.1Hz,2H),2.31(s,3H),1.40(t,J=7.1Hz,3H).

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

[0086] Example 4

[0087] The preparation of ethyl (E)-4-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate, the synthetic route is shown below.

[0088]

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

[0090] The synthesis method of ethyl 4-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate refers to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. Pale yellow solid (5610 mg, 93.2%). 1 HNMR (400MHz, Chloroform-d) δ8.05(d,J=8.1Hz,2H),7.85–7.71(m,4H),7.61(d,J=8.0Hz,2H),5.26(s,2H),4.37(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,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 method of ethyl 4-(aminooxy)methyl)benzoate hydrochloride refers to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (820 mg, 96.2%). 1 H NMR (400MHz, 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 ethyl (E)-4-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0094] The synthesis method of (E)-ethyl 4-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. White solid (103 mg, 50.2%).1 H NMR(600MHz,Chloroform-d)δ11.34(s,1H),8.06(d,J=8.3Hz,2H),7.46(d,J=8.1Hz,2H),6.89(d,J=8.8Hz,1H ), 6.50 (d, J = 8.8Hz, 1H), 5.55 (s, 2H), 5.21 (s, 2H), 4.38 (q, J = 7.1Hz, 2H), 2.32 (s, 3H), 1.39 (t, J = 7.1Hz, 3H). ESI-HRMS[M+1] + Calculate for C 18 H 19 NO6:346.1285,found:346.1286.

[0095] Example 5

[0096] Preparation of ethyl (E)-3-((((1-(3,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate.

[0097]

[0098] The synthesis method of ethyl (E)-3-((((1-(3,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. Light green solid (41 mg, 47.7%). 1 H NMR(600MHz,Chloroform-d)δ8.12(s,1H),7.97(d,J=7.7Hz,1H),7.59(d,J=7.5Hz,1H),7.42(t,J=7.7Hz,1H),7.20(s,1H),7. 01(d,J=8.0Hz,1H),6.80(d,J=8.2Hz,1H),6.10(s,2H),5.22(s,2H),4.38(q,J=7.1Hz,2H),2.19(s,3H),1.39(t,J=7.1Hz,3H).

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

[0100] Example 6

[0101] Preparation of ethyl (E)-3-((((1-(2,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0102]

[0103] The synthesis method of ethyl (E)-3-((((1-(2,4-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. Colorless liquid (36 mg, 75.0%). 1 H NMR(600MHz,Chloroform-d)δ11.29(s,1H),8.08(s,1H),8.01(d,J=7.7Hz,1H),7.59(d,J=7.5Hz,1H),7.45(t,J=7.7Hz,1H),7.25(d,J=8.7Hz ,1H),6.40(d,J=2.5Hz,1H),6.38(dd,J=8.5,2.7Hz,1H),5.65(s,1H),5.20(s,2H),4.39(q,J=7.1Hz,2H),2.31(s,3H),1.40(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 18 H 19 NO5:330.1336,found:330.1338.

[0104] Example 7

[0105] Preparation of ethyl (E)-3-((((1-(2,3-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0106]

[0107] The synthesis method of ethyl (E)-3-((((1-(2,3-dihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. White solid (75 mg, 61.5%). 1 H NMR (600MHz, Chloroform-d) δ11.27(s,1H),8.09(s,1H),8.03(d,J=7.7Hz,1H),7.60(d,J=7.4Hz,1H),7.47(t,J=7.7Hz,1H),6.96(dd,J=8. 1,1.5Hz,1H),6.95–6.91(m,1H),6.79(t,J=8.0Hz,1H),5.70(s,1H),5.25(s,2H),4.39(q,J=7.1Hz,2H),2.35(s,3H),1.41(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 18 H19 NO5:330.1336,found:330.1337.

[0108] Example 8

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

[0110]

[0111] The synthesis method of ethyl (E)-3-((((1-(4-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate was similar to that of Example 1. White solid (129 mg, 78.2%) 1 H NMR (600MHz, DMSO-d6) δ9.73(s,1H),8.00(s,1H),7.90(d,J=7.7Hz,1H),7.67(d,J=7.5Hz,1H),7.53(t,J=7.7Hz,1H) ,7.48(d,J=8.7Hz,2H),6.77(d,J=8.7Hz,2H),5.23(s,2H),4.32(q,J=7.1Hz,2H),2.18(s,3H),1.32(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 18 H 19 NO4:314.1387,found:314.1390.

[0112] Example 9

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

[0114]

[0115] The synthesis method of ethyl (E)-3-((((1-(3-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. White solid (124 mg, 78.6%) 1H NMR (600MHz, DMSO-d6) δ9.51(s,1H),8.00(s,1H),7.91(d,J=7.5Hz,1H),7.68(d,J=7.4Hz,1H),7.54(t,J=7.7Hz,1H),7.19(t ,J=8.1Hz,1H),7.08–7.05(m,2H),6.85–6.75(m,1H),5.27(s,2H),4.32(q,J=7.1Hz,2H),2.20(s,3H),1.32(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 18 H 19 NO4:314.1387,found:314.1390.

[0116] Example 10

[0117] Preparation of ethyl (E)-3-((((1-(2-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0118]

[0119] The synthesis method of ethyl (E)-3-((((1-(2-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate is similar to that of Example 1. White solid (106 mg, 99.1%) 1 H NMR(400MHz,Chloroform-d)δ11.01(s,1H),8.09(s,1H),8.02(d,J=7.7Hz,1H),7.60(d,J=7.5Hz,1H),7.46(t,J=7.7Hz,1H),7.41(dd,J=8.0,1.6Hz,1H), 7.25–7.21(m,1H),6.93(dd,J=8.3,1.3Hz,1H),6.88(ddd,J=7.9,7.3,1.3Hz ,1H),5.25(s,2H),4.39(q,J=7.1Hz,2H),2.37(s,3H),1.40(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 18 H 19 NO4:314.1387,found:314.1387.

[0120] Embodiment 11

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

[0122]

[0123] The synthesis method of ethyl (E)-3-((((1-(4-hydroxy-3-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. Colorless liquid (34 mg, 32.9%) 1 H NMR(600MHz,Chloroform-d)δ8.11(s,1H),7.99(d,J=7.4Hz,1H),7.61(d,J=7.5Hz,1H),7.43(t,J=7.7Hz,1H),7.26(d,J=1.9Hz,1H),7.10(d d,J=8.4,2.0Hz,1H),6.89(d,J=8.3Hz,1H),5.81(s,1H),5.26(s,2H),4.38(q,J=7.1Hz,2H),3.91(s,3H),2.25(s,3H),1.40(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 19 H 21 NO5:344.1492,found:344.1494.

[0124] Example 12

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

[0126]

[0127] The synthesis method of ethyl (E)-3-((((1-(3-hydroxy-4-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. Colorless liquid (56 mg, 54.4%) 1H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.98(d,J=7.8Hz,1H),7.61(d,J=7.5Hz,1H),7.43(t,J=7.7Hz,1H),7.27(d,J=2.2Hz,1H),7.13(d d,J=8.4,2.2Hz,1H),6.81(d,J=8.4Hz,1H),5.68(s,1H),5.25(s,2H),4.38(q,J=7.1Hz,2H),3.88(s,3H),2.23(s,3H),1.40(t,J=7.1Hz,3H). ESI-HRMS[M+1] + calcdfor C 19 H 21 NO5:344.1492,found:344.1495.

