Five-membered heterocyclic amide compound, preparation method and application thereof, and bactericide

Abstract

The invention provides a five-membered heterocyclic amide compound, a preparation method and application thereof, and a bactericide, and relates to the technical field of heterocyclic compound synthesis. The five-membered heterocyclic amide compound provided by the invention has a structure as shown in a formula I and a formula II. The five-membered heterocyclic amide compound provided by the invention comprises heterocyclic carboxylic acid acyl, amino and chiral alcohol fragments, has a certain inhibition effect on various plant pathogenic fungi, has excellent antibacterial activity on gaeumannomyces graminis, and can be used as a bactericide active component or directly used as a bactericide. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of heterocyclic compound synthesis, and specifically relates to a five-membered heterocyclic amide compound, a preparation method and application thereof, and a fungicide. Background Art

[0002] Florylpicoxamid is a pyridineamide 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 (Pest Management Science, 2022, 78, 2657-2666); however, its starting material, 3-hydroxy-4-methoxypyridinecarboxylic acid, is expensive and cumbersome to synthesize (Green Chemistry, 2020, 22, 6047-6054). The complexity of the synthesis process makes it expensive and its application has certain limitations. Therefore, finding cheap and readily available carboxylic acids 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 the present invention is to provide a five-membered heterocyclic amide compound and its preparation method and application, and a fungicide, which can replace 3-hydroxy-4-methoxypyridinecarboxylic acid, has excellent antibacterial activity, and can be used as a fungicide.

[0004] In order to achieve the purpose of the present invention, the present invention provides the following technical solutions:

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

[0006]

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

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

[0009] The R 1 including hydrogen, alkyl, alkyloxy, cyano, carbonyl, amino, nitro, hydroxyl, mercapto or halogen;

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

[0011] Preferably, the five-membered heterocyclic ring comprises aliphatic and / or aromatic substituted furan, thiophene, pyrazole, isoxazoline, isoxazole, oxazole, thiazole, triazole or oxadiazole.

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

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

[0014]

[0015]

[0016]

[0017] The present invention also provides a method for preparing the five-membered heterocyclic amide compound described in the above technical scheme, comprising the following steps:

[0018] The five-membered heterocyclic carboxylic acid ester is sequentially hydrolyzed and acidified to obtain a five-membered heterocyclic carboxylic acid;

[0019] The five-membered heterocyclic carboxylic acid, amino acid ester, organic base catalyst and condensation agent are mixed to carry out 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 Formula II and Formula I;

[0022] The five-membered heterocyclic carboxylate structure has a structure shown in Formula IV or Formula V:

[0023] Where R is Me or Et, As defined in formula I;

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

[0025] Preferably, the organic base catalyst includes 4-dimethylaminopyridine, N-hydroxybenzotriazole or N-hydroxysuccinimide; the condensing agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-tetramethyluronium hexafluorophosphate or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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; the molar ratio of the amino acid ester, the organic base catalyst and the condensation 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 to 25° C. and for a time of 8 to 12 hours.

[0028] The present invention also provides the use of the five-membered heterocyclic amide compound described in the above technical scheme or the five-membered heterocyclic amide compound prepared by the preparation method described in the above technical scheme 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 to the bactericidal component is 1:1-10; the active component is the five-membered heterocyclic amide compound described in the above technical scheme or the five-membered heterocyclic amide compound prepared by the preparation method described in the above technical scheme.

[0030] The present invention provides a five-membered heterocyclic amide compound having the structure shown in Formula I and Formula II: Including aliphatic, aryl substituted furan, thiophene, pyrazole, isoxazoline, isoxazole, oxazole, thiazole, triazole or oxadiazole; said R 2 Including hydrogen, methyl, isopropyl, isobutyl, tert-butyl, benzyl or phenyl; said R 1 Including hydrogen, hydrocarbon, hydrocarbonoxy, cyano, carbonyl, amino, nitro, hydroxyl, mercapto or halogen; said R 3 Including aliphatic, furan, thiophene or pyridine, and aliphatic, cyano, carbonyl, amino, nitro, trifluoromethyl, hydroxyl, mercapto or halogen substituted phenyl. The five-membered heterocyclic amide compound provided by the present invention includes a heterocyclic carboxylic acid acyl group, an amino group and a bifunctional alcohol fragment, and has a certain inhibitory effect on various plant pathogenic fungi (such as rape sclerotinia, wheat fusarium, pepper phytophthora, rice blast, tomato gray mold, pepper anthracnose, rice sheath blight, wheat sheath blight, potato late blight, tomato early blight, rice seedling pathogen, potato dry rot and cucumber anthracnose), among which it has excellent antibacterial activity against wheat take-all pathogen, and can be used as a fungicide active component or directly as a fungicide.

[0031] DETAILED DESCRIPTION

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

[0033]

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

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

[0036] The R 1 including hydrogen, alkyl, alkyloxy, cyano, carbonyl, amino, nitro, hydroxyl, mercapto or halogen;

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

[0038] In the present invention, the five-membered heterocyclic ring preferably includes furan, thiophene, pyrazole, isoxazoline, isoxazole, oxazole, thiazole, triazole or oxadiazole substituted by aliphatic and / or aryl groups; in a specific embodiment of the present invention, the five-membered heterocyclic ring can be aryl-substituted furan, aryl-substituted thiophene, aryl-substituted pyrazole, aryl-substituted isoxazole, aryl-substituted oxazole, aryl-substituted thiazole, aryl-substituted triazole, aryl-substituted isoxazoline, aryl and aliphatic substituted pyrazole, aryl and aliphatic substituted thiazole; the aliphatic group can be methyl or ethyl. In a specific embodiment of the present invention, when the five-membered heterocyclic ring is aryl and aliphatic substituted pyrazole, the aryl and aliphatic groups can be 1 substitution site and 2 substitution sites, 1 substitution site and 3 substitution sites; when the five-membered heterocyclic ring is aryl and aliphatic substituted thiazole; the aryl and aliphatic groups can be 2 substitution sites and 4 substitution sites.

