A five-membered heterocyclic amide compound, a preparation method and application thereof, and a bactericide

Abstract

The application provides a five-membered heterocyclic amide compound and a preparation method and application thereof and a bactericide, relates to the technical field of heterocyclic compound synthesis. The five-membered heterocyclic amide compound provided by the application has the structures shown in formula I and formula II. The five-membered heterocyclic amide compound provided by the application comprises a heterocyclic carboxylic acid acyl group, an amino group and a chiral alcohol fragment, has certain inhibiting effect on various plant pathogenic fungi, has excellent antibacterial activity on wheat take-all pathogen, and can be used as an active component of a bactericide or directly used as a bactericide.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compound synthesis technology, specifically relating to a five-membered heterocyclic amide compound, its preparation method and application, and a bactericide. Background Technology

[0002] Florylpicoxamid is a pyridine amide fungicide designed and synthesized based on the natural product UK-2A. It exerts its antifungal activity by binding to the ubiquitin Qi site of mitochondrial complex III (PestManagement Science, 2022, 78, 2657-2666). However, its starting material, 3-hydroxy-4-methoxypyridinecarboxylic acid, is expensive and its synthesis is cumbersome (Green Chemistry, 2020, 22, 6047-6054). The complexity of the synthesis process makes it expensive and limits its application. Therefore, finding a cheap and readily available carboxylic acid to replace 3-hydroxy-4-methoxypyridinecarboxylic acid to design and synthesize new highly active antifungal leads is of great significance for the prevention and control of agricultural diseases. Summary of the Invention

[0003] The purpose of this invention is to provide a five-membered heterocyclic amide compound, its preparation method and application, and a bactericide that can replace 3-hydroxy-4-methoxypyridine carboxylic acid and has excellent antibacterial activity, and can be used as a bactericide.

[0004] To achieve the objectives of this invention, the following technical solutions are provided:

[0005] A five-membered heterocyclic amide compound having the structures shown in Formula I and Formula II:

[0006]

[0007] Among them, the It is a five-membered heterocyclic ring;

[0008] The R 2 Including hydrogen, alkyl, benzyl or phenyl groups having 1 to 5 carbon atoms;

[0009] The R 1 Including hydrogen, hydrocarbon group, hydroxyl group, cyano group, carbonyl group, amino group, nitro group, hydroxyl group, mercapto group or halogen;

[0010] The R 3 Including aliphatic, furan, thiophene or pyridine, as well as phenyl groups substituted with aliphatic, cyano, carbonyl, amino, nitro, trifluoromethyl, hydroxyl, mercapto or halogen.

[0011] Preferably, the five-membered heterocycle includes aliphatic and / or aryl-substituted furan, thiophene, pyrazole, isoxazoline, isoxazole, oxazole, thiazole, triazole, or oxadiazole.

[0012] Preferably, the and R 3 The aliphatic groups in the aliphatic group are independent aliphatic groups with 1 to 6 carbon atoms.

[0013] Preferably, it has any of the following chemical structures:

[0014]

[0015]

[0016]

[0017] This invention also provides a method for preparing the five-membered heterocyclic amide compounds described in the above technical solution, comprising the following steps:

[0018] Five-membered heterocyclic carboxylic acid esters were hydrolyzed and acidified sequentially to obtain five-membered heterocyclic carboxylic acids;

[0019] The five-membered heterocyclic carboxylic acid, amino acid ester, organic base catalyst and condensing agent are mixed and subjected to condensation reaction to obtain the five-membered heterocyclic amide compound;

[0020] The amino acid ester structure has the structure shown in Formula III:

[0021] Where R 1 R 2 As defined in Equation II and Equation I;

[0022] The five-membered heterocyclic carboxylic ester structure has the structure shown in Formula IV or Formula V:

[0023] Where R is Me or Et. As defined in Equation I;

[0024] Where R 3 As defined in Equation II.

[0025] Preferably, the organic base catalyst comprises 4-dimethylaminopyridine, N-hydroxybenzotriazole, or N-hydroxysuccinimide; the condensing agent comprises 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0026] Preferably, the molar ratio of the five-membered heterocyclic carboxylic acid ester to the amino acid ester is 1.2-1.5:1-1.1; and the molar ratio of the amino acid ester, the organic base catalyst, and the condensing agent is 1-1.1:0.2-0.4:1.3-1.5.

[0027] Preferably, the condensation reaction is carried out at a temperature of 0–25°C for 8–12 hours.

[0028] This invention also provides the application of the five-membered heterocyclic amide compounds described in the above technical solutions or the five-membered heterocyclic amide compounds prepared by the preparation methods described in the above technical solutions in the prevention and control of agricultural diseases.

[0029] The present invention also provides a bactericide, comprising an active component and a bactericidal component; the molar concentration ratio of the active component and the bactericidal component is 1:1 to 10; the active component is a five-membered heterocyclic amide compound as described in the above technical solution or a five-membered heterocyclic amide compound prepared by the preparation method described in the above technical solution.

[0030] This invention provides a five-membered heterocyclic amide compound having the structures shown in Formula I and Formula II: wherein, the Including aliphatic, aryl-substituted furans, thiophenes, pyrazoles, isoxazolines, isoxazoles, oxazoles, thiazoles, triazoles, or oxadiazoles; said R 2 Including hydrogen, methyl, isopropyl, isobutyl, tert-butyl, benzyl, or phenyl; said R 1 Including hydrogen, hydrocarbon group, hydroxyl group, cyano group, carbonyl group, amino group, nitro group, hydroxyl group, mercapto group or halogen; the R 3 The compounds include aliphatic groups, furans, thiophenes, or pyridines, as well as aliphatic groups, cyano groups, carbonyl groups, amino groups, nitro groups, trifluoromethyl groups, hydroxyl groups, mercapto groups, or halogen-substituted phenyl groups. The five-membered heterocyclic amide compounds provided by this invention include heterocyclic carboxylic acid acyl groups, amino groups, and bisexual alcohol fragments, exhibiting inhibitory effects against various plant pathogenic fungi (such as *Sclerotinia sclerotiorum*, *Fusarium graminearum*, *Phytophthora capsici*, *Plastrum rice*, *Botrytis cinerea*, *Anthracnose fungi*, *Sheath blight*, *Sheath blight*, *Late blight*, *Early blight*, *Oxytoxinus rhamnoides*, *Dry rot*, and *Anthracnose fungi*). They exhibit excellent antibacterial activity against *Tricholoma materia humicinum*, and can be used as active components in fungicides or directly as fungicides.

[0031] Detailed Implementation

[0032] This invention provides a five-membered heterocyclic amide compound having the structures shown in Formula I and Formula II:

[0033]

[0034] Among them, the It is a five-membered heterocyclic ring;

[0035] The R 2 Including hydrogen, alkyl, benzyl or phenyl groups having 1 to 5 carbon atoms;

[0036] The R 1 Including hydrogen, hydrocarbon group, hydroxyl group, cyano group, carbonyl group, amino group, nitro group, hydroxyl group, mercapto group or halogen;

[0037] The R 3 Including aliphatic, furan, thiophene or pyridine, as well as phenyl groups substituted with aliphatic, cyano, carbonyl, amino, nitro, trifluoromethyl, hydroxyl, mercapto or halogen.

[0038] In this invention, the five-membered heterocycle preferably includes aliphatic and / or aryl-substituted furans, thiophenes, pyrazoles, isoxazolines, isoxazoles, oxazoles, thiazoles, triazoles, or oxadiazoles. In specific embodiments of this invention, the five-membered heterocycle can be aryl-substituted furans, aryl-substituted thiophenes, aryl-substituted pyrazoles, aryl-substituted isoxazoles, aryl-substituted oxazoles, aryl-substituted thiazoles, aryl-substituted triazoles, aryl-substituted isoxazolines, aryl and aliphatic-substituted pyrazoles, or aryl and aliphatic-substituted thiazoles; the aliphatic group can be methyl or ethyl. In specific embodiments of this invention, when the five-membered heterocycle is an aryl and aliphatic-substituted pyrazole, the aryl and aliphatic groups can be 1-substituted and 2-substituted sites, or 1-substituted and 3-substituted sites; when the five-membered heterocycle is an aryl and aliphatic-substituted thiazole, the aryl and aliphatic groups can be 2-substituted and 4-substituted sites.

[0039] In this invention, the alkyl group having 1 to 5 carbon atoms is preferably methyl, propyl, or butyl, the propyl group is preferably isopropyl, and the butyl group is preferably isobutyl or tert-butyl.

[0040] In this invention, the and R 3 The aliphatic group in the present invention is preferably an aliphatic group with 1 to 6 carbon atoms; in a specific embodiment of the present invention, the aliphatic group with 1 to 6 carbon atoms may be methyl, ethyl or n-propyl.

[0041] In a specific embodiment of the present invention, the halogen group can be -F, -Cl or -Br, more preferably -F.

[0042] In a specific embodiment of the present invention, the R 1 When the halogen is halogen, the number of halogens can be 1, 2, 3, 4 or 5.

[0043] In a specific embodiment of the present invention, the halogen-substituted phenyl group can be a fluorine-substituted phenyl group, a chlorine-substituted phenyl group, or a bromine-substituted phenyl group; the number of fluorine substituents in the fluorine-substituted phenyl group can be 1, 2, 3, 4, or 5.

[0044] In this invention, the five-membered heterocyclic amide compound has any of the following chemical structures:

[0045]

[0046]

[0047] This invention also provides a method for preparing the five-membered heterocyclic amide compounds described in the above technical solution, comprising the following steps:

[0048] Five-membered heterocyclic carboxylic acid esters were hydrolyzed and acidified sequentially to obtain five-membered heterocyclic carboxylic acids;

[0049] The five-membered heterocyclic carboxylic acid, amino acid ester, organic base catalyst and condensing agent are mixed and subjected to condensation reaction to obtain the five-membered heterocyclic amide compound;

[0050] The amino acid ester structure has the structure shown in Formula III:

[0051]

[0052] The five-membered heterocyclic carboxylic ester structure has the structures shown in Formula IV and Formula V:

[0053]

[0054] In this invention, unless otherwise specified, all raw materials used in the preparation are preferably commercially available products known to those skilled in the art or prepared using methods known to those skilled in the art.

[0055] This invention involves hydrolyzing and acidifying a five-membered heterocyclic carboxylic acid ester sequentially to obtain a five-membered heterocyclic carboxylic acid.

[0056] In this invention, the five-membered heterocyclic carboxylic ester preferably has the structures shown in Formula IV and Formula V:

[0057] Where R is Me or Et. As defined in Equation I;

[0058] Where R 3 As defined in Equation II.

[0059] In this invention, the preparation method of the five-membered heterocyclic carboxylic acid ester preferably includes the following steps:

[0060] The amide compound and ethyl 3-bromopyruvate were mixed and subjected to an intermolecular cyclization reaction to obtain the five-membered heterocyclic carboxylic acid ester.