[0128] Example 13

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

[0130]

[0131] The synthesis method of ethyl (E)-3-((((1-(2-hydroxy-3-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate was similar to that of Example 1. White solid (50 mg, 34.7%) 1 H NMR (600MHz, DMSO-d6) δ10.27(s,1H),8.02(s,1H),7.93(d,J=7.6Hz,1H),7.70(d,J=7.5Hz,1H),7.56(t,J=7.6Hz,1H),7.00 (d, J=7.8Hz, 2H), 6.81 (t, J=7.9Hz, 1H), 5.29 (s, 2H), 4.33 (q, J=7.0Hz, 2H), 3.77 (s, 3H), 2.29 (s, 3H), 1.33 (t, J=7.0Hz, 3H). ESI-HRMS[M+1] + Calculate for C 19 H 21 NO5:344.1492,found:344.1495.

[0132] Embodiment 14

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

[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 mixture was reacted at 70°C after the addition was complete. After the reaction was completed, 1N hydrochloric acid solution was added to adjust the pH to 2, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 8:1) to obtain the target compound (891 mg, 87.4%) as a light yellow solid. 1 H NMR (400MHz, Chloroform-d) δ12.44(s,1H),7.65(dd,J=8.1,1.6Hz,1H),7.27(dd,J=8.0,1.6Hz,1H),6.91(t,J=8.0Hz,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), iodomethane (321 mg, 2.27 mmol) and potassium carbonate (426 mg, 3.09 mmol) were added to 3 mL of DMF and reacted at room temperature. After the reaction, saturated brine was added, and ethyl acetate was extracted three times. 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 (223 mg, 52.0%) as a colorless liquid. 1 H NMR (400MHz, Chloroform-d) δ7.54 (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, the mixture was diluted with water and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain the target compound (141 mg, 91.0%) as a light yellow solid. 1 H NMR (400MHz, Chloroform-d) δ7.18 (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 ethyl (E)-3-((((1-(3-hydroxy-2-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate The synthesis method of ethyl (E)-3-((((1-(3-hydroxy-2-methoxyphenyl)ethylidene)amino)oxy)methyl)benzoate is similar to that of Example 1. Colorless liquid (76 mg, 52.8%) 1 H NMR (600MHz, DMSO-d6) δ9.48(s,1H),7.98(s,1H),7.90(d,J=7.6Hz,1H),7.65(d,J=7.5Hz,1H),7.53(t,J=7.7Hz,1H),6.88( d,J=4.6Hz,2H),6.64(t,J=4.6Hz,1H),5.23(s,2H),4.32(q,J=7.1Hz,2H),3.64(s,3H),2.17(s,3H),1.32(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 19 H 21 NO5:344.1492,found:344.1496.

[0142] Embodiment 15

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

[0144]

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

[0146] The synthesis method of methyl 3-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate refers to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (3850 mg, 94.2%). 1 H NMR (600MHz, Chloroform-d) δ8.16 (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 method of methyl 3-((aminooxy)methyl)benzoate hydrochloride refers to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (2118 mg, 88.1%). 1 H NMR (600MHz, Methanol-d4) δ8.11(s,1H),8.07(d,J=7.8Hz,1H),7.71(d,J=7.6Hz,1H),7.57(t,J=7.7Hz,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-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate

[0150] The synthesis method of methyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate is similar to that of Example 1. White solid (27 mg, 81.2%) 1H NMR(400MHz,Chloroform-d)δ11.39(s,1H),8.08(s,1H),8.01(d,J=7.7Hz,1H),7.60(d,J=7.5Hz,1H),7.47(t, J=7.7Hz,1H),6.89(d,J=8.8Hz,1H),6.50(d,J=8.8Hz,1H),5.49(s,2H),5.21(s,2H),3.93(s,3H),2.31(s,3H). ESI-HRMS[M+1] + Calculate for C 17 H 17 NO6:332.1129,found:332.1132.

[0151] Example 16

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

[0153]

[0154] Step 1: Synthesis of 3-formylbenzoic acid propyl ester

[0155] The synthesis method of 3-formylbenzoic acid propyl ester refers to the synthesis method of 3-formylbenzoic acid ethyl ester. White solid (3316 mg, 38.5%) 1 H NMR(600MHz,Chloroform-d)δ10.06(s,1H),8.50(s,1H),8.28(d,J=7.7Hz,1H),8.05(d,J=7.7Hz ,1H),7.60(t,J=7.7Hz,1H),4.30(t,J=6.7Hz,2H),1.79(h,J=7.2Hz,2H),1.02(t,J=7.4Hz,3H). ESI-MS:calcd for[M+H] + m / z 193.1 found:193.1.

[0156] Step 2: Synthesis of 3-(hydroxymethyl)benzoic acid propyl ester

[0157] The synthesis method of 3-(hydroxymethyl)benzoic acid propyl ester refers to 5-(hydroxymethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (2624 mg, 72.0%) 1H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.83(d,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.47(t,J=7.6Hz,1H),5.3 4(t,J=5.8Hz,1H), 4.56(d,J=5.7Hz,2H), 4.23(t,J=6.6Hz,2H), 1.73(h,J=7.1Hz,2H), 0.97(t,J=7.4Hz,3H). ESI-MS:calcd for[M+H] + m / z 195.1, found: 195.1.

[0158] Step 3: Synthesis of 3-(bromomethyl)benzoic acid propyl ester

[0159] The synthesis method of 3-(bromomethyl)benzoic acid propyl ester refers to the synthesis method of 5-(bromomethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (1917 mg, 63.5%) 1 H NMR(600MHz,Chloroform-d)δ8.06(s,1H),7.98(d,J=7.7Hz,1H),7.58(d,J=7.5Hz,1H),7.42(t ,J=7.5Hz,1H),4.52(s,2H),4.29(t,J=6.7Hz,2H),1.80(h,J=7.0Hz,2H),1.03(t,J=7.3Hz,3H). ESI-MS:calcd for[M+H]+m / z257.0found:257.0.

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

[0161] The synthesis method of propyl 3-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate refers to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (1886 mg, 83.8%). 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),8.07(d,J=7.6Hz,1H),7.86–7.69(m,5H),7.49(t,J =7.7Hz, 1H), 5.26 (s, 2H), 4.28 (t, J = 6.7Hz, 2H), 1.79 (h, J = 7.2Hz, 2H), 1.02 (t, J = 7.4Hz, 3H). ESI-MS:calcd for[M+H] +m / z 340.1 found:340.1.

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

[0163] The synthesis method of 3-(aminooxy)methyl)benzoic acid propyl ester hydrochloride is based on the synthesis method of 5-((aminooxy)methyl)furan-2-carboxylic acid ethyl ester hydrochloride. White solid (1159 mg, 94.3%). 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=8.8Hz,2H),7.69(d,J=7.9Hz,1H),7.58(t,J=7.6 Hz, 1H), 5.10 (s, 2H), 4.30 (t, J = 6.6Hz, 2H), 1.81 (h, J = 7.1Hz, 2H), 1.04 (t, J = 7.4Hz, 3H). ESI-MS:calcd for[M+H] + m / z 210.1 found: 210.1.