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

[0040] In the present invention, the and R 3 The aliphatic group in is independently 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 can be a methyl group, an ethyl group or a n-propyl group.

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

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

[0043] In a specific embodiment of the present invention, the halogen-substituted phenyl group may 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 may be 1, 2, 3, 4 or 5.

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

[0045]

[0046]

[0047] The present invention also provides a method for preparing the five-membered heterocyclic amide compound described in the above technical scheme, comprising the following steps:

[0048] The five-membered heterocyclic carboxylic acid ester is sequentially hydrolyzed and acidified to obtain a five-membered heterocyclic carboxylic acid;

[0049] The five-membered heterocyclic carboxylic acid, amino acid ester, organic base catalyst and condensation agent are mixed to carry out 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 carboxylate structure has the structure shown in Formula IV and Formula V:

[0053]

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

[0055] The invention hydrolyzes and acidifies a five-membered heterocyclic carboxylic acid ester in sequence to obtain a five-membered heterocyclic carboxylic acid.

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

[0057] Where R is Me or Et, As defined in formula I;

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

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

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

[0061] In the present 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 the present invention, the temperature of the intermolecular cyclization reaction is preferably 70 to 110° C., more preferably 75 to 85° C.; the time is preferably 6 to 8 hours, more preferably 6 to 7 hours.

[0063] In the present invention, the hydrolysis preferably includes: mixing a five-membered heterocyclic carboxylic acid ester, an organic solvent and an alkaline agent for hydrolysis; the organic solvent preferably includes 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 to 3:1, and more preferably 2:1; the alkaline agent is preferably one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide, and more preferably sodium hydroxide; the mass ratio of the five-membered heterocyclic carboxylic acid ester and the alkaline agent is preferably 1 to 1.1:3 to 4, and more preferably 1:3; the temperature of the hydrolysis is preferably room temperature, and the time is preferably 6 to 10 hours, and more preferably 6 to 8 hours; the hydrolysis is preferably carried out under stirring conditions. In the present invention, it is also preferred to remove the solvent after the hydrolysis; the method of removing the solvent is preferably reduced pressure distillation.

[0064] In the present invention, the acidifying agent 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 the present invention, it is preferred to acidify to a pH value of 3-5, more preferably 4-5. The present invention also preferably sequentially performs solid-liquid separation and drying on the obtained acidified product, and the present invention has no particular limitation on the conditions of the solid-liquid separation and drying.

[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 to carry out condensation reaction to obtain the five-membered heterocyclic amide compound.

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

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

[0068] In the present invention, the preparation method of the amino acid ester preferably comprises the following steps:

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

[0070] The intermediate 1, triethylsilane and trifluoroacetic acid are mixed and subjected to reductive deoxidation to obtain a chiral alcohol compound;

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

[0072] The intermediate 2 is mixed with trifluoroacetic acid and deprotected to obtain an amino acid ester.

[0073] In the present invention, L-lactide and phenylmagnesium bromide are mixed and subjected to carbonyl reduction to obtain intermediate 1. In the present invention, the phenylmagnesium bromide preferably includes 4-fluorophenylmagnesium bromide, phenylmagnesium bromide, 4-chlorophenylmagnesium bromide and 4-methoxyphenylmagnesium bromide, and more preferably 4-fluorophenylmagnesium bromide. In the present invention, the molar ratio of L-lactide and phenylmagnesium bromide is preferably 1-1.1:4.2-5, and more preferably 1:4.2-4.7; the L-lactide and phenylmagnesium bromide are preferably subjected to carbonyl reduction under organic solvent conditions; the organic solvent is preferably tetrahydrofuran or diethyl ether, and more preferably tetrahydrofuran.

[0074] In the present invention, the temperature of the carbonyl reduction is preferably 0-30°C, more preferably 25-30°C; the time is preferably 3-6h, more preferably 3-5h; the present invention also preferably performs the carbonyl reduction in sequence of removing solvent, extracting and drying; the method of removing solvent is preferably distillation under reduced pressure; the extraction reagent is preferably ethyl acetate; the drying preferably comprises: drying the organic phase after extraction with anhydrous sodium sulfate and distilling under reduced pressure in sequence.

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

[0076] In the present invention, the temperature of the reductive deoxidation is preferably 0 to 30°C, more preferably 25 to 30°C; the time is preferably 3 to 6 hours, more preferably 3 to 5 hours. The present invention also preferably extracts, dries and purifies the reductive deoxidation product in sequence; the reagent used for the extraction is preferably dichloromethane; the drying preferably includes: drying the washed organic phase in sequence with anhydrous sodium sulfate; the purification method is preferably column chromatography; the filler of the column chromatography is preferably silica gel, the eluent is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 3 to 5:1, more preferably 3 to 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 condensation agent to carry out a condensation reaction to obtain an 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, 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 Amine hydrochloride, O-benzotriazole-tetramethyluronium hexafluorophosphate or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, more preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); the molar ratio of the chiral alcohol compound to the N-Boc protected amino acid is preferably 1-1.3:1.2-2, more preferably 1. to 1.1:1.2-1.5; the molar ratio of the N-Boc protected amino acid, the organic base catalyst and the condensation agent is preferably 1.2 to 1.5:0.2 to 0.5:1.3 to 1.8, more preferably 1.2 to 1.3:0.2 to 0.4:1.3 to 1.5.

[0078] In the present invention, the temperature of the condensation reaction is preferably 0-30°C, more preferably 25-30°C; the time is preferably 3-6h, more preferably 3-5h; 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. The present invention also preferably washes, dries and concentrates the condensation product in sequence; the reagent used for washing is preferably sodium chloride solution; the drying preferably includes: drying the washed organic phase in sequence with anhydrous sodium sulfate.