[0061] In this invention, the amide compound preferably includes one of 4-bromobenzamide, thioacetamide, 3-fluorobenzamide, 2,4-difluorobenzamide, 3,4-difluorobenzamide, 2,3,4-trifluorobenzamide, 2,3,4,5-tetrafluorobenzamide, 2,3,4,5,6-pentafluorobenzamide, 4-methylthiobenzamide, 4-methoxythiobenzamide, 4-trifluoromethylthiobenzamide, 2-fluorothiobenzamide, 4-fluorothiobenzamide, 4-chlorothiobenzamide, thioformamide, thiophenethioformamide, 2-pyridinethioformamide, and 3-pyridinethioformamide; the molar ratio of the amide compound to ethyl 3-bromopyruvate is preferably 1-1.2:1.2-1.5, more preferably 1-1.1:1.2-1.3.

[0062] In this invention, the temperature of the intermolecular cyclization reaction is preferably 70-110°C, more preferably 75-85°C; the time is preferably 6-8h, more preferably 6-7h.

[0063] In this invention, the hydrolysis preferably includes: mixing a five-membered heterocyclic carboxylic acid ester, an organic solvent, and an alkaline reagent, and then hydrolyzing the mixture; the organic solvent preferably includes an alcohol and water, and the alcohol is preferably one of methanol, ethanol, and isopropanol; the volume ratio of the alcohol to water is preferably 2-3:1, more preferably 2:1; the alkaline reagent is preferably one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide, more preferably sodium hydroxide; the mass ratio of the five-membered heterocyclic carboxylic acid ester to the alkaline reagent is preferably 1-1.1:3-4, more preferably 1:3; the hydrolysis temperature is preferably room temperature, and the time is preferably 6-10 hours, more preferably 6-8 hours; the hydrolysis is preferably carried out under stirring conditions. In this invention, solvent removal is preferably performed after hydrolysis; the solvent removal method is preferably vacuum distillation.

[0064] In this invention, the acidifying reagent is preferably one or more of hydrochloric acid, nitric acid, and acetic acid, more preferably hydrochloric acid; the concentration of the dilute hydrochloric acid is preferably 40-60%, more preferably 40%. In this invention, acidification is preferably performed until the pH of the system is 3-5, more preferably 4-5. This invention also preferably involves sequentially performing solid-liquid separation and drying of the obtained acidified product; the conditions for solid-liquid separation and drying are not particularly limited in this invention.

[0065] After obtaining the five-membered heterocyclic carboxylic acid, the present invention mixes the five-membered heterocyclic carboxylic acid, amino acid ester, catalyst and coupling agent, and carries out a condensation reaction to obtain the five-membered heterocyclic amide compound.

[0066] In this invention, the amino acid ester has the structure shown in Formula III:

[0067] Where R 1 R 2 As defined in Equation II and Equation I;

[0068] In this invention, the method for preparing the amino acid ester preferably includes the following steps:

[0069] L-lactide and phenyl magnesium bromide were mixed and subjected to carbonyl reduction to obtain intermediate 1;

[0070] Intermediate 1, triethylsilane, and trifluoroacetic acid were mixed and subjected to reducing deoxidation to obtain a chiral alcohol compound;

[0071] The chiral alcohol compound, N-Boc protected amino acid, catalyst and coupling agent are mixed and subjected to condensation reaction to obtain intermediate 2;

[0072] Intermediate 2 and trifluoroacetic acid were mixed and deprotected to obtain an amino acid ester.

[0073] This invention involves mixing L-lactide and phenyl magnesium bromide, followed by carbonyl reduction to obtain intermediate 1. In this invention, the phenyl magnesium bromide preferably comprises 4-fluorophenyl magnesium bromide, phenyl magnesium bromide, 4-chlorophenyl magnesium bromide, and 4-methoxyphenyl magnesium bromide, more preferably 4-fluorophenyl magnesium bromide. In this invention, the molar ratio of L-lactide to phenyl magnesium bromide is preferably 1–1.1:4.2–5, more preferably 1:4.2–4.7; the L-lactide and phenyl magnesium bromide are preferably subjected to carbonyl reduction under organic solvent conditions; the organic solvent is preferably tetrahydrofuran or diethyl ether, more preferably tetrahydrofuran.

[0074] In this invention, the temperature of the carbonyl reduction is preferably 0–30°C, more preferably 25–30°C; the time is preferably 3–6 h, more preferably 3–5 h; the present invention also preferably involves the carbonyl reduction sequentially removing the solvent, extracting, and drying; the solvent removal method is preferably vacuum evaporation; the extraction reagent is preferably ethyl acetate; the drying preferably includes: drying the extracted organic phase sequentially with anhydrous sodium sulfate and vacuum evaporation.

[0075] After obtaining intermediate 1, the present invention mixes intermediate 1, triethylsilane, and trifluoroacetic acid, and performs reductive deoxidation to obtain a chiral alcohol compound. In the present invention, the molar ratio of intermediate 1, triethylsilane, and trifluoroacetic acid is preferably 1-1.1:10-12:10-12, more preferably 1:10:10; the reductive deoxidation of intermediate 1, triethylsilane, and trifluoroacetic acid is preferably performed under organic solvent conditions; the organic solvent is preferably one of dichloromethane, chloroform, and carbon tetrachloride, more preferably dichloromethane.

[0076] In this invention, the reductive deoxidation temperature is preferably 0–30°C, more preferably 25–30°C; the time is preferably 3–6 h, more preferably 3–5 h. This invention also preferably involves sequentially extracting, drying, and purifying the reductive deoxidation product; the reagent used for extraction is preferably dichloromethane; the drying preferably includes sequentially drying the washed organic phase with anhydrous sodium sulfate; the purification method is preferably column chromatography; the packing material for the column chromatography is preferably silica gel, and the eluent is preferably petroleum ether and ethyl acetate, with the volume ratio of petroleum ether to ethyl acetate preferably being 3–5:1, more preferably 3–4:1.

[0077] After obtaining the chiral alcohol compound, the present invention mixes the chiral alcohol compound, an N-Boc-protected amino acid, an organic base catalyst, and a condensing agent to carry out a condensation reaction to obtain intermediate 2. In the present invention, the N-Boc-protected amino acid is preferably one of N-boc-L-alanine, N-boc-glycine, N-boc-L-valine, N-boc-L-isoleucine, N-boc-L-tert-leucine, N-boc-L-phenylalanine, and N-boc-L-phenylglycine, more preferably N-boc-L-alanine, and even more preferably N-boc-L-alanine; the organic base catalyst preferably includes 4-dimethylaminopyridine, N-hydroxybenzotriazole, or N-hydroxysuccinimide, more preferably 4-dimethylaminopyridine (DMAP); the coupling agent preferably includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide. The amino acid hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, more preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); the molar ratio of the chiral alcohol compound and the N-Boc protected amino acid is preferably 1-1.3:1.2-2, more preferably 1-1.1:1.2-1.5; the molar ratio of the N-Boc protected amino acid, the organic base catalyst, and the condensing agent is preferably 1.2-1.5:0.2-0.5:1.3-1.8, more preferably 1.2-1.3:0.2-0.4:1.3-1.5.

[0078] In this invention, the temperature of the condensation reaction is preferably 0–30°C, more preferably 25–30°C; the time is preferably 3–6 h, more preferably 3–5 h; the condensation reaction is preferably carried out under organic solvent conditions; the organic solvent is preferably one or more of dichloromethane, chloroform, and carbon tetrachloride, more preferably dichloromethane. This invention also preferably involves sequentially washing, drying, and concentrating the condensation product; the washing reagent is preferably a sodium chloride solution; the drying preferably includes sequentially drying the washed organic phase with anhydrous sodium sulfate.

[0079] Intermediate 2 and trifluoroacetic acid are mixed and deprotected to obtain an amino acid ester. In this invention, the molar ratio of intermediate 2 to trifluoroacetic acid is preferably 1–1.2:15–18, more preferably 1:15–17; the deprotection temperature is preferably 0–30°C, more preferably 25–30°C; the time is preferably 4–8 h, more preferably 4–6 h; this invention also preferably involves sequentially extracting, drying, and purifying the deprotected product; the extraction, drying, and purification are preferably consistent with the above-described extraction, drying, and purification processes.

[0080] In this invention, the organic base catalyst preferably comprises 4-dimethylaminopyridine, N-hydroxybenzotriazole, or N-hydroxysuccinimide, more preferably 4-dimethylaminopyridine (DMAP); the condensing agent preferably comprises 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, more preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI).

[0081] In this invention, the molar ratio of the five-membered heterocyclic carboxylic acid ester and the amino acid ester is preferably 1.2-1.5:1-1.1, more preferably 1.2:1; the molar ratio of the amino acid ester, the organic base catalyst and the condensing agent is preferably 1-1.1:0.2-0.4:1.3-1.5, more preferably 1:0.2:1.3.

[0082] In this invention, the temperature of the condensation reaction is preferably 0–30°C, more preferably 25–30°C; the time is preferably 8–12 h, more preferably 8–10 h; the condensation reaction is preferably carried out under organic solvent conditions; the organic solvent is preferably one or more of dichloromethane, chloroform, and carbon tetrachloride. This invention also preferably involves sequentially washing, drying, and purifying the condensation product; the washing reagent is preferably a sodium chloride solution; the drying preferably includes: sequentially drying the washed organic phase with anhydrous sodium sulfate and removing the solvent under reduced pressure; the purification is preferably the same as described above.

[0083] This invention also provides the application of the five-membered heterocyclic amide compounds described in the above technical solutions or the five-membered heterocyclic amide compounds prepared by the preparation methods described in the above technical solutions in the prevention and control of agricultural diseases.

[0084] In this invention, the agricultural diseases preferably include one or more of the following: sclerotinia rot fungus of rapeseed, scab fungus of wheat, take-all fungus of wheat, Phytophthora in pepper, rice blast fungus, gray mold fungus of tomato, anthracnose fungus of pepper, sheath blight fungus of rice, sheath blight fungus of wheat, late blight fungus of potato, early blight fungus of tomato, rice seedling blight fungus, dry rot fungus of potato, and anthracnose fungus of cucumber.

[0085] The present invention also provides a bactericide, comprising an active component and a bactericidal component; the active component is a five-membered heterocyclic amide compound as described in the above technical solution or a five-membered heterocyclic amide compound prepared by the preparation method described in the above technical solution; the molar concentration ratio of the active component and the bactericidal component is 1:0 to 10, preferably 1:1 to 8.