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

[0165] The synthesis method of (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoic acid propyl ester is similar to the synthesis method of Example 1. White solid (103 mg, 48.3%) 1 H NMR (600MHz, DMSO-d6) δ10.74(s,1H),9.28(s,1H),8.24(s,1H),8.00(s,1H),7.93(d,J=7.6Hz,1H),7.69(d,J=7.5Hz,1H),7.56(t,J=7.7Hz,1 H), 6.83 (d, J = 8.8Hz, 1H), 6.35 (d, J = 8.8Hz, 1H), 5.27 (s, 2H), 4.24 (t, J = 6.6Hz, 2H), 2.27 (s, 3H), 1.72 (h, J = 7.2Hz, 2H), 0.96 (t, J = 7.3Hz, 3H). ESI-HRMS[M+1] + calcdfor C 19 H 21 NO6:360.1442,found:360.1444.

[0166] Embodiment 17

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

[0168]

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

[0170] 3-Carboxybenzaldehyde (5000 mg, 33.32 mmol), iodobutane (7279 mg, 39.99 mmol) and potassium carbonate (9198 mg, 66.65 mmol) were added to DMF and reacted at 70°C. After the reaction, ethyl acetate was added and the mixture was washed three times with saturated brine. The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 8:1) to obtain the target compound (5919 mg, 86.1%) as a colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ10.09(s,1H),8.52(s,1H),8.31(d,J=7.7Hz,1H),8.08(d,J=7.6Hz,1H),7 .63(t,J=7.7Hz,1H), 4.37(t,J=6.6Hz,2H), 1.84–1.72(m,2H), 1.55–1.41(m,2H), 0.99(t,J=7.4Hz,3H). ESI-MS:calcdfor[M+H] + m / z 207.1 found: 207.1.

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

[0172] The synthesis method of butyl 3-(hydroxymethyl)benzoate refers to the synthesis method of ethyl 5-(hydroxymethyl)thiophene-2-carboxylate. Colorless liquid (4785 mg, 94.8%). 1 H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.97(d,J=7.7Hz,1H),7.57(d,J=7.5Hz,1H),7.44(t,J=7.7Hz,1H) ,4.76(s,2H),4.33(t,J=6.6Hz,2H),1.80–1.70(m,2H),1.60(s,1H),1.54–1.41(m,2H),0.98(t,J=7.4Hz,3H). ESI-MS:calcd for[M+H] + m / z 209.1 found: 209.1.

[0173] Step 3: Synthesis of 3-(bromomethyl)benzoic acid butyl ester

[0174] The synthesis method of 3-(bromomethyl) butyl benzoate refers to the synthesis method of 5-(bromomethyl) thiophene-2-carboxylic acid ethyl ester. Colorless liquid (3858 mg, 70.8%) 1 H NMR(600MHz,Chloroform-d)δ8.05(s,1H),7.97(d,J=7.7Hz,1H),7.58(d,J=7.5Hz,1H),7.42(t,J=7.7Hz,1 H), 4.52 (s, 2H), 4.33 (t, J = 6.6Hz, 2H), 1.76 (p, J = 6.9Hz, 2H), 1.48 (h, J = 7.4Hz, 2H), 0.98 (t, J = 7.4Hz, 3H). ESI-MS:calcdfor[M+H] + m / z 271.0 found: 271.0.

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

[0176] The synthesis method of butyl 3-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate refers to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (2990 mg, 65.3%). 1 HNMR(400MHz,Chloroform-d)δ8.14(s,1H),8.06(d,J=7.9Hz,1H),7.87–7.68(m,5H),7.49(t,J=7.7Hz ,1H),5.25(s,2H),4.32(t,J=6.6Hz,2H),1.81–1.69(m,2H),1.53–1.40(m,2H),0.98(t,J=7.4Hz,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 method of butyl 3-(aminooxy)methyl)benzoate hydrochloride refers to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1699 mg, 92.6%) 1H NMR (400MHz, Methanol-d4) δ8.15–8.02(m,2H),7.70(d,J=7.6Hz,1H),7.58(t,J=7.6Hz,1H),5 .10(s,2H),4.35(t,J=6.6Hz,2H),1.86–1.69(m,2H),1.57–1.42(m,2H),1.00(t,J=7.4Hz,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)-butyl 3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. White solid (76 mg, 68.6%) 1 H NMR(600MHz,DMSO-d6)δ10.75(s,1H),9.29(s,1H),8.25(s,1H),8.00(s,1H ),7.93(d,J=7.4Hz,1H),7.69(d,J=7.5Hz,1H),7.56(t,J=7.7Hz,1H),6.83 (d,J=8.7Hz,1H),6.36(d,J=8.7Hz,1H),5.28(s,2H),4.28(t,J=6.5Hz,2H) ,2.28(s,3H),1.74–1.63(m,2H),1.48–1.37(m,2H),0.92(t,J=7.4Hz,3H). ESI-HRMS[M+1] + Calculate for C 20 H 23 NO6:374.1598,found:374.1602.

[0181] Embodiment 18

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

[0183]

[0184] Step 1: Synthesis of 3-formylbenzoic acid pentyl ester

[0185] 3-Carboxybenzaldehyde (5000 mg, 33.32 mol), bromopentane (6040 mg, 39.99 mmol) and potassium carbonate (9198 mg, 66.65 mmol) were added to DMF and reacted at 70°C. After the reaction, ethyl acetate was added, and then washed three times with saturated brine. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 8:1) to obtain the target compound (5830 mg, 79.5%) as a colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ10.09(s,1H),8.53(s,1H),8.31(d,J=7.7Hz,1H),8.09(d,J=7.7Hz,1H),7.6 3(t,J=7.7Hz,1H), 4.36(t,J=6.7Hz,2H), 1.80(p,J=6.9Hz,2H), 1.49–1.33(m,4H), 0.94(t,J=7.0Hz,3H). ESI-MS:calcd for[M+H] + m / z 221.1found:221.1.

[0186] Step 2: Synthesis of 3-(hydroxymethyl)benzoic acid pentyl ester

[0187] The synthesis method of pentyl 3-(hydroxymethyl)benzoate refers to the synthesis method of ethyl 5-(hydroxymethyl)thiophene-2-carboxylate. Colorless liquid (3400 mg, 67.4%). 1 H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.97(d,J=7.6Hz,1H),7.58(d,J=7.5Hz,1H),7.44(t,J=7.7Hz,1H),4 .76(s,2H),4.32(t,J=6.7Hz,2H),1.77(p,J=6.8Hz,2H),1.62(s,1H),1.46–1.35(m,4H),0.93(t,J=7.0Hz,3H). ESI-MS:calcd for[M+H] + m / z 223.1 found:223.1.