[0079] The intermediate 2 is mixed with trifluoroacetic acid, and the protecting groups are removed to obtain an amino acid ester. In the present invention, the molar ratio of the intermediate 2 to trifluoroacetic acid is preferably 1 to 1.2:15 to 18, and more preferably 1:15 to 17; in the present invention, the temperature of the deprotection is preferably 0 to 30°C, and more preferably 25 to 30°C; the time is preferably 4 to 8 hours, and more preferably 4 to 6 hours; the present invention also preferably extracts, dries, and purifies the deprotection product in sequence; the extraction, drying, and purification are preferably consistent with the above extraction, drying, and purification.

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

[0081] In the present invention, the molar ratio of the five-membered heterocyclic carboxylic acid ester to 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 condensation agent is preferably 1-1.1:0.2-0.4:1.3-1.5, more preferably 1:0.2:1.3.

[0082] In the present invention, the temperature of the condensation reaction is preferably 0-30°C, more preferably 25-30°C; the time is preferably 8-12h, more preferably 8-10h; 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. The present invention also preferably washes, dries and purifies the condensation product in sequence; the reagent used for washing is preferably sodium chloride solution; the drying preferably includes: drying the washed organic phase with anhydrous sodium sulfate and removing the solvent under reduced pressure in sequence; the purification is preferably consistent with the above purification.

[0083] The present invention also provides the use of the five-membered heterocyclic amide compound described in the above technical scheme or the five-membered heterocyclic amide compound prepared by the preparation method described in the above technical scheme in the prevention and control of agricultural diseases.

[0084] In the present invention, the agricultural diseases preferably include one or more of rapeseed sclerotinia, wheat fusarium rust, wheat take-all, pepper phytophthora, rice blast, tomato gray mold, pepper anthracnose, rice sheath blight, wheat sheath blight, potato infestation, tomato early blight, rice seedling rust, potato dry rot and cucumber anthracnose.

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

[0086] In the present invention, the bactericidal component preferably includes Flufenoxadiazam, Flumetylsulforim, Fluoxytioconazole, Metarylpicoxamid, Cyclobutrifluram, FlubeneteramFluoxapiprolin, Florylpicoxamid, Ipflufenoquin, Metyltetraprole, Pyridachlometyl, Pyrapropoyne, Aminopyrifen, Inpyrfluxam, Isoflucypram, Fenpicoxamid, Dichlobentiazox, Ipfentrifluconazole, Quinofum One or more of elin, Pydiflumetofen, Pyraziflumid, Picarbutrazox, Mandestrobin, Oxathiapiprolin, Enoxastrobin, Fenaminstrobin, Flufenoxystrobin, Isofetamid, Tolprocarb, Benzovindiflupyr, Fenpyrazamine, Pyriofenone, Dimethomorph, Azoxystrobin, Pyraclostrobin, Prothioconazole, Trifloxystrobin, Cyperconazole, Mancozeb, Fluepiconazole, Tebuconazole, Boscalid, Metalaxyl, Picoxystrobin, Difenoconazole, Propiconazole, Thiophanate, Thiamid, Isothiazide, Ningnanmycin, Propiramide, Flumorph and Dimethomorph.

[0087] In the present invention, the dosage form of the fungicide preferably includes emulsifiable concentrate, aqueous emulsion, microemulsion, wettable powder, water dispersible granule or suspension.

[0088] In order to further illustrate the present invention, the five-membered heterocyclic amide compounds provided by the present invention, their preparation methods and applications, and fungicides are described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

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

[0090] Synthesis of intermediate amino acid esters:

[0091]

[0092] The synthetic route of the intermediate thiazolecarboxylic acid ethyl ester:

[0093]

[0094] The synthetic routes of the five-membered heterocyclic amide compounds described in Examples 1 to 14 are:

[0095]

[0096] The synthetic routes of the five-membered heterocyclic amide compounds described in Examples 15 to 20 are:

[0097]

[0098] The synthetic routes of the five-membered heterocyclic amide compounds described in Examples 21 to 24 are:

[0099]

[0100] The synthetic routes of the five-membered heterocyclic amide compounds described in Examples 25 to 43 are:

[0101]

[0102] Example 1

[0103] Prepare a five-membered heterocyclic amide compound with the following structure:

[0104]

[0105] A Shrek bottle containing L-lactide (2.0 g, 13.9 mmol, 1.0 equiv.) and a stirring bar was evacuated and filled with N 2Repeat 3 times, add tetrahydrofuran (28 mL), slowly add 4-fluorophenylmagnesium bromide (40 mL, 58.3 mmol, 4.2 equiv., 2 mol / LinEt 2 O), after the addition was completed, the reaction system was transferred to room temperature for carbonyl reduction for 3 h. The reaction was complete as detected by TLC. The reaction system was transferred to 0 °C and saturated NH 4 The Cl solution was evaporated until bubbling stopped, tetrahydrofuran was removed under reduced pressure, and the residue was extracted with ethyl acetate (30 mL × 2). The obtained organic layer was washed with anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure to obtain intermediate 1;

[0106] The intermediate 1 and triethylsilane (Et 3 SiH, 16.3 mL, 102.2 mmol, 10.0 equiv.) was dissolved in dichloromethane (80 mL), 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 completed, it was transferred to room temperature for 3 h. The reaction was complete as detected by TLC. The reaction system was transferred to 0 ° C and the pH was adjusted to 7 with 40% sodium hydroxide solution. The dichloromethane extraction (30 mL) was used to obtain the organic layer. 2 SO 4 The residue was dried, concentrated, and purified by silica gel (200-300 m) column chromatography (eluent: V 石油醚 / V 乙酸乙酯 =8:1), to obtain 2.1 g of intermediate chiral alcohol A3 (colorless liquid, 61% yield in 2 steps);

[0107] The 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 above 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 complete as determined by TLC. The mixture was washed with a saturated sodium chloride solution (15 mL×2), and the organic phase was dried over anhydrous sodium sulfate to obtain intermediate 2.

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

[0109] Phenylfurancarboxylate (1.8 g, 8.9 mmol, 1.0 equiv.) was dissolved in 60 mL of methanol and 30 mL of aqueous solution. The above system was 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 completed by TLC, methanol was evaporated under reduced pressure. Water was added to dilute the obtained system. The pH of the system was adjusted to 4 with dilute hydrochloric acid (40%). The precipitated solid was filtered and dried to obtain 1.4 g of phenylfurancarboxylic acid (white solid, 81% yield).