[0086] In this invention, the bactericidal components preferably include Flufenoxadiazam, Flumetylsulforim, Fluoxytioconazole, Metarylpicoxamid, Cyclobutrifluram, Flubeneteram, Fluoxapiprolin, Florylpicoxamid, Ipflufenoquin, Metyltetraprole, Pyridachlometyl, Pyrapropoyne, Aminopyrifen, Inpyrfluxam, Isoflucypram, Fenpicoxamid, Dichlobentiazox, Ipfentrifluconazole, and Quinofum. One or more of the following: elin, Pydiflumetofen, Pyraziflumid, Picarbutrazox, Mandestrobin, Oxathiapiprolin, Enoxastrobin, Fenaminstrobin, Flufenoxystrobin, Isofetamid, Tolprocarb, Benzovindiflupyr, Fenpyrazamine, Pyriofenone, Dimethomorph, Azoxystrobin, Pyraziflumetrozine, Prothioconazole, Azoxystrobin, Cyclopyr, Mancozeb, Flutriafol, Tebuconazole, Cyclopyr, Metalaxyl, Cyclopyr, Difenoconazole, Propiconazole, Chlorothalonil, Thiamethoxam, Methoxystrobin, Isothiazine, Ningnanmycin, Allylisothiazide, Flumorpholine, and Dimethomorpholine.

[0087] In this invention, the formulation of the bactericide preferably includes emulsifiable concentrate, water emulsion, microemulsion, wettable powder, water-dispersible granules, or suspension.

[0088] To further illustrate the present invention, the following detailed descriptions of the five-membered heterocyclic amide compounds, their preparation methods, applications, and bactericides provided by the present invention are provided in conjunction with the embodiments, but these descriptions should not be construed as limiting the scope of protection of the present invention.

[0089] In this invention, the preparation process of the five-membered heterocyclic amide compounds with the structures shown in Formula I and Formula II is as follows:

[0090] Synthesis of intermediate amino acid esters:

[0091]

[0092] Synthetic route of intermediate thiazole carboxylic acid ethyl ester:

[0093]

[0094] Synthetic routes of the five-membered heterocyclic amide compounds described in Examples 1-14:

[0095]

[0096] Synthetic routes of the five-membered heterocyclic amide compounds described in Examples 15-20:

[0097]

[0098] Synthetic routes of the five-membered heterocyclic amide compounds described in Examples 21-24:

[0099]

[0100] Synthetic routes of the five-membered heterocyclic amide compounds described in Examples 25-43:

[0101]

[0102] Example 1

[0103] Prepare five-membered heterocyclic amide compounds with the following structures:

[0104]

[0105] A Shrek flask containing L-lactide (2.0 g, 13.9 mmol, 1.0 equiv.) and a stir bar was evacuated and filled with N2. This process was repeated three times. Tetrahydrofuran (28 mL) was added, and 4-fluorophenyl magnesium bromide (40 mL, 58.3 mmol, 4.2 equiv., 2 mol / LinEt2O) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was transferred to room temperature for carbonyl reduction for 3 h. The reaction was confirmed to be complete by TLC. The reaction system was then transferred to 0 °C and saturated NH4Cl solution was added dropwise until no more bubbles were observed. Tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate (30 mL × 2). The resulting organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure to obtain intermediate 1.

[0106] Intermediate 1 and triethylsilane (Et3SiH, 16.3 mL, 102.2 mmol, 10.0 equiv.) were dissolved in dichloromethane (80 mL). The mixture was transferred to 0 °C, and trifluoroacetic acid (TFA, 7.8 mL, 102.2 mmol, 10.0 equiv.) was slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 h. The reaction was confirmed to be complete by TLC. The reaction system was then transferred to 0 °C, and the pH was adjusted to 7 with 40% sodium hydroxide solution. The mixture was extracted with dichloromethane (30 mL). The resulting organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel (200-300 μm) column chromatography (eluent: V). 石油醚 / V 乙酸乙酯 =8:1), yielding 2.1 g of intermediate chiral alcohol A3 (colorless liquid, 61% yield in 2 steps);

[0107] Chiral alcohol A3 was dissolved in dichloromethane (20 mL), and 4-dimethylaminopyridine (DMAP, 113.2 mg, 0.93 mmol, 0.2 equiv.) and N-boc-L-alanine (1.1 g, 5.6 mmol, 1.2 equiv.) were added. The system was then transferred to an ice bath and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.2 g, 6.0 mmol, 1.3 equiv.) was added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The mixture was washed with saturated sodium chloride solution (15 mL × 2), and the organic phase was dried over anhydrous sodium sulfate to obtain intermediate 2.

[0108] Intermediate 2 was dissolved in dichloromethane (20 mL), and the mixture was transferred to 0 °C. Trifluoroacetic acid (TFA, 4.4 mL, 57.2 mmol, 15 equiv.) was slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and reacted for 4 h. The reaction was confirmed to be complete by TLC. The reaction system was then transferred to 0 °C and the pH was adjusted to 7 with 40% sodium hydroxide solution. The mixture was extracted with dichloromethane (15 mL × 2). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel (200-300 μm) column chromatography (eluent: ethyl acetate) to give 1.08 g of intermediate L-alanine ester (colorless liquid, 44% yield in 4 steps).

[0109] Phenylacetic acid ester (1.8 g, 8.9 mmol, 1.0 equiv.) was dissolved in 60 mL of methanol and 30 mL of aqueous solution. The system was then transferred to an ice bath (0 °C) and sodium hydroxide (1.1 g, 26.7 mmol, 3.0 equiv.) was added. The mixture was stirred at room temperature for 6 h. After the reaction was confirmed to be complete by TLC, methanol was removed under reduced pressure. The resulting system was then diluted with water and the pH was adjusted to 4 using dilute hydrochloric acid (40%). The precipitated solid was filtered and dried to obtain 1.4 g of phenylfuran carboxylic acid (white solid, 81% yield).

[0110] The above-mentioned phenylfuran carboxylic acid (57 mg, 0.3 mmol, 1.2 equiv.) and L-alanine ester (80 mg, 0.25 mmol, 1.0 equiv.) were dissolved in dichloromethane (25 mL), and 4-dimethylaminopyridine (DMAP, 6.1 mg, 0.05 mmol, 0.2 equiv.) was added. The system was then transferred to an ice bath (0 °C) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 62.4 mg, 0.33 mmol, 1.3 equiv.) was added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The mixture was washed with saturated sodium chloride solution (15 mL × 2), and the resulting organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel (200-300 μm) column chromatography (eluent: petroleum ether and ethyl acetate, v / v ratio 3:1) to obtain 72 mg of the target compound D1 (colorless). liquid, 48% in 2 steps)

[0111] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0112] 1HNMR(CDCl3,500MHz)δ:1.00(d,J=7.2Hz,3H),1.26(d,J=6.2Hz,3H),4.06(d,J=9.9Hz,1H),4.59-4.65(m,1H),5.73-5.79(m,1H),6.74(d,J=3.7 Hz,1H),6.82(d,J=7.6Hz,1H),6.96-7.02(m,4H),7.18-7.19(m,1H),7.2 2-7.28(m,4H),7.34-7.38(m,1H),7.42-7.45(m,2H),7.71-7.74(m,2H). 13 C NMR (CDCl3, 101MHz) δ: 18.2, 19.3, 48.0, 56.3, 73.5, 107.4, 115.8 (dd, J1=27.8Hz, J2=21.3Hz, 4C), 117.0 (2C), 124.7 (2C), 128.9, 129.0 (2C), 129.6 (d, J = 8.0Hz, 4C), 136.9 (d, J = 16.7Hz, 2C), 146.6, 155.8, 157.7, 160.6 (d, J = 8.8Hz), 163.1 (d, J = 9.3Hz), 172.5.

[0113] Example 2

[0114] Prepare five-membered heterocyclic amide compounds with the following structures:

[0115]

[0116] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiophene carboxylic acid;

[0117] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0118] 1 H NMR(CDCl3,400MHz)δ:0.98(d,J=7.1Hz,3H),1.25(d,J=6.0Hz,3H),4.06(d,J=9.9Hz,1H),4.56-4.64(m,1H),5.71-5.78(m,1 H),6.46(d,J=7.3Hz,1H),6.95-7.03(m,4H),7.21-7.28(m,5H),7.32-7.43(m,3H),7.46(d,J=3.9Hz,1H),7.60-7.63(m,2H). 13CNMR(CDCl3,101MHz)δ:18.2,19.3,48.6,56.3,73.5,115.8(dd,J1=28.0Hz,J2=21.4Hz,4C),123.5,126.2(2C),128.7,129.2(2C),129.4,129.6( dd, J1=8.0Hz, J2=1.5Hz, 4C), 133.5, 136.8 (d, J=2.7Hz), 136.8, 137.0 (d ,J=3.2Hz),149.4,160.6(d,J=8.3Hz),161.2,163.1(d,J=8.9Hz),172.6.

[0119] Example 3

[0120] Prepare five-membered heterocyclic amide compounds with the following structures:

[0121]

[0122] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 3-methyl-1-phenyl-pyrazole-5-carboxylic acid;

[0123] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0124] 1 H NMR(CDCl3,500MHz)δ:0.83(d,J=7.1Hz,3H),1.21(d,J=6.2Hz,3H),2.35(s,3H),4.02(d,J=10.0Hz,1H),4.42-4.48(m ,1H),5.66-5.72(m,1H),6.24(d,J=7.5Hz,1H),6.54(s,1H),6.94-7.00(m,4H),7.17-7.24(m,4H),7.38-7.43(m,5H). 13 C NMR (CDCl3, 126MHz) δ: 13.5, 17.7, 19.3, 48.3, 56.3, 73.5, 109.1, 115.7 (dd, J1=40.3Hz, J2=21.4Hz, 4C), 125.3 (2C), 128.4, 129.0 ( 2C), 129.5 (d, J = 8.3Hz, 4C), 136.7, 137.0 (d, J = 7.5Hz, 2C), 139.9, 149.1, 159.0, 160.8 (d, J = 13.4Hz), 162.8 (d, J = 14.7Hz), 172.1.

[0125] Example 4

[0126] Prepare five-membered heterocyclic amide compounds with the following structures:

[0127]

[0128] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 5-methyl-1-phenyl-pyrazole-3-carboxylic acid;

[0129] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0130] 1 H NMR(CDCl3,500MHz)δ:0.98(d,J=7.3Hz,3H),1.23(d,J=6.2Hz,3H),2.33(s,3H),4.04(d,J=9.7Hz,1H),4.56-4.65( m,1H),5.68-5.74(m,1H),6.71(s,1H),6.91-6.99(m,4H),7.20-7.28(m,5H),7.43-7.46(m,3H),7.49-7.53(m,2H). 13 CNMR(CDCl3,126MHz)δ:12.5,17.9,19.2,47.8,56.2,73.1,107.5,115.6(dd,J1=38.1Hz,J2=21.4Hz,4C),125.2(2C),128.6,129.3(2C),129.6( dd, J1=7.8Hz, J2=3.7Hz, 4C), 137.0 (dd, J1=9.3Hz, J2=3.2Hz, 2C), 139.2, 140.9, 146.1, 160.7 (d, J=12.1Hz), 161.6, 162.7 (d, J=12.3Hz), 172.4.