[0188] Step 3: Synthesis of 3-(bromomethyl)benzoic acid pentyl ester

[0189] The synthesis method of 3-(bromomethyl)benzoic acid pentyl ester refers to the synthesis method of 5-(bromomethyl)thiophene-2-carboxylic acid ethyl ester. Colorless liquid (3160 mg, 77.2%) 1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.98(d,J=7.9Hz,1H),7.59(d,J=7.7Hz,1H),7.43(t,J=7.7Hz ,1H),4.53(s,2H),4.32(t,J=6.7Hz,2H),1.78(p,J=6.8Hz,2H),1.49–1.34(m,4H),0.94(t,J=7.0Hz,3H). ESI-MS:calcd for[M+H] + m / z 285.0 found: 285.0.

[0190] Step 4: Synthesis of pentyl 3-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate

[0191] The synthesis method of pentyl 3-(((1,3-dioxoisoindol-2-yl)oxy)methyl)benzoate refers to the synthesis method of ethyl 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylate. White solid (2930 mg, 75.6%) 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),8.06(d,J=7.8Hz,1H),7.85–7.71(m,5H),7.49(t,J=7.7Hz,1 H), 5.26 (s, 2H), 4.31 (t, J = 6.7Hz, 2H), 1.77 (p, J = 6.9Hz, 2H), 1.48–1.31 (m, 4H), 0.93 (t, J = 7.0Hz, 3H). ESI-MS:calcd for[M+H] + m / z 268.1 found:268.1.

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

[0193] The synthesis method of pentyl 3-(aminooxy)methyl)benzoate hydrochloride refers to the synthesis method of ethyl 5-((aminooxy)methyl)furan-2-carboxylate hydrochloride. White solid (1730 mg, 86.1%). 1H NMR (400MHz, Methanol-d4) δ8.13–8.02(m,2H),7.69(d,J=7.5Hz,1H),7.58(t,J=7.6Hz,1H),5 .10(s,2H),4.34(t,J=6.6Hz,2H),1.87–1.69(m,2H),1.48–1.33(m,4H),0.96(t,J=6.7Hz,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 method of pentyl (E)-3-((((1-(2,3,4-trihydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. Gray solid (150 mg, 65.2%) 1 H NMR(600MHz,DMSO-d6)δ10.74(s,1H),9.28(s,1H),8.24(s,1H),8.00(s,1H ),7.92(d,J=7.4Hz,1H),7.68(d,J=7.7Hz,1H),7.55(t,J=7.7Hz,1H),6.82 (d,J=8.8Hz,1H),6.35(d,J=8.8Hz,1H),5.27(s,2H),4.26(t,J=6.5Hz,2H) ,2.27(s,3H),1.75–1.64(m,2H),1.41–1.28(m,4H),0.87(t,J=7.0Hz,3H). ESI-HRMS[M+1]+calcd for C 21 H 25 NO6:388.1755,found:388.1757.

[0196] Embodiment 19

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

[0198]

[0199] The synthesis method of ethyl (E)-3-((((1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethylidene)amino)oxy)methyl)benzoate refers to the synthesis method of Example 1. Colorless liquid (53 mg, 66.3%)1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.98(d,J=7.9Hz,1H),7.60(d,J=7.4Hz,1H),7.47–7.41(m,3H),7.33(d,J =2.3Hz,1H),6.84(d,J=8.5Hz,1H),5.24(s,2H),4.83(s,2H),4.38(q,J=7.1Hz,2H),2.22(s,3H),1.43–1.37(m,4H). ESI-HRMS[M+1] + Calculate for C 19 H 21 NO5:344.1492,found:344.1491.

[0200] Embodiment 20

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

[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 to 20 mL of DMF and reacted at room temperature. After the reaction, it was diluted with 50 mL of ethyl acetate, washed three times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 8:1) to obtain the target compound (3800 mg, 84.6%) as a light yellow solid. 1 H NMR(600MHz,Chloroform-d)δ8.43(d,J=2.3Hz,1H),8.11(dd,J=8.8,2.2Hz,1H),7.45(d,J=7.5Hz, 2H), 7.40 (t, J = 7.5Hz, 2H), 7.35 (t, J = 7.2Hz, 1H), 7.19 (d, J = 8.8Hz, 1H), 5.32 (s, 2H), 2.59 (s, 3H). ESI-MS:calcd for[M+H] + 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)ethane-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 tetrahydroxydiboron (2976 mg, 33.20 mmol) was added in batches at 0°C, and the reaction was allowed to proceed at room temperature. After the reaction was completed, the mixture was diluted with saturated saline, extracted with ethyl acetate three times, and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (dichloromethane: methanol = 50: 1) to obtain the target compound (2390 mg, 89.6%) as a yellow solid. 1 HNMR(600MHz,Chloroform-d)δ7.43(d,J=7.2Hz,2H),7.40(t,J=7.6Hz,2H),7. 38–7.33(m,3H),6.87(d,J=8.9Hz,1H),5.16(s,2H),3.95(s,2H),2.52(s,3H). ESI-MS:calcdfor[M+H] + m / z 242.1found:242.1.

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

[0208] 1-(3-Amino-4-(benzyloxy)phenyl)ethane-1-one (1500mg, 6.22mmol) and pyridine (1229mg, 15.56mmol) were dissolved in 10mL of anhydrous dichloromethane. Methanesulfonyl chloride (855mg, 7.47mmol) was added dropwise at 0℃ and reacted at room temperature. After the reaction was completed, 1N hydrochloric acid was added to acidify, and ethyl acetate was used for extraction 3 times. The organic phases were combined, washed with saturated brine 2 times, dried over anhydrous sodium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain the target compound (1880mg, 94.7%) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ8.13(d,J=2.1Hz,1H),7.79(dd,J=8.5,2.1Hz,1H),7.48– 7.32(m,5H),7.06(d,J=8.6Hz,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 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, the mixture was filtered and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (dichloromethane: methanol = 20: 1) to obtain the target compound (570 mg, 66.2%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.99(s,1H),7.79(d,J=2.2Hz,1H),7.72(dd,J=8.4,2.2Hz,1H),6.97(d,J=8.4Hz,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 ethyl (E)-3-((((1-(4-hydroxy-3-(methylsulfonamido)phenyl)ethylidene)amino)oxy)methyl)benzoate

[0212] The synthesis method of ethyl (E)-3-((((1-(4-hydroxy-3-(methylsulfonamido)phenyl)ethylidene)amino)oxy)methyl)benzoate was similar to that of Example 1. White solid (43 mg, 20.3%) 1 HNMR(600MHz,Chloroform-d)δ8.12(s,1H),7.98(d,J=7.7Hz,1H),7.62(d,J=2.2Hz,1H),7.60(d,J=7.6Hz,1H),7.43(t,J=7.7Hz,1H),7. 39–7.31(m,2H),6.89(d,J=8.4Hz,1H),6.72(s,1H),5.23(s,2H),4.39(q,J=7.1Hz,2H),2.99(s,3H),2.21(s,3H),1.40(t,J=7.1Hz,3H). ESI-HRMS[M+1] + calcdfor C 19 H 22 N2O6S:407.1271,found:407.1274.