[0110] The above phenylfurancarboxylic 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. Then, the above system was 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 completed as determined by TLC. The mixture was washed with saturated sodium chloride solution (15 mL×2). The obtained organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel (200-300 m) column chromatography (eluent: petroleum ether and ethyl acetate in a volume ratio of 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] 1 HNMR (CDCl 3,500MHz)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=3.7Hz,1H ),6.82(d,J=7.6Hz,1H),6.96-7.02(m,4H),7.18-7.19(m,1H),7.22-7.28(m,4H),7.34-7.38(m,1H),7.42-7.45(m,2H),7.71-7.74(m,2H). 13 C NMR (CDCl 3 ,101MHz)δ:18.2,19.3,48.0,56.3,73.5,107.4,115.8(dd,J 1 =27.8Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0115]

[0116] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiophenecarboxylic acid;

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

[0118] 1 H NMR (CDCl 3 ,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,1H),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).13 CNMR (CDCl 3 ,101MHz)δ:18.2,19.3,48.6,56.3,73.5,115.8(dd,J 1 =28.0Hz,J 2 =21.4Hz,4C),123.5,126.2(2C),128.7,129.2(2C),129.4,129.6(dd,J 1 =8.0Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0121]

[0122] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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 (CDCl 3 ,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 (CDCl 3 ,126MHz)δ:13.5,17.7,19.3,48.3,56.3,73.5,109.1,115.7(dd,J 1 =40.3Hz,J 2=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 a five-membered heterocyclic amide compound with the following structure:

[0127]

[0128] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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 (CDCl 3 ,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 (CDCl 3 ,126MHz)δ:12.5,17.9,19.2,47.8,56.2,73.1,107.5,115.6(dd,J 1 =38.1Hz,J 2 =21.4Hz,4C),125.2(2C),128.6,129.3(2C),129.6(dd,J 1 =7.8Hz,J 2 =3.7Hz,4C),137.0(dd,J 1 =9.3Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0133]

[0134] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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] 1 H NMR (CDCl 3 ,400MHz)δ:0.96(dd,J 1 =5.6Hz,J 2 =4.4Hz,3H),1.24(dd,J 1 =5.2Hz,J 2 =2.8Hz,3H),3.18-3.24(m,1H),3.57-3.65(m,1H),4.04(dd,J 1 =8.0Hz,J 2 =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 (CDCl 3 ,101MHz)δ:17.8(2C),19.3,41.1,48.3,56.3,73.4,85.0,115.8(dd,J 1 =28.6Hz,J 2 =17.2Hz,4C),126.1(2C),128.8,129.0(2C),129.6(dd,J 1 =6.3Hz,J 2 =1.9Hz,4C),136.8(d,J=2.9Hz),137.0(dd,J 1 =4.9Hz,J 2 =2.7Hz),139.6(d,J=1.7Hz),153.1,159.1(d,J=3.0Hz),111.8(dd,J 1 =197.6Hz,J 2 =10.9Hz),171.7(d,J=4.8Hz).

[0137] Example 6

[0138] Prepare a five-membered heterocyclic amide compound with the following structure:

[0139]

[0140] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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 (CDCl 3 ,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). 13 C NMR (CDCl 3 ,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,J 1 =20.0Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0145]

[0146] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 3-phenyl-isoxazole-5-carboxylic acid;

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

[0148] 1H NMR (CDCl 3 ,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),5.73-5. 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 (CDCl 3 ,126MHz)δ:17.8,19.2,48.4,56.3,73.7,105.6,115.8(dd,J 1 =35.7Hz,J 2 =21.3Hz,4C),127.0(2C),128.0,129.2(2C),129.5(dd,J 1 =9.7Hz,J 2 =7.9Hz,4C),130.7,136.8(dd,J 1 =35.3Hz,J 2 =3.4Hz, 2C), 155.2, 160.8 (d, J = 15.0Hz), 162.8 (d, J = 15.4Hz), 163.3 (d, J = 23.6Hz, 2C), 171.6.

[0149] Example 8

[0150] Prepare a five-membered heterocyclic amide compound with the following structure:

[0151]

[0152] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2-phenyl-oxazole-4-carboxylic acid;

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

[0154] 1 H NMR (CDCl 3,400MHz)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,1 H),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 (CDCl 3 ,101MHz)δ:18.0,19.3,47.9,56.3,73.4,115.7(dd,J 1 =29.1Hz,J 2 =21.3Hz,4C),126.7,126.8(2C),129.0(2C),129.6(dd,J 1 =8.0Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0157]

[0158] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2-phenyl-thiazole-4-carboxylic acid;

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

[0160] 1 H NMR (CDCl 3 ,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,1 H),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,J 1 =36.5Hz,J 2 =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,J 1 =21.7Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0163]

[0164] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-phenyl-thiazole-2-carboxylic acid;

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

[0166] 1 H NMR (CDCl 3 ,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). 13 C NMR (CDCl 3 ,101MHz)δ:18.0,19.3,48.5,56.3,73.5,115.8(dd,J 1 =28.0Hz,J 2 =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,J 1 =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] Embodiment 11

[0168] Prepare a five-membered heterocyclic amide compound with the following structure:

[0169]

[0170] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-methyl-2-phenyl-thiazole-5-carboxylic acid;

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

[0172] 1 H NMR (CDCl 3 ,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,1H),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 (CDCl 3 ,101MHz)δ:17.7,18.2,19.3,48.8,56.3,73.7,115.8(dd,J 1 =29.4Hz,J 2 =21.4Hz,4C),125.5,126.9(2C),129.2(2C),129.6(dd,J 1 =7.9Hz,J 2 =2.5Hz,4C),131.0,132.9,136.9(dd,J 1 =24.9Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0175]

[0176] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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 (CDCl 3 ,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 (CDCl 3 ,126MHz)δ:18.0,19.2,48.1,56.2,73.4,115.7(dd,J 1 =36.9Hz,J 2 =21.3Hz,4C),120.4(2C),129.0,129.6(d,J=7.9Hz,4C),129.9(2C),136.6,136.9(dd,J 1 =24.3Hz,J 2 =3.3Hz, 2C), 141.7, 157.3, 158.2, 160.8 (d, J = 12.0Hz), 162.7 (d, J = 12.2Hz), 172.1.