[0131] Example 5

[0132] Prepare five-membered heterocyclic amide compounds with the following structures:

[0133]

[0134] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid;

[0135] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0136] 1H NMR(CDCl3,400MHz)δ:0.96(dd,J1=5.6Hz,J2=4.4Hz,3H),1.24(dd,J1=5.2Hz,J2=2.8Hz,3H),3.18-3.24(m,1H),3.57-3.65(m,1H) ,4.04(dd,J1=8.0Hz,J2=2.2Hz,1H),4.43-4.50(m,1H),5.68-5.76(m,2H),6.95-7.07(m,5H),7.20-7.26(m,4H),7.31-7.41(m,5H). 13 C NMR(CDCl3,101MHz)δ:17.8(2C),19.3,41.1,48.3,56.3,73.4,85.0,115.8(dd,J1= 28.6Hz, J2=17.2Hz, 4C), 126.1(2C), 128.8, 129.0(2C), 129.6(dd, J1=6.3Hz, J2=1. 9Hz, 4C), 136.8 (d, J = 2.9Hz), 137.0 (dd, J1 = 4.9Hz, J2 = 2.7Hz), 139.6 (d, J = 1.7Hz), 153.1, 159.1 (d, J = 3.0Hz), 111.8 (dd, J1 = 197.6Hz, J2 = 10.9Hz), 171.7 (d, J = 4.8Hz).

[0137] Example 6

[0138] Prepare five-membered heterocyclic amide compounds with the following structures:

[0139]

[0140] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 5-phenyl-isoxazole-3-carboxylic acid;

[0141] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0142] 1 H NMR (CDCl3, 400MHz) δ: 1.04 (d, J = 7.2Hz, 3H), 1.25 (d, J = 6.1Hz, 3H), 4.05 (d, J = 10.0Hz, 1H), 4.56-4.63 (m,1H),5.68-5.78(m,1H),6.92-7.04(m,6H),7.21-7.27(m,4H),7.45-7.52(m,3H),7.77-7.83(m,2H). 13C NMR(CDCl3,101MHz)δ:17.8,19.3,48.3,56.3,73.5,99.2,115.5-116.0(m,4C),126.0(2C),126.8,129.3(2C),129.5-129.7(m,4C),130.2(d,J =8.0Hz), 130.9, 136.9 (dd, J1 = 20.0Hz, J2 = 3.4Hz), 158.5 (d, J = 28.0Hz, 2C), 160.6 (d, J = 10.5Hz), 163.0 (d, J = 10.8Hz), 171.7 (d, J = 4.6Hz, 2C).

[0143] Example 7

[0144] Prepare five-membered heterocyclic amide compounds with the following structures:

[0145]

[0146] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 3-phenyl-isoxazole-5-carboxylic acid;

[0147] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0148] 1 H NMR(CDCl3,500MHz)δ:1.03(d,J=7.2Hz,3H),1.26(d,J=6.0Hz,3H),4.06(d,J=10.1Hz,1H),4.55-4.63(m,1H),5.7 3-5.78(m,1H),6.95-7.01(m,4H),7.07(d,J=7.5Hz,1H),7.21-7.28(m,5H),7.45-7.52(m,3H),7.79-7.85(m,2H). 13 C NMR (CDCl3, 126MHz) δ: 17.8, 19.2, 48.4, 56.3, 73.7, 105.6, 115.8 (dd, J1=35.7Hz, J2=21.3Hz, 4C), 127.0 (2C), 128.0, 129.2 (2C), 129.5 (dd, J1=9. 7Hz, J2=7.9Hz, 4C), 130.7, 136.8 (dd, J1=35.3Hz, J2=3.4Hz, 2C), 155.2, 1 60.8(d,J=15.0Hz), 162.8(d,J=15.4Hz), 163.3(d,J=23.6Hz, 2C), 171.6.

[0149] Example 8

[0150] Prepare five-membered heterocyclic amide compounds with the following structures:

[0151]

[0152] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2-phenyl-oxazol-4-carboxylic acid;

[0153] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0154] 1 H NMR (CDCl3, 400MHz) δ: 1.03 (d, J = 7.2Hz, 3H), 1.25 (d, J = 6.2Hz, 3H), 4.06 (d, J = 9.8Hz, 1H), 4.57-4.65 (m, 1H), 5.71-5.78 (m,1H),6.93-7.02(m,4H),7.20-7.29(m,4H),7.40(d,J=7.9Hz,1H),7.47-7.51(m,3H),8.04-8.09(m,2H),8.21(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 18.0, 19.3, 47.9, 56.3, 73.4, 115.7 (dd, J1=29.1Hz, J2=21.3Hz, 4C), 126.7, 126.8 (2C), 129.0 (2C), 129.6 (dd, J1=8.0Hz, J2=1.5Hz, 4C),131.2,136.9-137.1(m,3C),141.1,160.2,160.6(d,J=9.3Hz),161.6,163.1(d,J=9.9Hz),172.2.

[0155] Example 9

[0156] Prepare five-membered heterocyclic amide compounds with the following structures:

[0157]

[0158] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2-phenyl-thiazolyl-4-carboxylic acid;

[0159] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0160] 1H NMR(CDCl3,500MHz)δ:1.04(d,J=7.2Hz,3H),1.26(d,J=6.2Hz,3H),4.06(d,J=9.9Hz,1H),4.60-4.66(m,1H),5.73-5.78 (m,1H),6.94-7.02(m,4H),7.21-7.29(m,4H),7.45-7.50(m,3H),7.82(d,J=7.8Hz,1H),7.96-7.99(m,2H),8.07(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 18.0, 19.3, 48.2, 56.2, 73.3, 115.7 (dd, J1=36.5Hz, J2=21.3Hz, 4C), 123.5, 126.8 (2C), 129.2 (2C), 129.6 (d, J= 7.9Hz, 4C), 130.8, 132.8, 136.9 (dd, J1=21.7Hz, J2=3.4Hz, 2C), 150.2, 160.5, 160.7 (d, J=12.1Hz), 162.8 (d, J=12.5Hz), 168.3, 172.4.

[0161] Example 10

[0162] Prepare five-membered heterocyclic amide compounds with the following structures:

[0163]

[0164] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-phenyl-thiazolyl-2-carboxylic acid;

[0165] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0166] 1 H NMR (CDCl3, 400MHz) δ: 1.06 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 4.06 (d, J = 9.9Hz, 1H), 4.58-4.65 (m, 1H), 5.72-5.79 ( m,1H),6.92-7.02(m,4H),7.20-7.28(m,4H),7.37-7.41(m,1H),7.44-7.49(m,2H),7.69-7.73(m,2H),7.91-7.94(m,2H). 13C NMR (CDCl3, 101MHz) δ: 18.0, 19.3, 48.5, 56.3, 73.5, 115.8 (dd, J1=28.0Hz, J2=21.3Hz, 4C), 118.4, 126.6 (2C), 128.9, 129.0 (2C), 129. 6(d,J=7.9Hz,4C),133.7,136.9(dd,J1=16.4Hz,J2=3.3Hz,2C),156.6,159.0,160.6(d,J=10.2Hz),162.7,163.1(d,J=10.5Hz),172.0.

[0167] Example 11

[0168] Prepare five-membered heterocyclic amide compounds with the following structures:

[0169]

[0170] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-methyl-2-phenyl-thiazolyl-5-carboxylic acid;

[0171] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0172] 1 H NMR (CDCl3, 400MHz) δ: 0.97 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 2.74 (s, 3H), 4.06 (d, J = 10.0Hz, 1H), 4.54-4.61 (m, 1 H),5.72-5.79(m,1H),6.33(d,J=7.1Hz,1H),6.96-7.02(m,4H),7.21-7.28(m,4H),7.43-7.48(m,3H),7.92-7.96(m,2H). 13 C NMR (CDCl3, 101MHz) δ: 17.7, 18.2, 19.3, 48.8, 56.3, 73.7, 115.8 (dd, J1=29.4Hz, J2=21.4Hz, 4C), 125.5, 126.9 (2C), 129.2 (2C), 129.6 (dd, J1= 7.9Hz, J2=2.5Hz, 4C), 131.0, 132.9, 136.9 (dd, J1=24.9Hz, J2=3.3Hz, 2C), 156.5, 160.6 (d, J=9.2Hz), 161.2, 163.1 (d, J=9.4Hz), 167.8, 172.5.

[0173] Example 12

[0174] Prepare five-membered heterocyclic amide compounds with the following structures:

[0175]

[0176] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 1-phenyl-1,2,4-triazole-3-carboxylic acid;

[0177] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0178] 1 H NMR(CDCl3,500MHz)δ:1.02(d,J=7.2Hz,3H),1.25(d,J=6.2Hz,3H),4.06(d,J=10.0Hz,1H),4.66-4.72(m,1H),5.71-5.77(m,1H), 6.95-7.02(m,4H),7.21-7.28(m,4H),7.43-7.46(m,1H),7.51-7.56(m,2H),7.61(d,J=8.0Hz,1H),7.72-7.76(m,2H),8.58(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 18.0, 19.2, 48.1, 56.2, 73.4, 115.7 (dd, J1=36.9Hz, J2=21.3Hz, 4C), 120.4 (2C), 129.0, 129.6 (d, J=7.9Hz, 4 C),129.9(2C),136.6,136.9(dd,J1=24.3Hz,J2=3.3Hz,2C),141.7,157.3,158.2,160.8(d,J=12.0Hz),162.7(d,J=12.2Hz),172.1.

[0179] Example 13

[0180] Prepare five-membered heterocyclic amide compounds with the following structures:

[0181]

[0182] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 3-phenyl-1,2,4-oxadiazole-5-carboxylic acid;

[0183] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0184] 1H NMR (CDCl3, 400MHz) δ: 1.04 (d, J = 7.2Hz, 3H), 1.27 (d, J = 6.2Hz, 3H), 4.07 (d, J = 10.0Hz, 1H), 4.56-4.65 (m, 1H), 5.7 1-5.80(m,1H),6.96-7.02(m,4H),7.20-7.28(m,4H),7.48-7.57(m,3H),7.61(d,J=7.7Hz,1H),8.10-8.13(m,2H). 13 C NMR (CDCl3, 101MHz) δ: 17.6, 19.2, 48.8, 56.3, 74.0, 115.8 (dd, J1=28.1Hz, J2=21.4Hz, 4C), 125.8, 127.7 (2C), 129.1 (2C), 129.6 (dd, J1= 8.0Hz, J2=2.7Hz, 4C), 131.9, 136.8 (dd, J1=30.6Hz, J2=3.3Hz, 2C), 152.4, 160.6 (d, J=9.7Hz), 163.1 (d, J=10.1Hz), 168.2, 168.9, 171.3.