[0213] Embodiment 21

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

[0215]

[0216] The synthesis method of ethyl (E)-3-((((1-(3-carbamoyl-4-hydroxyphenyl)ethylidene)amino)oxy)methyl)benzoate was similar to that of Example 1. White solid (28 mg, 14.7%) 1 H NMR (600MHz, DMSO-d6) δ13.25(s,1H),8.55(s,1H),8.07(d,J=2.4Hz,1H),8.00(s,1H),7.97(s,1H),7.90(d,J=7.6Hz,1H),7.75(dd,J=8.8,2.2Hz ,1H),7.68(d,J=7.6Hz,1H),7.53(t,J=7.7Hz,1H),6.90(d,J=8.8Hz,1H) ,5.26(s,2H),4.32(q,J=7.1Hz,2H),2.24(s,3H),1.32(t,J=7.1Hz,3H). ESI-HRMS[M+1] + Calculate for C 19 H 20 N2O5:357.1445,found:357.1447.

[0217] Embodiment 22

[0218] Preparation of (E)-1-(3,4-dihydroxyphenyl)ethane-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] Monomethyl isophthalate (5400 mg, 30.00 mmol) was dissolved in 40 mL of anhydrous dichloromethane, and then thionyl chloride (10703 mg, 90.00 mol) and 1 drop of DMF were added, and the reaction was carried out at 60 ° C. After the reaction was completed, the solvent was dried to obtain a solid. The solid was dissolved in 30 mL of anhydrous dioxane, and (Z)-N'-hydroxyisobutyramide (2886 mg, 39.00 mmol) and N,N-diisopropylethylamine (7740 mg, 60.00 mmol) were added successively. After stirring at room temperature for 30 min, the reaction was carried out 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 3 times, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the target compound (3570 mg, 54.6%) as a white solid. 1 H NMR (600MHz, Chloroform-d) δ 8.79 (s, 1H), 8.30 (d, J = 7.7Hz, 1H), 8.26 (d, J = 7.9Hz, 1H), 7.63 (t, J = 7.8Hz, 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 26 mL of 1.5 M DIBAL-H toluene solution was added dropwise at 0 °C. After the addition was complete, the mixture was reacted at room temperature for 36 h. After the reaction was completed, 20 mL of 0 °C saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, and concentrated. The residue obtained after concentration was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target compound as a white solid (2420 mg, 94.4%). 1 HNMR(400MHz,Chloroform-d)δ8.12(s,1H),8.03(d,J=7.5Hz,1H),7.60(d,J=7.4Hz, 1H), 7.52 (t, J = 7.7Hz, 1H), 4.79 (d, J = 5.8Hz, 2H), 2.47 (s, 3H), 2.02 (t, J = 5.9Hz, 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-1,2,4-oxadiazole

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

[0226] Step 4: Synthesis of 2-((3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)oxy)isoindole-1,3-dione

[0227] The synthesis method of 2-((3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)oxy)isoindole-1,3-dione refers to the synthesis method of 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. White solid (1820 mg, 91.3%) 1 HNMR (600MHz, Chloroform-d) δ8.26 (s, 1H), 8.13 (d, J = 7.7Hz, 1H), 7.86–7.70 (m, 5H), 7.58 (t, J = 7.8Hz, 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-1,2,4-oxadiazol-5-yl)benzyl)hydroxylamine hydrochloride

[0229] The synthesis method of O-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)hydroxylamine hydrochloride refers to the synthesis method of 5-((aminooxy)methyl)furan-2-carboxylic acid ethyl ester hydrochloride. White solid (596 mg, 69.5%). 1HNMR (600MHz, DMSO-d6) δ11.21(s,3H),8.13(s,1H),8.10(d,J=7.8Hz,1H),7.74(d,J=7.7Hz,1H),7.68(t,J=7.7Hz,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)ethane-1-one O-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)oxime The synthesis method of (E)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)oxime is similar to that of Example 1. White solid (32 mg, 13.4%) 1 H NMR (600MHz, DMSO-d6) δ9.21(s,1H),9.05(s,1H),8.10(s,1H),8.02(d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.63(t,J=7. 7Hz, 1H), 7.11 (d, J = 2.1Hz, 1H), 6.94 (dd, J = 8.3, 2.2Hz, 1H), 6.73 (d, J = 8.2Hz, 1H), 5.27 (s, 2H), 2.42 (s, 3H), 2.18 (s, 3H). ESI-HRMS[M+1] + Calculate for C 18 H 17 N3O4:340.1292,found:340.1294.

[0231] Embodiment 23

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

[0233]

[0234] Step 1: Synthesis of methyl (Z)-3-(N'-hydroxycarbamoylamino)benzoate

[0235] Methyl 3-cyanobenzoate (8000 mg, 49.67 mmol), hydroxylamine hydrochloride (5253 mg, 74.51 mmol) and triethylamine (8042 mg, 79.47 mmol) were added to 100 mL of ethanol successively and reacted at room temperature for 12 h. After the reaction, the solvent was dried to obtain a solid, and 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 (400MHz, DMSO-d6) δ9.79 (s, 1H), 8.30 (s, 1H), 8.06–7.78 (m, 2H), 7.54 (t, J = 7.8Hz, 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'-hydroxycarbamoylamino)benzoic acid methyl ester (2500mg, 12.88mmol) and acetic anhydride (2631mg, 25.77mmol) were dissolved in 20mL acetic acid and reacted at 118℃. After the reaction, the mixture was spin-dried, water and ethyl acetate were added, and the mixture was 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 chromatographed on a silica gel column (petroleum ether: ethyl acetate = 8:1) to obtain the target compound as a white solid (4706mg, 76.1%). 1 H NMR (400MHz, Chloroform-d) δ 8.73 (s, 1H), 8.25 (d, J = 7.6Hz, 1H), 8.18 (d, J = 7.8Hz, 1H), 7.57 (t, J = 7.8Hz, 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] Dissolve methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (4000 mg, 18.34 mmol) in 25 mL of anhydrous tetrahydrofuran, add 3.67 mL of 2.5 M LiAlH4 tetrahydrofuran solution at 0°C, and react at room temperature for 4 hours. After the reaction, add 1N hydrochloric acid, extract 3 times with ethyl acetate, combine the organic phases, dry and concentrate. The residue obtained after concentration is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain the target compound as a white solid (3128 mg, 89.8%) 1 H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.98(d,J=7.3Hz,1H),7.52(d,J=7.7Hz,1 H), 7.47 (t, J = 7.6Hz, 1H), 4.77 (d, J = 5.7Hz, 2H), 2.66 (s, 3H), 1.92 (t, J = 6.0Hz, 1H). ESI-MS:calcd for[M+H]+m / z 191.1found:191.1.

[0240] Step 4: Synthesis of 3-(3-(bromomethyl)phenyl)-5-methyl-1,2,4-oxadiazole

[0241] (3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)methanol (3000mg, 15.78mmol) and PPh3 (5689mg, 17.36mol) were dissolved in 20mL of anhydrous tetrahydrofuran. CBr4 (4548mg, 17.36mmol) was added in batches at 0℃ and reacted at room temperature for 12h. After the reaction was completed, the filtrate was filtered and concentrated. The residue obtained after concentration was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain the target compound as a white solid (2693mg, 67.7%) 1 H NMR (400MHz, Chloroform-d) δ 8.10 (s, 1H), 8.00 (d, J = 7.7Hz, 1H), 7.54 (d, J = 7.5Hz, 1H), 7.47 (t, J = 7.7Hz, 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-1,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-1,3-dione

[0243] The synthesis method of 2-((3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-1,3-dione refers to the synthesis method of 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. White solid (2903 mg, 91.0%) 1 HNMR (400MHz, Chloroform-d) δ8.20(s,1H),8.08(d,J=7.8Hz,1H),7.86–7.68(m,5H),7.52(t,J=7.7Hz,1H),5.27(s,2H),2.66(s,3H). ESI-MS:calcd for[M+H]+m / z 336.1found:336.1.