[0179] Embodiment 13

[0180] Prepare a five-membered heterocyclic amide compound with the following structure:

[0181]

[0182] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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] 1 H NMR (CDCl 3 ,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),5.71-5. 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 (CDCl 3 ,101MHz)δ:17.6,19.2,48.8,56.3,74.0,115.8(dd,J 1 =28.1Hz,J 2 =21.4Hz,4C),125.8,127.7(2C),129.1(2C),129.6(dd,J 1 =8.0Hz,J 2 =2.7Hz,4C),131.9,136.8(dd,J 1 =30.6Hz,J 2 =3.3Hz, 2C), 152.4, 160.6 (d, J = 9.7Hz), 163.1 (d, J = 10.1Hz), 168.2, 168.9, 171.3.

[0185] Embodiment 14

[0186] Prepare a five-membered heterocyclic amide compound with the following structure:

[0187]

[0188] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 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 (CDCl 3,400MHz)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). 13 CNMR (CDCl 3 ,101MHz)δ:17.7,19.3,48.8,56.4,73.8,115.8(dd,J 1 =30.0Hz,J 2 =21.3Hz,4C),123.0,127.7(2C),127.9(d,J=16.4Hz,2C),129.4(2C),129.6(dd,J 1 =7.9Hz,J 2 =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] Embodiment 15

[0192] Prepare a five-membered heterocyclic amide compound with the following structure:

[0193]

[0194] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and L-alanine ester was replaced by glycine ester;

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

[0196] 1 H NMR (CDCl 3 ,400MHz)δ:1.16(d,J=6.2Hz,3H),3.85(dd,J 1 =18.3Hz,J 2 =5.4Hz,1H),3.96(d,J=9.2Hz,1H),4.09(dd,J 1 =18.2Hz,J 2=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 (CDCl 3 ,101MHz)δ:19.2,41.3,55.7,73.6,115.6(dd,J 1 =26.8Hz,J 2 =21.3Hz,4C),123.5,126.7(2C),129.1(2C),129.7(d,J=8.1Hz,4C),130.8,132.7,136.7(dd,J 1 =16.9Hz,J 2 =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 a five-membered heterocyclic amide compound with the following structure:

[0199]

[0200] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and L-alanine ester was replaced by L-valine ester;

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

[0202] 1 H NMR (CDCl 3 ,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,J 1 =9.4Hz,J 2 =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 (CDCl 3 ,101MHz)δ:17.2,19.3,19.4,31.3,56.1,57.3,73.6,115.7(dd,J 1 =24.6Hz,J 2 =21.3Hz,4C),123.5,126.8(2C),129.2(2C),129.6(dd,J 1 =8.0Hz,J 2 =5.7Hz,4C),130.8,132.8,137.0(dd,J 1 =6.3Hz,J 2 =3.2Hz, 2C), 150.3, 160.6 (d, J = 5.2Hz), 161.0, 163.0 (d, J = 5.6Hz), 168.3, 171.2.

[0203] Embodiment 17

[0204] Prepare a five-membered heterocyclic amide compound with the following structure:

[0205]

[0206] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and L-alanine ester was replaced by L-isoleucine ester;

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

[0208] 1 H NMR (CDCl 3 ,400MHz)δ:0.63(t,J=7.3Hz,3H),0.69(d,J=6.9Hz,3H),0.79-0.89(m,1H),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,J 1 =9.2Hz,J 2 =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 (CDCl 3,101MHz)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),129.6( 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] Embodiment 18

[0210] Prepare a five-membered heterocyclic amide compound with the following structure:

[0211]

[0212] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and L-alanine ester was replaced by L-tert-leucine ester;

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

[0214] 1 H NMR (CDCl 3 ,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 (CDCl 3 ,101MHz)δ:19.4,26.4(3C),34.7,55.9,60.6,73.4,115.6(dd,J 1 =24.7Hz,J 2 =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,J 1 =6.6Hz,J 2=3.2Hz, 2C), 150.3, 160.5 (d, J = 6.4Hz), 160.6, 162.9 (d, J = 6.8Hz), 168.1, 170.5.

[0215] Embodiment 19

[0216] Prepare a five-membered heterocyclic amide compound with the following structure:

[0217]

[0218] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and L-alanine ester was replaced by L-phenylalanine ester;

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

[0220] 1 H NMR (CDCl 3 ,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). 13 C NMR (CDCl 3 ,101MHz)δ:19.3,37.7,53.1,55.9,74.0,115.7(dd,J 1 =21.4Hz,J 2 =18.5Hz,4C),123.4,126.7(2C),127.2,128.6(2C),129.1(2C),129.3(2C),129.8(dd,J 1 =15.8Hz,J 2 =7.9Hz,4C),130.8,132.8,135.7,136.9(dd,J 1 =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] Embodiment 20

[0222] Prepare a five-membered heterocyclic amide compound with the following structure:

[0223]

[0224] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and L-alanine ester was replaced by L-phenylglycine ester;

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

[0226] 1 H NMR (CDCl 3 ,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,2 H),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). 13 C NMR (CDCl 3 ,101MHz)δ:19.4,55.7,56.8,73.9,115.5(dd,J 1 =34.5Hz,J 2 =21.3Hz,4C),123.7,126.8(2C),127.2(2C),128.5,129.0(2C),129.2(2C),129.5(dd,J 1 =11.9Hz,J 2 =7.9Hz,4C),130.8,132.8,135.9,136.56(dd,J 1 =70.1Hz,J 2 =3.3Hz,2C),150.0,160.4(d,J=16.0Hz,2C),162.8(d,J=17.7Hz),168.4,170.1.