[0185] Example 14

[0186] Prepare five-membered heterocyclic amide compounds with the following structures:

[0187]

[0188] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 5-phenyl-1,3,4-oxadiazole-2-carboxylic acid;

[0189] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0190] 1 H NMR (CDCl3, 400MHz) δ: 1.07 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.3Hz, 3H), 4.06 (d, J = 10.1Hz, 1H), 4.57-4.63 (m, 1H), 5 .71-5.78(m,1H),6.94-7.00(m,4H),7.21-7.25(m,4H),7.35-7.44(m,2H),7.49-7.55(m,3H),8.14-8.15(m,1H). 13CNMR(CDCl3,101MHz)δ:17.7,19.3,48.8,56.4,73.8,115.8(dd,J1=30.0Hz,J2=21.3Hz,4C),123.0,127.7(2C),127.9(d,J=16.4Hz, 2C),129.4(2C),129.6(dd,J1=7.9Hz,J2=5.4Hz,4C),132.8,152.8,158.1,160.5(d,J=10.3Hz),162.9(d,J=10.8Hz),166.7,171.2.

[0191] Example 15

[0192] Prepare five-membered heterocyclic amide compounds with the following structures:

[0193]

[0194] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and L-alanine ester was replaced with glycine ester.

[0195] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0196] 1 H NMR (CDCl3, 400MHz) δ: 1.16 (d, J = 6.2Hz, 3H), 3.85 (dd, J1 = 18.3Hz, J2 = 5.4Hz, 1H), 3.96 (d, J = 9.2Hz, 1H), 4.09 (dd, J1 = 18.2Hz, J2 = 5.8Hz ,1H),5.60-5.67(m,1H),6.82-6.92(m,4H),7.07-7.16(m,4H),7.34-7.38(m,3H),7.71(t,J=5.5Hz,1H),7.83-7.87(m,2H),7.99(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 19.2, 41.3, 55.7, 73.6, 115.6 (dd, J1=26.8Hz, J2=21.3Hz, 4C), 123.5, 126.7 (2C), 129.1 (2C), 129.7 (d, J=8.1 Hz, 4C), 130.8, 132.7, 136.7 (dd, J1=16.9Hz, J2=3.3Hz, 2C), 149.9, 160.5 (d, J=10.3Hz), 161.1, 162.9 (d, J=10.8Hz), 168.3, 169.1.

[0197] Example 16

[0198] Prepare five-membered heterocyclic amide compounds with the following structures:

[0199]

[0200] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and L-alanine ester was replaced with L-valine ester.

[0201] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0202] 1 H NMR(CDCl3,400MHz)δ:0.54(d,J=6.8Hz,3H),0.74(d,J=6.8Hz,3H),1.16(d,J=6.2Hz,3H),1.72-1.81(m,1H),3.99(d,J=9.8Hz,1H),4.54(dd,J1=9.4 Hz,J2=4.6Hz,1H),5.63-5.70(m,1H),6.81-6.92(m,4H),7.11-7.21(m,4H) ,7.39-7.43(m,3H),7.69(d,J=9.3Hz,1H),7.87-7.92(m,2H),8.00(s,1H). 13 CNMR (CDCl3, 101MHz) δ: 17.2, 19.3, 19.4, 31.3, 56.1, 57.3, 73.6, 115.7 (dd, J1=24.6Hz, J2=21.3Hz, 4C), 123.5, 126.8 (2C), 129.2 (2C), 129.6 (dd, J1=8.0Hz, J2=5.7Hz, 4C), 130.8, 132.8, 137.0 (dd, J1=6.3Hz, J2=3.2Hz, 2C), 150.3, 160.6 (d, J=5.2Hz), 161.0, 163.0 (d, J=5.6Hz), 168.3, 171.2.

[0203] Example 17

[0204] Prepare five-membered heterocyclic amide compounds with the following structures:

[0205]

[0206] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and L-alanine ester was replaced with L-isoleucine ester.

[0207] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0208] 1 H NMR(CDCl3,400MHz)δ:0.63(t,J=7.3Hz,3H),0.69(d,J=6.9Hz,3H),0.79-0.89(m,1 H),0.97-1.07(m,1H),1.15(d,J=6.1Hz,3H),1.55-1.64(m,1H),3.99(d,J=9.8Hz,1H ),4.57(dd,J1=9.2Hz,J2=4.8Hz,1H),5.65-5.72(m,1H),6.81-6.93(m,4H),7.10-7. 22(m,4H),7.38-7.42(m,3H),7.71(d,J=9.1Hz,1H),7.87-7.92(m,2H),7.99(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 11.5, 15.2, 19.4, 24.5, 37.7, 56.1, 57.0, 73.5, 115.7 (t, J = 21.3Hz, 4C), 123.4, 126.8 (2C), 129.2 (2C), 12 9.6(d,J=8.1Hz,4C),130.8,132.8,137.1(d,J=3.2Hz,2C),150.3,160.6(d,J=3.2Hz),160.8,163.5(d,J=3.7Hz),168.3,171.2.

[0209] Example 18

[0210] Prepare five-membered heterocyclic amide compounds with the following structures:

[0211]

[0212] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and L-alanine ester was replaced with L-tert-leucine ester.

[0213] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0214] 1H NMR (CDCl3, 400MHz) δ: 0.76 (s, 9H), 1.15 (d, J = 6.1Hz, 3H), 3.99 (d, J = 9.6Hz, 1H), 4.41 (d, J = 9.8Hz, 1H), 5.64-5.71 (m ,1H),6.73-6.87(m,4H),7.07-7.17(m,4H),7.39-7.43(m,3H),7.74(d,J=9.8Hz,1H),7.87-7.89(m,2H),7.98(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 19.4, 26.4 (3C), 34.7, 55.9, 60.6, 73.4, 115.6 (dd, J1=24.7Hz, J2=21.5Hz, 4C), 123.4, 126.8 (2C), 129.2 (2C), 129. 6(t,J=7.4Hz,4C),130.8,132.8,137.0(dd,J1=6.6Hz,J2=3.2Hz,2C),150.3,160.5(d,J=6.4Hz),160.6,162.9(d,J=6.8Hz),168.1,170.5.

[0215] Example 19

[0216] Prepare five-membered heterocyclic amide compounds with the following structures:

[0217]

[0218] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and L-alanine ester was replaced with L-phenylalanine ester.

[0219] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0220] 1 H NMR(CDCl3,400MHz)δ:1.16(d,J=6.1Hz,3H),2.67-2.82(m,2H),3.99(d,J=9.2Hz,1H),4.81-4.86(m,1H),5.57-5.64( m,1H),6.82-6.90(m,6H),7.10-7.19(m,7H),7.36-7.39(m,3H),7.61(d,J=8.6Hz,1H),7.79-7.83(m,2H),7.94(s,1H). 13C NMR (CDCl3, 101MHz) δ: 19.3, 37.7, 53.1, 55.9, 74.0, 115.7 (dd, J1=21.4Hz, J2= 18.5Hz,4C),123.4,126.7(2C),127.2,128.6(2C),129.1(2C),129.3(2C),129 .8(dd,J1=15.8Hz,J2=7.9Hz,4C),130.8,132.8,135.7,136.9(dd,J1=5.9Hz,J 2=3.2Hz,2C),150.0,160.5(d,J=4.7Hz,2C),163.0(d,J=5.4Hz),168.1,170.8.

[0221] Example 20

[0222] Prepare five-membered heterocyclic amide compounds with the following structures:

[0223]

[0224] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and L-alanine ester was replaced with L-phenylglycine ester.

[0225] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0226] 1 H NMR (CDCl3, 400MHz) δ: 1.20 (d, J = 6.2Hz, 3H), 3.88 (d, J = 9.0Hz, 1H), 5.54 (d, J = 7.4Hz, 1H), 5.60-5.67 (m, 1H), 6.60-6.66 (m, 2H), 6.79-6.84 (m,2H),6.89-6.94(m,2H),6.95-7.00(m,2H),7.06-7.21(m,5H),7.37-7.41(m,3H),7.87-7.91(m,2H),7.99(s,1H),8.19(d,J=7.4Hz,1H). 13C NMR (CDCl3, 101MHz) δ: 19.4, 55.7, 56.8, 73.9, 115.5 (dd, J1=34.5Hz, J2=21.3H z,4C),123.7,126.8(2C),127.2(2C),128.5,129.0(2C),129.2(2C),129.5(dd ,J1=11.9Hz,J2=7.9Hz,4C),130.8,132.8,135.9,136.56(dd,J1=70.1Hz,J2=3 .3Hz,2C),150.0,160.4(d,J=16.0Hz,2C),162.8(d,J=17.7Hz),168.4,170.1.

[0227] Example 21

[0228] Prepare five-membered heterocyclic amide compounds with the following structures:

[0229]

[0230] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and 4-fluorophenyl magnesium bromide was replaced with phenyl magnesium bromide.

[0231] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0232] 1 H NMR(CDCl3,400MHz)δ:0.95(d,J=7.2Hz,3H),1.27(d,J=6.2Hz,3H),4.07(d,J=10.0Hz,1H),4.57-4.65(m,1H),5 .78-5.89(m,1H),7.09-7.34(m,10H),7.45-7.47(m,3H),7.84(d,J=7.8Hz,1H),7.95-7.98(m,2H),8.05(s,1H). 13 CNMR(CDCl3,101MHz)δ:17.9,19.3,48.2,58.0,73.5,123.3,126.7(3C),127.0,128.1(2C),128.2 (2C),128.6(2C),128.8(2C),129.1(2C),130.7,132.8,141.2,141.5,150.3,160.5,168.2,172.4.

[0233] Example 22

[0234] Prepare five-membered heterocyclic amide compounds with the following structures:

[0235]

[0236] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and 4-fluorophenyl magnesium bromide was replaced with 4-methoxyphenyl magnesium bromide.

[0237] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0238] 1 H NMR(CDCl3,400MHz)δ:1.03(d,J=7.2Hz,3H),1.24(d,J=6.0Hz,3H),3.73(s,3H),3.75(s,3H),4.00(d,J=3.8Hz,1H),4.59-4.66(m,1H ),5.73-5.78(m,1H),6.79-6.83(m,4H),7.18-7.24(m,4H),7.47-7.49(m,3H),7.85(d,J=7.8Hz,1H),7.98-8.01(m,2H),8.06(s,1H). 13 C NMR(CDCl3,101MHz)δ:18.5,19.1,48.2,55.3(2C),55.6,73.9,113.9(2C),114.1(2C),123.3,126 .8(2C),129.1(4C),129.2(2C),129.3(2C),130.8,133.9(2C),150.5,158.4,160.4,168.3,172.0.

[0239] Example 23

[0240] Prepare five-membered heterocyclic amide compounds with the following structures:

[0241]

[0242] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and 4-fluorophenyl magnesium bromide was replaced with 4-chlorophenyl magnesium bromide.