[0244] Step 6: Synthesis of O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride

[0245] The synthesis method of O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride refers to the synthesis method of 5-((aminooxy)methyl)furan-2-carboxylic acid ethyl ester hydrochloride. White solid (1593 mg, 88.5%). 1 HNMR (400MHz, Methanol-d4) δ8.20–8.05(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)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0247] The synthesis method of (E)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime is similar to that of Example 1. Pale yellow solid (73 mg, 54.9%) 1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.04(s,1H),8.01(s,1H),7.93(d,J=7.5Hz,1H),7.63–7.53(m,2H),7.1 0(d,J=2.2Hz,1H),6.93(dd,J=8.2,2.2Hz,1H),6.72(d,J=8.2Hz,1H),5.24(s,2H),2.67(s,3H),2.16(s,3H). ESI-HRMS[M+1] + Calculate for C 18 H 17 N3O4:340.1292,found:340.1291.

[0248] Embodiment 24

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

[0250]

[0251] Step 1: The synthesis method of (Z)-3-(N'-hydroxycarbamoylamino)benzoic acid methyl ester is listed in Example 23

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

[0253] The synthesis method of methyl 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoate is based on the synthesis method of methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate. White solid (4729 mg, 74.8%) 1 H NMR(400MHz,Chloroform-d)δ8.74(s,1H),8.27(d,J=7.7Hz,1H),8.17(d,J=7.8Hz,1 H), 7.57 (t, J = 7.7Hz, 1H), 3.95 (s, 3H), 3.00 (q, J = 7.6Hz, 2H), 1.47 (t, J = 7.6Hz, 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-1,2,4-oxadiazol-3-yl)phenyl)methanol is based on the synthesis method of (3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)methanol. White solid (3312 mg, 81.4%) 1 H NMR(400MHz,Chloroform-d)δ8.07(s,1H),8.00(d,J=7.4Hz,1H),7.52(d,J=7.6Hz,1H),7. 48(t,J=7.5Hz,1H), 4.78(s,2H), 2.98(q,J=7.6Hz,2H), 1.81(s,1H), 1.46(t,J=7.6Hz,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-1,2,4-oxadiazole

[0257] The synthesis method of 3-(3-(bromomethyl)phenyl)-5-ethyl-1,2,4-oxadiazole is based on the synthesis method of 3-(3-(bromomethyl)phenyl)-5-methyl-1,2,4-oxadiazole. White solid (3169 mg, 76.0%) 1 H NMR(400MHz,Chloroform-d)δ8.11(s,1H),8.02(d,J=7.6Hz,1H),7.53(d,J=7.8Hz,1 H), 7.46 (t, J = 7.7Hz, 1H), 4.54 (s, 2H), 2.99 (q, J = 7.6Hz, 2H), 1.46 (t, J = 7.6Hz, 3H). ESI-MS:calcd for[M+H] + m / z 267.0 found: 267.0.

[0258] Step 5: Synthesis of 2-((3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-1,3-dione

[0259] The synthesis method of 2-((3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-1,3-dione refers to the synthesis method of 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. White solid (3580 mg, 90.9%) 1HNMR(400MHz,Chloroform-d)δ8.21(s,1H),8.09(d,J=7.8Hz,1H),7.87–7.70(m,5H ), 7.52 (t, J = 7.7Hz, 1H), 5.27 (s, 2H), 2.98 (q, J = 7.6Hz, 2H), 1.45 (t, J = 7.6Hz, 3H). ESI-MS:calcdfor[M+H] + m / z 350.1 found:350.1.

[0260] Step 6: Synthesis of O-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride

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

[0262] Step 7: Synthesis of (E)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0263] The synthesis method of (E)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Colorless liquid (82 mg, 89.1%) 1H NMR (400MHz, Chloroform-d) δ8.15(s,1H),8.01(d,J=7.6Hz,1H),7.54(d,J=7.8Hz,1H),7.47(t,J=7.6Hz,1H),7.26(d,J=2.1Hz,1H),7.03(d d,J=8.3,2.1Hz,1H),6.82(d,J=8.3Hz,1H),5.85(s,1H),5.61(s,1H),5.24(s,2H),2.99(q,J=7.6Hz,2H),2.20(s,3H),1.46(t,J=7.6Hz,3H). ESI-HRMS[M+1] + Calculate for C 19 H 19 N3O4:354.1448,found:354.1448.

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

[0265]

[0266] Step 1: The synthesis method of (Z)-3-(N'-hydroxycarbamoylamino)benzoic acid methyl ester is listed in Example 23

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

[0268] Methyl (Z)-3-(N'-hydroxycarbamoylamino)benzoate (3500mg, 18.04mmol) and butyryl chloride (2305mg, 21.64mmol) were added to 30mL of anhydrous dioxane, and then N,N-diisopropylethylamine (4652mg, 36.07mmol) was added dropwise. After reacting at room temperature for 30min, the reaction was continued at 110℃ for 8h. After the reaction was completed, saturated brine was added, and the mixture was 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 silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain the target compound as a light yellow liquid (4032mg, 88.4%). 1H NMR(400MHz,Chloroform-d)δ8.74(s,1H),8.27(d,J=7.7Hz,1H),8.17(d,J=7.8Hz,1H),7.57(t ,J=7.8Hz,1H),3.95(s,3H),2.94(t,J=7.5Hz,2H),1.93(h,J=7.4Hz,2H),1.07(t,J=7.4Hz,3H). ESI-MS:calcd for[M+H] + m / z 247.1found:247.1.

[0269] Step 3: Synthesis of (3-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl)methanol

[0270] The synthesis method of (3-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl)methanol refers to the synthesis method of (3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)methanol. Colorless liquid (2522 mg, 79.1%) 1 H NMR(400MHz,Chloroform-d)δ8.07(s,1H),7.99(d,J=7.2Hz,1H),7.51(d,J=7.8Hz,1H),7.47( t,J=7.5Hz,1H),4.77(s,2H),2.92(t,J=7.5Hz,2H),2.08–1.86(m,3H),1.06(t,J=7.4Hz,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-1,2,4-oxadiazole

[0272] The synthesis method of 3-(3-(bromomethyl)phenyl)-5-propyl-1,2,4-oxadiazole is based on the synthesis method of 3-(3-(bromomethyl)phenyl)-5-methyl-1,2,4-oxadiazole. Colorless liquid (2569 mg, 85.1%) 1 H NMR(400MHz,Chloroform-d)δ8.11(s,1H),8.01(d,J=7.6Hz,1H),7.53(d,J=7.8Hz,1H),7.46(t ,J=7.7Hz,1H),4.54(s,2H),2.94(t,J=7.5Hz,2H),1.92(h,J=7.4Hz,2H),1.07(t,J=7.4Hz,3H). ESI-MS:calcd for[M+H]+ m / z 281.1found:281.1.