[0227] Embodiment 21

[0228] Prepare a five-membered heterocyclic amide compound with the following structure:

[0229]

[0230] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and 4-fluorophenylmagnesium bromide was replaced by phenylmagnesium bromide;

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

[0232] 1 H NMR (CDCl 3 ,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 (CDCl 3 ,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] Embodiment 22

[0234] Prepare a five-membered heterocyclic amide compound with the following structure:

[0235]

[0236] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and 4-fluorophenylmagnesium bromide was replaced by 4-methoxyphenylmagnesium bromide;

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

[0238] 1 H NMR (CDCl 3,400MHz)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 (CDCl 3 ,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] Embodiment 23

[0240] Prepare a five-membered heterocyclic amide compound with the following structure:

[0241]

[0242] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and 4-fluorophenylmagnesium bromide was replaced by 4-chlorophenylmagnesium bromide;

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

[0244] 1 H NMR (CDCl 3 ,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,1 H),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 (CDCl 3,101MHz)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] Embodiment 24

[0246] Prepare a five-membered heterocyclic amide compound with the following structure:

[0247]

[0248] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by phenylthiazolecarboxylic acid, and 4-fluorophenylmagnesium bromide was replaced by 3-fluorophenylmagnesium bromide;

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

[0250] 1 H NMR (CDCl 3 ,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). 13 C NMR (CDCl 3 ,101MHz)δ:17.9,19.2,48.2,57.2,72.9,114.1(dd,J 1 =27.6Hz,J 2 =21.0Hz,2C),115.2(dd,J 1 =21.6Hz,J 2 =2.0Hz,2C),123.4,123.8-123.9(m,2C),126.8(2C),129.1(2C),130.4(dd,J 1 =27.1Hz,J 2 =8.2Hz,2C),130.7,132.8,143.2(dd,J 1 =28.1Hz,J 2=6.9Hz, 2C), 150.3, 160.5, 161.7 (d, J = 8.4Hz), 164.2 (d, J = 8.9Hz), 168.3, 172.3.

[0251] Embodiment 25

[0252] Prepare a five-membered heterocyclic amide compound with the following structure:

[0253]

[0254] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by methylthiazolecarboxylic acid;

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

[0256] 1 H NMR (CDCl 3 ,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),4.56-4.6 2(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 (CDCl 3 ,126MHz)δ:18.0,19.2,19.3,48.1,56.2,73.2,115.7(dd,J 1 =39.3Hz,J 2 =21.3Hz,4C),123.5,129.6(dd,J 1 =8.0Hz,J 2 =2.2Hz,4C),137.0(dd,J 1 =18.7Hz,J 2 =3.4Hz, 2C), 149.1, 160.6, 160.8 (d, J = 12.3Hz), 162.8 (d, J = 12.6Hz), 166.2, 172.3.

[0257] Embodiment 26

[0258] Prepare a five-membered heterocyclic amide compound with the following structure:

[0259]

[0260] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by ethylthiazolecarboxylic acid;

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

[0262] 1 H NMR (CDCl 3 ,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,J 1 =15.3Hz,J 2 =7.7Hz,2H),4.05(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 (CDCl 3 ,126MHz)δ:14.1,18.0,19.3,27.0,48.1,56.3,73.3,115.7(dd,J 1 =39.0Hz,J 2 =21.2Hz,4C),123.0,129.7(dd,J 1 =7.4Hz,J 2 =2.0Hz,4C),137.0(dd,J 1 =19.0Hz,J 2 =3.3Hz,2C),149.0,160.7,160.8(d,J=12.2Hz),162.8(d,J=12.6Hz),172.4,173.1.

[0263] Embodiment 27

[0264] Prepare a five-membered heterocyclic amide compound with the following structure:

[0265]

[0266] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-methylphenylthiazolecarboxylic acid;

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

[0268] 1 H 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 (CDCl 3 ,126MHz)δ:18.0,19.3,21.6,48.2,56.3,73.3,115.7(dd,J 1 =36.0Hz,J 2 =21.3Hz,4C),123.0,126.7(2C),129.6(d,J=7.9Hz,4C),129.8(2C),130.2,137.0(dd,J 1 =19.4Hz,J 2 =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] Embodiment 28

[0270] Prepare a five-membered heterocyclic amide compound with the following structure:

[0271]

[0272] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-methoxyphenylthiazolecarboxylic acid;

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

[0274] 1 H NMR (CDCl 3 ,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).13 C NMR (CDCl 3 ,126MHz)δ:18.0,19.3,48.1,55.6,56.2,73.3,114.4(2C),115.7(dd,J 1 =35.9,J 2 =21.2Hz,4C),122.6,125.8,128.3(2C),129.6(d,J=7.8Hz,4C),136.9(dd,J 1 =19.3Hz,J 2 =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] Embodiment 29

[0276] Prepare a five-membered heterocyclic amide compound with the following structure:

[0277]

[0278] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-trifluoromethylphenylthiazolecarboxylic acid;

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

[0280] 1 H NMR (CDCl 3 ,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,1 H),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 (CDCl 3 ,126MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J 1 =37.8Hz,J 2 =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,J 2 =32.6Hz),135.9,136.9(dd,J 1 =27.8Hz,J 2 =3.4Hz,2C),150.7(2C),160.3,160.8(d,J=13.0Hz),162.8(d,J=13.5Hz),166.5,172.3.

[0281] Embodiment 30

[0282] Prepare a five-membered heterocyclic amide compound with the following structure:

[0283]

[0284] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-fluorophenylthiazolecarboxylic acid;

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

[0286] 1 H NMR (CDCl 3 ,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,1 H),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 (CDCl 3 ,126MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J 1 =37.2Hz,J 2 =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, J 1 =24.0Hz,J 2 =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] Embodiment 31

[0288] Prepare a five-membered heterocyclic amide compound with the following structure:

[0289]

[0290] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-chlorophenylthiazolecarboxylic acid;

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

[0292] 1 H NMR (CDCl 3 ,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,1 H),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 (CDCl 3 ,126MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J 1 =37.4,J 2 =21.3Hz,4C),123.7,128.0(2C),129.4(2C),129.6(d,J=8.0Hz,4C),131.3,136.8-1 37.0(m,3C),150.4,160.4,160.8(d,J=12.6Hz),162.8(d,J=13.1Hz),167.0,172.4.