[0243] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0244] 1H NMR (CDCl3, 400MHz) δ: 1.06 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.1Hz, 3H), 4.04 (d, J = 9.8Hz, 1H), 4.59-4.67 (m, 1H), 5.69-5.79 (m,1H),7.14-7.21(m,4H),7.24-7.28(m,3H),7.45-7.50(m,4H),7.80(d,J=7.8Hz,1H),7.95-7.99(m,2H),8.07(s,1H). 13 C NMR(CDCl3,101MHz)δ:18.0,19.3,48.2,56.5,72.9,126.8(4C),128.9(2C),129.2 (4C),129.5(4C),130.8,132.8,133.1,139.3,139.5,150.2,160.6,168.3,172.3.

[0245] Example 24

[0246] Prepare five-membered heterocyclic amide compounds with the following structures:

[0247]

[0248] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with phenylthiazol carboxylic acid and 4-fluorophenyl magnesium bromide was replaced with 3-fluorophenyl magnesium bromide.

[0249] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0250] 1 H NMR (CDCl3, 400MHz) δ: 1.05 (d, J = 7.2Hz, 3H), 1.28 (d, J = 6.2Hz, 3H), 4.08 (d, J = 9.9Hz, 1H), 4.60-4.68 (m, 1H), 5.74-5.81 (m, 1H), 6 .87-6.94(m,2H),6.96-7.12(m,4H),7.22-7.29(m,2H),7.45-7.48(m,3H),7.84(d,J=7.8Hz,1H),7.95-7.98(m,2H),8.06(s,1H). 13C NMR (CDCl3, 101MHz) δ: 17.9, 19.2, 48.2, 57.2, 72.9, 114.1 (dd, J1=27.6Hz, J2=21.0H z,2C),115.2(dd,J1=21.6Hz,J2=2.0Hz,2C),123.4,123.8-123.9(m,2C),126.8(2C), 129.1(2C),130.4(dd,J1=27.1Hz,J2=8.2Hz,2C),130.7,132.8,143.2(dd,J1=28.1Hz ,J2=6.9Hz,2C),150.3,160.5,161.7(d,J=8.4Hz),164.2(d,J=8.9Hz),168.3,172.3.

[0251] Example 25

[0252] Prepare five-membered heterocyclic amide compounds with the following structures:

[0253]

[0254] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with methylthiazol carboxylic acid;

[0255] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0256] 1 H NMR (CDCl3, 500MHz) δ: 1.00 (d, J = 7.2Hz, 3H), 1.24 (d, J = 6.2Hz, 3H), 2.72 (s, 3H), 4.05 (d, J = 9.9Hz, 1H), 4.5 6-4.62(m,1H),5.70-5.76(m,1H),6.93-7.01(m,4H),7.20-7.25(m,4H),7.66(d,J=7.9Hz,1H),7.92(s,1H). 13 CNMR(CDCl3,126MHz)δ:18.0,19.2,19.3,48.1,56.2,73.2,115.7(dd,J1=39.3Hz,J2=21.3Hz,4C),123.5,129.6(dd,J1=8.0Hz ,J2=2.2Hz,4C),137.0(dd,J1=18.7Hz,J2=3.4Hz,2C),149.1,160.6,160.8(d,J=12.3Hz),162.8(d,J=12.6Hz),166.2,172.3.

[0257] Example 26

[0258] Prepare five-membered heterocyclic amide compounds with the following structures:

[0259]

[0260] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with ethylthiazole carboxylic acid;

[0261] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0262] 1 H NMR (CDCl3, 500MHz) δ: 1.00 (d, J = 7.2Hz, 3H), 1.24 (d, J = 6.2Hz, 3H), 1.41 (t, J = 7.6Hz, 3H), 3.03 (dd, J1 = 15.3Hz, J2 = 7.7Hz, 2H), 4.0 5(d,J=9.7Hz,1H),4.56-4.62(m,1H),5.70-5.76(m,1H),6.93-7.01(m,4H),7.20-7.26(m,4H),7.67(d,J=7.9Hz,1H),7.94(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 14.1, 18.0, 19.3, 27.0, 48.1, 56.3, 73.3, 115.7 (dd, J1=39.0Hz, J2=21.2Hz, 4C), 123.0, 129.7 (dd, J1=7.4 Hz, J2=2.0Hz, 4C), 137.0 (dd, J1=19.0Hz, J2=3.3Hz, 2C), 149.0, 160.7, 160.8 (d, J=12.2Hz), 162.8 (d, J=12.6Hz), 172.4, 173.1.

[0263] Example 27

[0264] Prepare five-membered heterocyclic amide compounds with the following structures:

[0265]

[0266] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-methylphenylthiazol carboxylic acid;

[0267] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0268] 1H NMR (CDCl3, 500MHz) δ: 1.04 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.1Hz, 3H), 2.42 (s, 3H), 4.06 (d, J = 9.8Hz, 1H), 4.60-4.66 (m, 1H),5.72-5.78(m,1H),6.93-7.,01(m,4H),7.21-7.29(m,6H),7.81(d,J=7.8Hz,1H),7.85-7.87(m,2H),8.03(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 18.0, 19.3, 21.6, 48.2, 56.3, 73.3, 115.7 (dd, J1=36.0Hz, J2=21.3Hz, 4C), 123.0, 126.7 (2C), 129.6 (d, J=7.9Hz, 4C ),129.8(2C),130.2,137.0(dd,J1=19.4Hz,J2=3.2Hz,2C),141.2,150,1,160.6,160.8(d,J=11.8Hz),162.8(d,J=12.1Hz),168.5,172.4.

[0269] Example 28

[0270] Prepare five-membered heterocyclic amide compounds with the following structures:

[0271]

[0272] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-methoxyphenylthiazol carboxylic acid;

[0273] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0274] 1 H NMR(CDCl3,500MHz)δ:1.03(d,J=7.2Hz,3H),1.26(d,J=6.2Hz,3H),3.87(s,3H),4.06(d,J=9.8Hz,1H),4.60-4.65(m ,1H),5.72-5.78(m,1H),6.93-7.01(m,6H),7.21-7.29(m,4H),7.81(d,J=7.9Hz,1H),7.89-7.92(m,2H),8.00(s,1H). 13C NMR(CDCl3,126MHz)δ:18.0,19.3,48.1,55.6,56.2,73.3,114.4(2C),115.7(dd,J1=35.9,J2=21.2Hz,4C),122.6,125.8,128.3(2C),129 .6(d,J=7.8Hz,4C),136.9(dd,J1=19.3Hz,J2=3.3Hz,2C),149.9,160.6,160.8(d,J=11.3Hz),161.7,162.8(d,J=12.0Hz),168.2,172.4.

[0275] Example 29

[0276] Prepare five-membered heterocyclic amide compounds with the following structures:

[0277]

[0278] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-trifluoromethylphenylthiazol carboxylic acid;

[0279] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0280] 1 H NMR(CDCl3,500MHz)δ:1.04(d,J=7.2Hz,3H),1.27(d,J=6.2Hz,3H),4.07(d,J=9.8Hz,1H),4.61-4.67(m,1H),5.73-5.79 (m,1H),6.94-7.02(m,4H),7.21-7.29(m,4H),7.71-7.74(m,2H),7.79(d,J=7.8Hz,1H),8.07-8.10(m,2H),8.15(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 18.0, 19.3, 48.2, 56.3, 73.4, 115.7 (dd, J1=37.8Hz, J2= 21.3Hz,4C),124.4,126.2(d,J=3.8Hz,2C),127.1(2C),129.6(d,J=7.8Hz,4C) ,132.4(dd,J1=65.4Hz,J2=32.6Hz),135.9,136.9(dd,J1=27.8Hz,J2=3.4Hz,2 C),150.7(2C),160.3,160.8(d,J=13.0Hz),162.8(d,J=13.5Hz),166.5,172.3.

[0281] Example 30

[0282] Prepare five-membered heterocyclic amide compounds with the following structures:

[0283]

[0284] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-fluorophenylthiazol carboxylic acid;

[0285] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0286] 1 H NMR(CDCl3,500MHz)δ:1.03(d,J=7.2Hz,3H),1.26(d,J=6.1Hz,3H),4.07(d,J=9.8Hz,1H),4.60-4.66(m,1H),5.73-5.78 (m,1H),6.93-7.01(m,4H),7.14-7.19(m,2H),7.21-7.29(m,4H),7.79(d,J=7.8Hz,1H),7.94-7.98(m,2H),8.06(s,1H). 13 C NMR(CDCl3,126MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J1=37.2Hz,J2 =21.3Hz, 4C), 116.3 (d, J = 22.0Hz), 123.4, 128.8 (d, J = 8.5Hz, 2C), 129.2 (d, J = 3.4Hz), 129.6 (d, J=7.9Hz, 4C), 136.9 (dd, J1=24.0Hz, J2=3.4Hz, 2C), 150.3, 160.4, 160.8 (d, J = 12.2Hz), 162.8 (d, J = 12.8Hz), 163.3, 165.3, 167.1, 172.4.

[0287] Example 31

[0288] Prepare five-membered heterocyclic amide compounds with the following structures:

[0289]

[0290] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-chlorophenylthiazol carboxylic acid;

[0291] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0292] 1 H NMR(CDCl3,500MHz)δ:1.03(d,J=7.2Hz,3H),1.26(d,J=6.2Hz,3H),4.07(d,J=9.9Hz,1H),4.60-4.66(m,1H),5.73-5.78 (m,1H),6.93-7.02(m,4H),7.21-7.29(m,4H),7.43-7.46(m,2H),7.78(d,J=7.9Hz,1H),7.90-7.92(m,2H),8.08(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 18.0, 19.3, 48.2, 56.3, 73.4, 115.7 (dd, J1=37.4, J2=21.3Hz, 4C), 123.7, 128.0 (2C), 129.4 (2C), 1 29.6(d,J=8.0Hz,4C),131.3,136.8-137.0(m,3C),150.4,160.4,160.8(d,J=12.6Hz),162.8(d,J=13.1Hz),167.0,172.4.

[0293] Example 32

[0294] Prepare five-membered heterocyclic amide compounds with the following structures:

[0295]

[0296] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-bromophenylthiazol carboxylic acid;

[0297] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0298] 1 H NMR(CDCl3,500MHz)δ:1.03(d,J=7.2Hz,3H),1.26(d,J=6.1Hz,3H),4.06(d,J=9.9Hz,1H),4.60-4.66(m,1H),5.72-5.78 (m,1H),6.94-7.02(m,4H),7.21-7.29(m,4H),7.59-7.62(m,2H),7.77(d,J=7.9Hz,1H),7.83-7.86(m,2H),8.08(s,1H). 13C NMR (CDCl3, 126MHz) δ: 18.0, 19.3, 48.2, 56.3, 73.4, 115.7 (dd, J1=37.5Hz, J2=21.3Hz, 4C), 123.7, 125.2, 128.2 (2C), 129.6 (d, J=7.9 Hz, 4C), 131.7, 132.4 (2C), 136.9 (dd, J1 = 25.2, J2 = 3.2Hz, 2C), 150.4, 160.4, 160.8 (d, J = 12.8Hz), 162.8 (d, J = 13.0Hz), 167.1, 172.4.