[0273] Step 5: Synthesis of 2-((3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-1,3-dione

[0274] The synthesis method of 2-((3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)isoindole-1,3-dione refers to the synthesis method of 5-(((1,3-dioxoisoindol-2-yl)oxy)methyl)furan-2-carboxylic acid ethyl ester. White solid (2757 mg, 83.6%) 1 HNMR(400MHz,Chloroform-d)δ8.21(s,1H),8.09(d,J=7.8Hz,1H),7.88–7.67(m,5H),7.52(t, J=7.7Hz,1H),5.27(s,2H),2.92(t,J=7.5Hz,2H),1.91(h,J=7.4Hz,2H),1.06(t,J=7.4Hz,3H). ESI-MS:calcd for[M+H] + m / z 364.1 found:364.1.

[0275] Step 6: Synthesis of O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)hydroxylamine hydrochloride

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

[0277] Step 7: Synthesis of (E)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0278] The synthesis method of (E)-1-(3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Colorless liquid (74 mg, 77.1%) 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),8.01(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.25(d,J=2.0Hz,1 H),7.03(dd,J=8.3,2.0Hz,1H),6.82(d,J=8.3Hz,1H),5.86(s,1H),5.71(s,1H),5.24(s,2H),2.94(t,J=7.5Hz,2H),2.20(s,3H),

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

[0280] Embodiment 26

[0281] Preparation of (E)-1-(3-fluoro-4,5-dihydroxyphenyl)ethane-1-one O-(3-(5-methyl-1,2,4-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, and then sulfamic 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 stirred for 30 min, then sodium bisulfite aqueous solution was added to quench, and ethyl acetate was added to extract 3 times, the organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the target product as a white solid (856 mg, 78.4%). 1H NMR (400MHz, DMSO-d6) δ12.86(s,1H),10.12(s,1H),7.43–7.19(m,2H),3.86(s,3H). ESI-MS:calcd for[MH] - 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), dimethylhydroxylamine hydrochloride (1642 mg, 16.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2318 mg, 12.09 mmol) and 1-hydroxybenzotriazole (326 mg, 2.42 mmol) were dissolved in 25 mL of anhydrous dichloromethane, and triethylamine (3257 mg, 32.25 mmol) was added and refluxed for 8 h. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with dichloromethane 3 times, the organic phases were combined, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained after concentration was subjected to silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain the target compound as a light yellow solid (758 mg, 41.0%) 1 H NMR (400MHz, Chloroform-d) δ7.26 (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 1-(3-fluoro-4-hydroxy-5-methoxyphenyl)ethan-1-one

[0288] 3-Fluoro-4-hydroxy-N,5-dimethoxy-N-methylbenzamide (500 mg, 2.18 mmol) was dissolved in 10 mL of anhydrous 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 hours. After the reaction, ice water was added, and 1N dilute hydrochloric acid was used to adjust the pH to 2. The mixture was extracted with ethyl acetate 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 (dichloromethane: methanol = 20: 1) to obtain the target compound as a white solid (317 mg, 79.0%). 1H NMR (400MHz, Chloroform-d) δ7.41–7.34 (m, 2H), 5.87 (d, J = 1.6Hz, 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 1-(3-fluoro-4,5-dihydroxyphenyl)ethan-1-one

[0290] 1-(3-Fluoro-4-hydroxy-5-methoxyphenyl)ethane-1-one (300 mg, 1.63 mmol) was dissolved in 5 mL of anhydrous dichloromethane, and nitrogen was protected. 9.78 mL of 1M BBr3 dichloromethane solution was added dropwise at -78°C, stirred for 15 min, and then heated to 0°C for reaction. After the reaction was completed, ice water was added to dilute, and then saturated brine was added. The mixture was extracted with ethyl acetate three times, and the organic phases were 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 (400MHz, DMSO-d6) δ10.00(s,1H),9.94(s,1H),7.27(dd,J=11.2,2.1Hz,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)ethane-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)ethane-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Gray solid (83 mg, 79.8%) 1H NMR(400MHz,Chloroform-d)δ8.12(s,1H),8.00(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.48(t,J=7.6Hz,1H),7.0 5(t,J=1.5Hz,1H),6.98(dd,J=11.2,2.0Hz,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] + Calculate for C 18 H 16 FN3O4:358.1198,found:358.1198.

[0293] Embodiment 27

[0294] Preparation of (E)-1-(3-chloro-4,5-dihydroxyphenyl)ethane-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 the synthesis method of 3-fluoro-4-hydroxy-N,5-dimethoxy-N-methylbenzamide. White solid (2282 mg, 62.7%) 1 H NMR (400MHz, Chloroform-d) δ7.46 (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)ethane-1-one refers to the synthesis method of 1-(3-fluoro-4-hydroxy-5-methoxyphenyl)ethane-1-one. White solid (711 mg, 62.3%) 1H NMR (400MHz, Chloroform-d) δ7.60 (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)ethane-1-one refers to the synthesis method of 1-(3-fluoro-4,5-dihydroxyphenyl)ethane-1-one. White solid (257 mg, 79.1%) 1 H NMR (400MHz, DMSO-d6) δ10.14(s,2H),7.47(d,J=2.0Hz,1H),7.30(d,J=2.1Hz,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)ethane-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)ethane-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime is similar to that of Example 1. Pale yellow solid (67 mg, 83.8%) 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),8.00(d,J=7.5Hz,1H),7.54(d,J=7.7Hz,1H), 7.48(t,J=7.6Hz,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] + Calculate for C 18 H 16 ClN3O4:374.0902,found:374.0905.

[0304] Embodiment 28

[0305] Preparation of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethane-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] Dissolve AlCl3 (999 mg, 7.49 mmol) in 10 mL of anhydrous dichloromethane at -20 °C, then drop acetyl chloride (678 mg, 8.65 mmol) and 1-fluoro-2,3-dimethoxybenzene (900 mg, 5.77 mmol) in dichloromethane. After the addition is complete, warm to room temperature and react for 5 hours. After the reaction is completed, pour into ice water, extract with dichloromethane 3 times, combine the organic phases, dry over anhydrous magnesium sulfate, and concentrate. The residue obtained after concentration is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 8:1) to obtain the target compound as a white solid (1036 mg, 90.7%) 1 H NMR (400MHz, Chloroform-d) δ7.64 (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)ethane-1-one refers to the synthesis method of 1-(3-fluoro-4,5-dihydroxyphenyl)ethane-1-one. White solid (66 mg, 15.4%) 1 H NMR (400MHz, DMSO-d6) δ7.21 (t, J = 8.4Hz, 1H), 6.70 (dd, J = 8.7, 1.4Hz, 1H), 2.50 (d, J = 4.6Hz, 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)ethane-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime

[0312] The synthesis method of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethane-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 (51 mg, 60.8%) 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),8.01(d,J=7.5Hz,1H),7.55(d,J=7.7Hz,1H),7.48(t,J=7.7Hz,1 H),6.83(t,J=8.3Hz,1H),6.64–6.55(m,1H),5.81(s,2H),5.27(s,2H),2.67(s,3H),2.24(d,J=2.2Hz,3H). ESI-HRMS[M+1] + Calculate for C 18 H 16 FN3O4:358.1198,found:358.1201.