[0299] Example 33

[0300] Prepare five-membered heterocyclic amide compounds with the following structures:

[0301]

[0302] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2-furanthiazole carboxylic acid;

[0303] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0304] 1 H NMR(CDCl3,500MHz)δ:1.03(d,J=7.2Hz,3H),1.25(d,J=6.2Hz,3H),4.06(d,J=9.8Hz,1H),4.58-4.64(m,1H),5.71-5.77(m,1H),6.57(dd,J1=3.5H z,J2=1.7Hz,1H),6.93-7.01(m,4H),7.07(dd,J1=3.5Hz,J2=0.6Hz,1H), 7.20-7.28(m,4H),7.53-7.55(m,1H),7.70(d,J=7.9Hz,1H),8.03(s,1H). 13 CNMR (CDCl3, 126MHz) δ: 18.0, 19.3, 48.2, 56.3, 73.3, 110.0, 112.5, 115.7 (dd, J1=37.0Hz, J2=21.3Hz, 4C), 122.8, 129.6 (d, J=7.8H z, 4C), 137.0 (dd, J1 = 20.3Hz, J2 = 3.3Hz, 2C), 144.3, 148.3, 150.2, 158.1, 160.4, 160.8 (d, J = 12.1Hz), 162.8 (d, J = 12.5Hz), 172.3.

[0305] Example 34

[0306] Prepare five-membered heterocyclic amide compounds with the following structures:

[0307]

[0308] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2-thiophenthiazole carboxylic acid;

[0309] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0310] 1 H NMR(CDCl3,500MHz)δ:1.04(d,J=7.2Hz,3H),1.26(d,J=6.1Hz,3H),4.06(d, J=9.8Hz,1H),4.57-4.63(m,1H),5.71-5.77(m,1H),6.93-7.01(m,4H),7.11( dd,J1=5.1Hz,J2=3.7Hz,1H),7.21-7.28(m,4H),7.46(dd,J1=5.0Hz,J2=1.3 Hz,1H),7.55(dd,J1=3.7,J2=1.3Hz,1H),7.69(d,J=7.8Hz,1H),7.99(s,1H). 13 C NMR (CDCl3, 126MHz) δ: 17.9, 19.3, 48.3, 56.3, 73.3, 115.7 (dd, J1=36.6Hz, J2=21.3Hz, 4C), 122.9, 127.7, 128.1, 128.7, 129.6 (d ,J=7.9Hz,4C),136.3,137.0(dd,J1=19.6,J2=3.3Hz,2C),149.8,160.3,160.8(d,J=12.6Hz),161.9,162.8(d,J=12.9Hz),172.2.

[0311] Example 35

[0312] Prepare five-membered heterocyclic amide compounds with the following structures:

[0313]

[0314] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2-pyridithiazole carboxylic acid;

[0315] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0316] 1 H NMR(CDCl3,500MHz)δ:1.04(d,J=7.2Hz,3H),1.26(d,J=6.2Hz,3H),4.07(d,J=9.9Hz,1H),4.61-4.67(m,1H),5.74-5.79(m,1H),6.95-7.02 (m,4H),7.21-7.30(m,4H),7.37-7.39(m,1H),7.80(d,J=7.8Hz,1H),7.82-7.86(m,1H),8.18(s,1H),8.22-8.24(m,1H),8.62-8.64(m,1H). 13 C NMR (CDCl3, 126MHz) δ: 18.0, 19.3, 48.2, 56.3, 73.4, 115.7 (dd, J1=36.4Hz, J2=21.3Hz, 4C), 120.0, 125.2, 125.9, 129.6 (d, J=7.9Hz, 4C), 136.9 (dd, J1=24.9, J2=3.3Hz, 2C), 137.3, 149.7, 150.5 (d, J=6.9Hz, 2C), 160.5, 160.8 (d, J=10.9Hz), 162.8 (d, J=11.5Hz), 169.2, 172.5.

[0317] Example 36

[0318] Prepare five-membered heterocyclic amide compounds with the following structures:

[0319]

[0320] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 4-pyridithiazole carboxylic acid;

[0321] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0322] 1 H NMR (CDCl3, 400MHz) δ: 1.05 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 4.07 (d, J = 9.8Hz, 1H), 4.60-4.67 (m, 1H), 5.72-5.79 (m,1H),6.93-7.02(m,4H),7.20-7.29(m,4H),7.77(d,J=7.8Hz,1H),7.83-7.85(m,2H),8.20(s,1H),8.75-8.77(m,2H). 13C NMR (CDCl3, 101MHz) δ: 18.0, 19.3, 48.3, 56.3, 73.5, 115.7 (dd, J1=30.7Hz, J2=21.3Hz, 4C), 120.5 (2C), 125.1, 129.6 (d, J=7.9Hz, 4 C),136.9(dd,J1=20.9Hz,J2=3.2Hz,2C),139.6,150.9(2C),151.0,160.1,160.6(d,J=10.5Hz),163.1(d,J=11.1Hz),165.4,172.3.

[0323] Example 37

[0324] Prepare five-membered heterocyclic amide compounds with the following structures:

[0325]

[0326] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2-fluorophenylthiazol carboxylic acid;

[0327] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0328] 1 H NMR (CDCl3, 400MHz) δ: 1.05 (d, J = 7.3Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 4.07 (d, J = 9.8Hz, 1H), 4.60-4.68 (m, 1H), 5.72-5.79 (m,1H),6.93-7.02(m,4H),7.20-7.32(m,6H),7.42-7.48(m,1H),7.82(d,J=7.8Hz,1H),8.19(s,1H),8.30-8.35(m,1H). 13 C NMR (CDCl3, 101MHz) δ: 18.1, 19.3, 48.2, 56.3, 73.4, 115.7 (dd, J1=29.0Hz, J2=21. 3Hz, 4C), 116.4 (d, J = 21.7Hz), 120.7 (d, J = 11.5Hz), 124.8 (2C), 129.0 (d, J = 2.3Hz ),129.64(dd,J1=7.9Hz,J2=2.5Hz,4C),131.9(d,J=8.6Hz),137.0(dd,J1=15.6,J 2=3.3Hz,2C),149.2,159.1,160.5-160.8(2C),161.6,163.1(d,J=9.3Hz),172.4.

[0329] Example 38

[0330] Prepare five-membered heterocyclic amide compounds with the following structures:

[0331]

[0332] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 3-fluorophenylthiazol carboxylic acid;

[0333] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0334] 1 H NMR (CDCl3, 400MHz) δ: 1.05 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 4.07 (d, J = 9.8Hz, 1H), 4.59-4.66 (m, 1H) ,5.72-5.79(m,1H),6.93-7.02(m,4H),7.15-7.28(m,5H),7.42-7.47(m,1H),7.70-7.77(m,3H),8.10(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 18.0, 19.3, 48.3, 56.3, 73.4, 113.7 (d, J=23.6Hz), 115.7 (dd, J1= 29.3Hz, J2=21.3Hz, 4C), 117.7 (d, J=21.4Hz), 122.6 (d, J=3.1Hz), 123.9, 129.6 (d, J=7. 9Hz, 4C), 130.9 (d, J = 8.2Hz), 134.9 (d, J = 8.1Hz), 137.0 (dd, J1 = 15.9, J2 = 3.3Hz, 2C), 15 0.5, 160.4, 160.6 (d, J = 9.8Hz), 163.1 (d, J = 10.5Hz), 164.4, 166.8 (d, J = 3.1Hz), 172.3.

[0335] Example 39

[0336] Prepare five-membered heterocyclic amide compounds with the following structures:

[0337]

[0338] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2,4-difluorophenylthiazol carboxylic acid;

[0339] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0340] 1 H NMR (CDCl3, 400MHz) δ: 1.04 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 4.07 (d, J = 10.1Hz, 1H), 4.61-4.67 (m, 1H), 5.73-5.79(m,1H),6.95-7.02(m,6H),7.22-7.29(m,4H),7.79(d,J=7.8Hz,1H),8.18(s,1H),8.29-8.36(m,1H). 13 CNMR(CDCl3,101MHz)δ:18.1,19.3,48.2,56.3,73.4,104.7(t,J=25.7Hz),112.5(dd,J1=21.7Hz,J2=3.5 Hz), 115.7 (dd, J1=29.6Hz, J2=21.4Hz, 4C), 117.3 (dd, J1=11.8Hz, J2=3.9Hz), 124.5 (d, J=8.9Hz, 2C), 129 .6 (dd, J1=7.9Hz, J2=2.9Hz, 4C), 129.8 (dd, J1=7.9Hz, J2=5.9Hz), 130.3 (dd, J1=9.8Hz, J2=4.0Hz), 137. 0(dd, J1=18.1Hz, J2=3.3Hz), 149.2, 159.2, 160.4, 160.6 (d, J=9.0Hz), 163.1 (d, J=9.6Hz), 165.2, 172.4.

[0341] Example 40

[0342] Prepare five-membered heterocyclic amide compounds with the following structures:

[0343]

[0344] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 3,4-difluorophenylthiazol carboxylic acid;

[0345] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0346] 1H NMR (CDCl3, 400MHz) δ: 1.04 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.2Hz, 3H), 4.07 (d, J = 9.8Hz, 1H), 4.59-4.66 (m, 1H), 5.72-5.79 (m,1H),6.93-7.02(m,4H),7.20-7.30(m,5H),7.66-7.70(m,1H),7.73(d,J=7.8Hz,1H),7.82-7.87(m,1H),8.08(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 18.0, 19.3, 48.2, 56.3, 73.4, 115.7 (dd, J1=30.0Hz, J2=21.2Hz, 5C), 11 8.2(d,J=17.9Hz),123.2(dd,J1=6.7Hz,J2=3.6Hz),123.9,128.6(d,J=26.1Hz),129.6(d,J=7 .9Hz, 4C), 129.9 (dd, J1=6.3Hz, J2=3.9Hz), 136.7 (dd, J1=18.4Hz, J2=3.4Hz, 2C), 150.5, 152. 7(dd,J1=122.9Hz,J2=13.1Hz),160.2,160.6(d,J=10.1Hz),163.1(d,J=10.6Hz),165.8,172.3

[0347] Example 41

[0348] Prepare five-membered heterocyclic amide compounds with the following structures:

[0349]

[0350] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2,3,4-trifluorophenylthiazol carboxylic acid;

[0351] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0352] 1H NMR (CDCl3, 400MHz) δ: 1.03 (d, J = 7.2Hz, 3H), 1.26 (d, J = 6.1Hz, 3H), 4.07 (d, J = 9.8Hz, 1H), 4.59-4.67 (m, 1H), 5.72-5.79 (m,1H),6.93-7.02(m,4H),7.10-7.17(m,1H),7.20-7.29(m,4H),7.76(d,J=7.8Hz,1H),8.03-8.09(m,1H),8.21(s,1H). 13 C NMR (CDCl3, 101MHz) δ: 18.1, 19.3, 48.2, 56.3, 73.5, 113.1 (d, J = 21.2Hz), 115.8 (dd, J1 = 30.5 Hz,J2=21.3Hz,4C),118.5-118.6(m),122.7-122.9(m),125.0(d,J=8.3Hz),129.6(dd,J1=7. 9Hz, J2=2.8Hz, 4C), 136.9 (dd, J1=20.8Hz, J2=3.3Hz, 2C), 139.2 (d, J=15.6Hz), 146.6, 149.5 ,150.9-151.1(m),158.9-159.0(m),160.2,160.6(d,J=9.5Hz),163.1(d,J=10.2Hz),172.4.

[0353] Example 42

[0354] Prepare five-membered heterocyclic amide compounds with the following structures:

[0355]

[0356] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2,3,4,5,-tetrafluorophenylthiazol carboxylic acid;

[0357] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0358] 1H NMR (CDCl3, 400MHz) δ: 1.04 (d, J = 7.1Hz, 3H), 1.26 (d, J = 6.1Hz, 3H), 4.07 (d, J = 10.0Hz, 1H), 4.60-4.67 (m, 1H), 5.73-5.80(m,1H),6.94-7.02(m,4H),7.20-7.29(m,4H),7.72(d,J=7.6Hz,1H),7.94-8.01(m,1H),8.25(s,1H). 13 CNMR(CDCl3,101MHz)δ:18.0,19.3,48.3,56.3,73.5,109.8(d,J=21.2Hz),115.4,1 15.7(dd,J1=30.0Hz,J2=21.3Hz,4C),125.7(d,J=8.7Hz),129.6(d,J=7.9Hz,4C),12 9.8(dd,J1=8.0Hz,J2=2.7Hz,2C),136.9(dd,J1=22.2Hz,J2=3.2Hz),149.6(m,2C),1 57.7-157.8(m,2C),160.0,160.6(d,J=10.3Hz),163.1(d,J=10.8Hz),172.0,172.3.

[0359] Example 43

[0360] Prepare five-membered heterocyclic amide compounds with the following structures:

[0361]

[0362] Five-membered heterocyclic amide compounds were prepared according to the preparation method of Example 1, except that phenylfuran carboxylic acid was replaced with 2,3,4,5,6-pentafluorophenylthiazol carboxylic acid;

[0363] The structure of the obtained product was characterized, and the structural characterization data are as follows:

[0364] 1 H NMR (CDCl3, 400MHz) δ: 1.05 (d, J = 7.2Hz, 3H), 1.25 (d, J = 6.1Hz, 3H), 4.06 (d, J = 9.8Hz, 1H), 4.56-4.63 (m,1H),5.70-5.77(m,1H),6.90-7.01(m,4H),7.18-7.25(m,4H),7.76(d,J=7.8Hz,1H),8.27(s,1H). 13C NMR (CDCl3, 101MHz) δ: 17.9, 19.3, 48.3, 56.3, 73.4, 106.5 (t, J = 14.0Hz), 115.69 (dd, J1=32.0Hz, J2=21.3Hz, 4C), 125.2-125.4 (m, 2C), 129.6 (d, J=7.9Hz, 4C), 129 .7-129.9(m,2C),137.0(dd,J1=13.7Hz,J2=3.4Hz,2C),139.7-139.9(m),146.3, 150.2,153.6-153.7(m),160.1,160.6(d,J=10.7Hz),163.0(d,J=11.2Hz),172.1.

[0365] Test case

[0366] The antibacterial activity of the compounds prepared in Examples 1 to 43 of this invention was tested, and the results are shown below:

[0367] The mycelial growth rate method was used to evaluate the in vitro antibacterial activity. Test strains were activated on PDA plates, including *Magnaporthegrisea* (rice blast fungus), *Rhizoctonia solani* (rice sheath blight), *Rhizoctonia cerealis* (wheat sheath blight), *Sclerotinia scleotiorum* (rapeseed sclerotinia scleotiorum), *Fusarium graminearum* (wheat scab), *Gaeumanomycegraminis* (wheat take-all), *Botrytis cinerea* (tomato gray mold), *Phytophthora infestans* (potato late blight), *Phytophthora capsici* (pepper phytosis), *Alternaria solani* (tomato early blight), *Fusarium fujikuroi* (rice bakanae disease), *Fusarium sulphureum* (potato dry rot), and *Colletotrichum lagenarium* (cucumber anthracnose). The compound was prepared into a series of PDA-containing plates with gradient concentrations of 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10, and 0.05 μM. Test strains were prepared into 5 mm diameter mycelial discs and placed in the center of the drug-containing plates. The plates were incubated at 25°C until the test strains in the blank control plates reached near the edge of the plates. The colony diameter of each drug-containing plate was measured using the cross-crossing method. The inhibition rate of the compound on mycelial growth was calculated, and the inhibition rate on disease was calculated using the following formula:

[0368]

[0369] The concentration of the compound at an inhibition rate of 50%, i.e., the EC50 value, was calculated using SPSS 26.0 statistical software. The results were repeated three times and the average value was taken. The results are shown in Table 1.

[0370] Table 1. Results of the antibacterial activity of compounds D1-D14 prepared in Examples 1-14 against various pathogens.

[0371]

[0372] Note: SS: Sclerotinia sclerotiorum; FG: Fusarium graminearum; PC: Phytophthora capsici; MG: Magnaporthegrisea; BC: Botrytis cinerea; CC: Colletotrichum capsici; GG: Gaeumanomycegraminis.

[0373] Table 2. EC50 of compounds D1-D14 prepared in Examples 1-14 against *Thunb. take-all*. 50 value

[0374]

[0375]

[0376] As shown in Tables 1 and 2, compounds D1-D14 prepared in Examples 1-14 exhibited excellent antibacterial activity against wheat take-all pathogens, with compound D9 showing the best antibacterial activity against wheat take-all pathogens, with an EC50 value of 1.61 μM.

[0377] Table 3. EC5 activity of compounds D15-D24 prepared in Examples 15-24 against *Thunb. take-all*. 50 value

[0378]

[0379] As shown in Table 3, when the L-alanine linker in compound D9 was replaced with other amino acids, the compound lost its antibacterial activity against wheat take-all pathogen (D9 VSD15-20); when the bis(4-fluorophenyl) chiral alcohol in compound D9 was replaced with phenyl chiral alcohols with other substituents, the compound also lost its antibacterial activity against wheat take-all pathogen (D9 VSD21-24).

[0380] Table 4. EC5 activity of compounds D25-D43 prepared in Examples 25-43 against *Thunb. take-all*. 50 value

[0381]

[0382] Table 4 shows that when the phenyl group at the 2-position of thiazole in compound D9 was replaced by methyl (D25) and ethyl (D26), the antifungal activity of the compound against *Tricholoma materia malata* (take-all) decreased significantly. Introducing a strong electron-withdrawing group into the phenyl group at the 2-position of thiazole in compound D9 was more beneficial for inhibiting the growth of *Tricholoma materia malata* (D30 vs. D26). (D9, D27, D28) Among compounds, when a fluorine atom was introduced at the 3- or 4-position of the phenyl group at the 2-position of thiazole in compound D9, the EC50 values ​​of compounds D30 and D38 against *T. take-all* were 0.41 and 0.96 μM, respectively, which were 0.7 and 2.9 times higher than those of compound D9. Therefore, we also introduced fluorine atoms at other sites in the 4-fluorophenyl group at the 2-position of thiazole in compound D30. Excitingly, when both the 3- and 4-positions of the phenyl group at the 2-position of thiazole were substituted with fluorine atoms, the antifungal activity of the compound against *T. take-all* was further enhanced, with an EC50 value of 0.14 μM, which was 10.5 and 1.9 times higher than those of compounds D9 and D30, respectively. When the phenyl group at the 2-position of thiazole in compound D9 was replaced with other heterocycles, it was detrimental to the inhibition of *T. take-all* growth (D9 vs. SD33-36).

[0383] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A five-membered heterocyclic amide compound, characterized in that, It has the structure shown in Formula II: Formula II; R1is hydrogen, an alkyl group having a carbon number of 1 to 5, a benzyl group, or a phenyl group; 2 R1is hydrogen, an alkyl group having a carbon number of 1 to 5, a benzyl group, or a phenyl group; The R 1 It is hydrogen or halogen; The R 3 It is an aliphatic group, furan, thiophene, or pyridine, wherein the aliphatic group is an aliphatic group having 1 to 6 carbon atoms; and an aliphatic group, trifluoromethyl, or halogen-substituted phenyl group, wherein the aliphatic group is an aliphatic group having 1 to 6 carbon atoms.

2. A five-membered heterocyclic amide compound, characterized by, It has any of the following chemical structures: , , , , , , , , 、 , 、 、 , 、 , , , , , , , , , , , , , , , , , , , , , , , , , , or .

3. A process for the preparation of the five-membered heterocyclic amide compound according to claim 1, characterized by, Includes the following steps: Five-membered heterocyclic carboxylic acid esters were hydrolyzed and acidified sequentially to obtain five-membered heterocyclic carboxylic acids; The five-membered heterocyclic carboxylic acid, amino acid ester, organic base catalyst and condensing agent are mixed and subjected to condensation reaction to obtain the five-membered heterocyclic amide compound; The amino acid ester structure has the structure shown in Formula III: Formula III, wherein R 1 , R 2 as defined in Formula II; The five-membered heterocyclic carboxylic ester structure has the structure shown in Formula V: Equation V, where R 3 As defined in Equation II.

4. The preparation method according to claim 3, characterized in that, The organic base catalyst is 4-dimethylaminopyridine, N-hydroxybenzotriazole, or N-hydroxysuccinimide; the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

5. The preparation method according to claim 3, characterized in that, The molar ratio of the five-membered heterocyclic carboxylic acid ester to the amino acid ester is 1.2~1.5:1~1.1; the molar ratio of the amino acid ester, the organic base catalyst, and the condensing agent is 1~1.1:0.2~0.4:1.3~1.

5.

6. The preparation method according to claim 3, characterized in that, The condensation reaction is carried out at a temperature of 0-25°C for 8-12 hours.

7. The application of the five-membered heterocyclic amide compound according to claim 1 or 2 or the five-membered heterocyclic amide compound prepared by the preparation method according to any one of claims 3 to 6 in the prevention and control of agricultural diseases; The agricultural diseases mentioned are one or more of the following: Sclerotinia sclerotiorum var. sclerotiorum, Fusarium head blight, Take-all, Phytophthora indicum, Blast in rice, Gray mold in tomato, Sheath blight in rice, Sheath blight in wheat, Late blight in potato, Early blight in tomato, Oxytoxin blight in rice, Dry rot in potato, and Anthracnose in cucumber.

8. A bactericide characterized by, It includes an active component and a bactericidal component; the molar concentration ratio of the active component and the bactericidal component is 1:1 to 10; the active component is a five-membered heterocyclic amide compound as described in claim 1 or 2 or a five-membered heterocyclic amide compound prepared by the preparation method described in any one of claims 3 to 6.

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