[0313] Embodiment 29

[0314] Preparation of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethane-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), dimethylhydroxylamine 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, it was diluted with water and extracted with dichloromethane three times. The organic phases were combined, washed with 1N 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 light yellow solid (1173 mg, 48.9%) 1H NMR (400MHz, Chloroform-d) δ7.06 (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)ethane-1-one refers to the synthesis method of 1-(3-fluoro-4-hydroxy-5-methoxyphenyl)ethane-1-one. White solid (730 mg, 87.9%) 1 H NMR (400MHz, Chloroform-d) δ7.43 (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)ethane-1-one refers to the synthesis method of 1-(3-fluoro-4,5-dihydroxyphenyl)ethane-1-one. Yellow solid (129 mg, 29.7%) 1 H NMR (400MHz, Methanol-d4) δ7.17 (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)ethane-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)ethane-1-one O-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxime is similar to that of Example 1. Pale yellow solid (26 mg, 14.3%)1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),8.01(d,J=7.5Hz,1H),7.55(d,J=7.5Hz,1H),7.48( t,J=7.6Hz,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+1] + Calculate for C 18 H 16 ClN3O4:374.0902,found:374.0906.

[0324] Embodiment 30

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

[0326]

[0327] The synthesis method of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Pale yellow solid (39 mg, 60.0%) 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),8.02(d,J=7.5Hz,1H),7.55(d,J=7.5Hz,1H),7.48(t,J=7.7Hz,1H),6.83(t,J=8.3Hz ,1H),6.61(dd,J=8.6,1.6Hz,1H),5.88(s,2H),5.27(s,2H),2.99(q,J=7.6Hz,2H),2.24(d,J=2.3Hz,3H),1.46(t,J=7.6Hz,3H). ESI-HRMS[M+1] + Calculate for C 19 H 18 FN3O4:372.1354,found:372.1354.

[0328] Embodiment 31

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

[0330]

[0331] The synthesis method of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)oxime refers to the synthesis method of Example 1. Gray solid (46 mg, 50.5%) 1 H NMR(400MHz,Chloroform-d)δ8.13(s,1H),8.02(d,J=7.5Hz,1H),7.54(d,J=7.7Hz,1H),7.48(t,J=7.6Hz,1H), 6.78(s,2H),5.81(s,1H),5.73(s,1H),5.28(s,2H),2.99(q,J=7.6Hz,2H),2.24(s,3H),1.46(t,J=7.7Hz,3H). ESI-HRMS[M+1] + Calculate for C 19 H 18 ClN3O4:388.1059,found:388.1060.

[0332] Embodiment 32

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

[0334]

[0335] The synthesis method of (E)-1-(2-fluoro-3,4-dihydroxyphenyl)ethane-1-one O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)oxime is similar to that of Example 1. Pale yellow solid (45 mg, 80.4%) 1 H NMR (400MHz, Chloroform-d) δ8.14(s,1H),8.02(d,J=7.5Hz,1H),7.55(d,J=7.7Hz,1H),7.48(t,J=7.6Hz,1H),6.86(t,J=8.3Hz,1H),6.64( dd,J=8.6,1.6Hz,1H),5.74(s,2H),5.27(s,2H),2.94(t,J=7.5Hz,2H),2.24(d,J=2.3Hz,3H),1.92(h,J=7.4Hz,2H),1.06(t,J=7.4Hz,3H). ESI-HRMS[M+1] + calcdfor C20 H 20 FN3O4:386.1511,found:386.1514.

[0336] Embodiment 33

[0337] Preparation of (E)-1-(2-chloro-3,4-dihydroxyphenyl)ethane-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)ethane-1-one O-(3-(5-propyl-1,2,4-oxadiazol-3-yl)benzyl)oxime is similar to that of Example 1. Pale yellow solid (68 mg, 79.1%) 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),8.02(d,J=7.6Hz,1H),7.55(d,J=7.7Hz,1H),7.48(t,J=7.6Hz,1H),6.78(s,2H ), 5.81 (s, 1H), 5.68 (s, 1H), 5.28 (s, 2H), 2.94 (t, J = 7.5Hz, 2H), 2.24 (s, 3H), 1.92 (h, J = 7.4Hz, 2H), 1.07 (t, J = 7.4Hz, 3H). ESI-HRMS[M+1] + Calculate for C 20 H 20 ClN3O4:402.1215,found:402.1219.

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

[0341] RAW264.7 (mouse macrophages) in the logarithmic growth phase were cultured at 4×10 5Each well was seeded in a 96-well plate (100 μL / well), and gradient dilution compounds (50 μL / well) and DMEM medium (30 μL / well) were added. The cells were cultured at 37°C and 5% CO2 for 2 hours, and then TLR2 / 1 ligand Pam3CSK4 (10 ng / ml, 20 μL / well) was added. In addition, a blank control group (100 μL DMEM medium containing 10% fetal bovine serum and 100 μL RAW264.7 cells) and a stimulation control group (80 μL DMEM medium containing 10% fetal bovine serum, 100 μL RAW264.7 cells and 20 μL Pam3CSK4) were set up. The cells were cultured at 37°C and 5% CO2 for 24 hours, and the supernatant was collected. Tumor necrosis factor-α (TNF-α) in the cell culture supernatant was detected by ELISA, and the OD value was detected by microplate reader. The IC was obtained by fitting the compound concentration and cytokine inhibition rate using Graphpadprism 8.0.1 software. 50 .

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

[0343]

[0344]

[0345]

[0346]

[0347] The results showed that the IC values ​​of some compounds in the examples were 50 Better than the positive compound CUCPT-22 (34.96±1.98μM).

[0348] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt, cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate and N-oxide or amino acid conjugate thereof; In formula I, 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 substituted or unsubstituted phenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; R6 is any one of an ester group, 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 having 1 to 15 carbon atoms, and the substituted group substituent is: 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 heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 1-6 Any one of the alkyl groups.

2. The compound according to claim 1, when ring A is substituted, it may be substituted at any position by one or more substituents; The substituent of ring A is 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 heterocycloalkylalkyl, phenylalkyl, 5-6 membered heteroarylalkyl, amino, 3-8 membered heterocycloalkylalkoxy, C 3-8 Cycloalkylalkoxy, phenylalkoxy, 5-6 membered heteroarylalkoxy, aminoC 1-6 Any one of the alkyl groups.

3. Use of the compound according to claim 1 or 2 in the preparation of a medicament for treating and / or preventing inflammatory diseases, autoimmune diseases or neurodegenerative diseases mediated by TLR2.

4. A pharmaceutical composition, characterized in that Comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, an ester thereof or a cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate, N-oxide or amino acid conjugate thereof.

5. A pharmaceutical preparation, characterized in that A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, an ester thereof or a cis-trans isomer, enantiomer, diastereomer, tautomer, racemate, solvate, N-oxide or amino acid conjugate thereof, or a pharmaceutical composition of claim 4, and a pharmaceutically acceptable carrier.

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