[0293] Embodiment 32

[0294] Prepare a five-membered heterocyclic amide compound with the following structure:

[0295]

[0296] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-bromophenylthiazolecarboxylic acid;

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

[0298] 1 H NMR (CDCl 3 ,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,1 H),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). 13 C NMR (CDCl 3 ,126MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J 1 =37.5Hz,J 2 =21.3Hz,4C),123.7,125.2,128.2(2C),129.6(d,J=7.9Hz,4C),131.7,132.4(2C),136.9(dd,J 1 =25.2,J 2 =3.2Hz, 2C), 150.4, 160.4, 160.8 (d, J = 12.8Hz), 162.8 (d, J = 13.0Hz), 167.1, 172.4.

[0299] Embodiment 33

[0300] Prepare a five-membered heterocyclic amide compound with the following structure:

[0301]

[0302] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2-furanthiazolecarboxylic acid;

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

[0304] 1 H NMR (CDCl 3 ,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,J 1 =3.5Hz,J 2=1.7Hz,1H),6.93-7.01(m,4H),7.07(dd,J 1 =3.5Hz,J 2 =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 (CDCl 3 ,126MHz)δ:18.0,19.3,48.2,56.3,73.3,110.0,112.5,115.7(dd,J 1 =37.0Hz,J 2 =21.3Hz,4C),122.8,129.6(d,J=7.8Hz,4C),137.0(dd,J 1 =20.3Hz,J 2 =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] Embodiment 34

[0306] Prepare a five-membered heterocyclic amide compound with the following structure:

[0307]

[0308] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2-thiophenethiazolecarboxylic acid;

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

[0310] 1 H NMR (CDCl 3 ,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,J 1 =5.1Hz,J 2 =3.7Hz,1H),7.21-7.28(m,4H),7.46(dd,J 1 =5.0Hz,J 2 =1.3Hz,1H),7.55(dd,J 1 =3.7,J2 =1.3Hz,1H),7.69(d,J=7.8Hz,1H),7.99(s,1H). 13 C NMR (CDCl 3 ,126MHz)δ:17.9,19.3,48.3,56.3,73.3,115.7(dd,J 1 =36.6Hz,J 2 =21.3Hz,4C),122.9,127.7,128.1,128.7,129.6(d,J=7.9Hz,4C),136.3,137.0(dd,J 1 =19.6,J 2 =3.3Hz, 2C), 149.8, 160.3, 160.8 (d, J = 12.6Hz), 161.9, 162.8 (d, J = 12.9Hz), 172.2.

[0311] Embodiment 35

[0312] Prepare a five-membered heterocyclic amide compound with the following structure:

[0313]

[0314] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2-pyridinethiazolecarboxylic acid;

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

[0316] 1 H NMR (CDCl 3 ,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,4 H),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 (CDCl 3 ,126MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J 1 =36.4Hz,J 2=21.3Hz,4C),120.0,125.2,125.9,129.6(d,J=7.9Hz,4C),136.9(dd,J 1 =24.9,J 2 =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] Embodiment 36

[0318] Prepare a five-membered heterocyclic amide compound with the following structure:

[0319]

[0320] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 4-pyridinethiazolecarboxylic acid;

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

[0322] 1 H NMR (CDCl 3 ,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,1 H),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). 13 C NMR (CDCl 3 ,101MHz)δ:18.0,19.3,48.3,56.3,73.5,115.7(dd,J 1 =30.7Hz,J 2 =21.3Hz,4C),120.5(2C),125.1,129.6(d,J=7.9Hz,4C),136.9(dd,J 1 =20.9Hz,J 2 =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] Embodiment 37

[0324] Prepare a five-membered heterocyclic amide compound with the following structure:

[0325]

[0326] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2-fluorophenylthiazolecarboxylic acid;

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

[0328] 1 H NMR (CDCl 3 ,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,1 H),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 (CDCl 3 ,101MHz)δ:18.1,19.3,48.2,56.3,73.4,115.7(dd,J 1 =29.0Hz,J 2 =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,J 1 =7.9Hz,J 2 =2.5Hz,4C),131.9(d,J=8.6Hz),137.0(dd,J 1 =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] Embodiment 38

[0330] Prepare a five-membered heterocyclic amide compound with the following structure:

[0331]

[0332] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 3-fluorophenylthiazolecarboxylic acid;

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

[0334] 1 H NMR (CDCl 3 ,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 (CDCl 3 ,101MHz)δ:18.0,19.3,48.3,56.3,73.4,113.7(d,J=23.6Hz),115.7(dd,J 1 =29.3Hz,J 2 =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, J 1 =15.9,J 2 =3.3Hz, 2C), 150.5, 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] Embodiment 39

[0336] Prepare a five-membered heterocyclic amide compound with the following structure:

[0337]

[0338] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2,4-difluorophenylthiazolecarboxylic 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 (CDCl 3 ,101MHz)δ:18.1,19.3,48.2,56.3,73.4,104.7(t,J=25.7Hz),112.5(dd,J 1 =21.7Hz,J 2 =3.5Hz),115.7(dd,J 1 =29.6Hz,J 2 =21.4Hz,4C),117.3(dd,J 1 =11.8Hz,J 2 =3.9Hz),124.5(d,J=8.9Hz,2C),129.6(dd,J 1 =7.9Hz,J 2 =2.9Hz,4C),129.8(dd,J 1 =7.9Hz,J 2 =5.9Hz),130.3(dd,J 1 =9.8Hz,J 2 =4.0Hz),137.0(dd,J 1 =18.1Hz,J 2 =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] Embodiment 40

[0342] Prepare a five-membered heterocyclic amide compound with the following structure:

[0343]

[0344] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 3,4-difluorophenylthiazolecarboxylic acid;

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

[0346] 1 H NMR (CDCl 3 ,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,1 H),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 (CDCl 3 ,101MHz)δ:18.0,19.3,48.2,56.3,73.4,115.7(dd,J 1 =30.0Hz,J 2 =21.2Hz,5C),118.2(d,J=17.9Hz),123.2(dd,J 1 =6.7Hz,J 2 =3.6Hz),123.9,128.6(d,J=26.1Hz),129.6(d,J=7.9Hz,4C),129.9(dd,J 1 =6.3Hz,J 2 =3.9Hz),136.7(dd,J 1 =18.4Hz,J 2 =3.4Hz,2C),150.5,152.7(dd,J 1 =122.9Hz,J 2 =13.1Hz),160.2,160.6(d,J=10.1Hz),163.1(d,J=10.6Hz),165.8,172.3

[0347] Embodiment 41

[0348] Prepare a five-membered heterocyclic amide compound with the following structure:

[0349]

[0350] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2,3,4-trifluorophenylthiazolecarboxylic acid;

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

[0352] 1 H NMR (CDCl 3,400MHz)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,1 H),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 (CDCl 3 ,101MHz)δ:18.1,19.3,48.2,56.3,73.5,113.1(d,J=21.2Hz),115.8(dd,J 1 =30.5Hz,J 2 =21.3Hz,4C),118.5-118.6(m),122.7-122.9(m),125.0(d,J=8.3Hz),129.6(dd,J 1 =7.9Hz,J 2 =2.8Hz,4C),136.9(dd,J 1 =20.8Hz,J 2 =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] Embodiment 42

[0354] Prepare a five-membered heterocyclic amide compound with the following structure:

[0355]

[0356] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2,3,4,5-tetrafluorophenylthiazolecarboxylic acid;

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

[0358] 1 H NMR (CDCl 3,400MHz)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 (CDCl 3 ,101MHz)δ:18.0,19.3,48.3,56.3,73.5,109.8(d,J=21.2Hz),115.4,115.7(dd,J 1 =30.0Hz,J 2 =21.3Hz,4C),125.7(d,J=8.7Hz),129.6(d,J=7.9Hz,4C),129.8(dd,J 1 =8.0Hz,J 2 =2.7Hz,2C),136.9(dd,J 1 =22.2Hz,J 2 =3.2Hz),149.6(m,2C),157.7-157.8(m,2C),160.0,160.6(d,J=10.3Hz),163.1(d,J=10.8Hz),172.0,172.3.

[0359] Embodiment 43

[0360] Prepare a five-membered heterocyclic amide compound with the following structure:

[0361]

[0362] A five-membered heterocyclic amide compound was prepared by referring to the preparation method of Example 1, except that phenylfurancarboxylic acid was replaced by 2,3,4,5,6-pentafluorophenylthiazolecarboxylic acid;

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

[0364] 1 H NMR (CDCl 3,400MHz)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,1 H),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). 13 C NMR (CDCl 3 ,101MHz)δ:17.9,19.3,48.3,56.3,73.4,106.5(t,J=14.0Hz),115.69(dd,J 1 =32.0Hz,J 2 =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,J 1 =13.7Hz,J 2 =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 the present invention was tested, and the results are as follows:

[0367] The mycelium growth rate method was used to evaluate the in vitro antibacterial activity, and the test strains were selected for activation on PDA plates, including rice blast pathogen (Magnaporthe grisea), rice sheath blight pathogen (Rhizoctonia solani), wheat sheath blight pathogen (Rhizoctonia cerealis), rapeseed sclerotinia (sclerotinia scleotiorum), wheat fusarium (Fusarium graminearum), wheat take-all pathogen (Gaeumanomycegraminis), tomato gray mold pathogen (Botrytis cinerea), potato late blight pathogen (Phytophthora infestans), pepper blight pathogen (Phytophthora capsici), tomato early blight pathogen (Alternaria solani), rice seedling pathogen (Fusarium fujikuroi), potato dry rot pathogen (Fusarium sulphureum), and cucumber anthracnose pathogen (Colletotrichum lagenarium). The compound was prepared into a series of PDA drug-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. The test strain was made into a 5 mm diameter bacterial cake and placed in the center of the drug-containing culture dish. The test strain in the blank control dish was cultured at 25°C until it grew close to the edge of the culture dish. The colony diameter of each drug-containing plate was measured by the cross method, and the inhibition rate of the compound on mycelial growth was calculated. The inhibition rate on the disease was calculated according to the following formula:

[0368]

[0369] The statistical software SPSS26.0 was used to calculate the concentration of the compound when the inhibition rate was 50%, that is, the EC50 value. The results were repeated 3 times and the average value was taken. The results are shown in Table 1.

[0370] Table 1 Antibacterial activity results 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 EC of compounds D1-D14 prepared in Examples 1-14 against Psoralea tritici 50 value

[0374]

[0375]

[0376] It can be seen from Table 1 and Table 2 that compounds D1-D14 prepared in Examples 1 to 14 exhibited excellent antibacterial ability against take-all pathogen, among which compound D9 had the best antibacterial activity against take-all pathogen, with an EC50 value of 1.61 μM.

[0377] Table 3 EC of compounds D15-D24 prepared in Examples 15-24 against Psoralea tritici 50 value

[0378]

[0379] As shown in Table 3, when the L-alanine linker in compound D9 is replaced with other amino acids, the compound loses its antibacterial activity against wheat take-all pathogen (D9 VSD15-20); when the di-4-fluorophenyl chiral alcohol in compound D9 is replaced with phenyl chiral alcohol with other substituents, the compound also loses its antibacterial activity against wheat take-all pathogen (D9VSD21-24).

[0380] Table 4 EC of compounds D25-D43 prepared in Examples 25-43 against Psoralea tritici 50 value

[0381]

[0382] As shown in Table 4, when the phenyl group at the 2-position of thiazole in compound D9 was replaced by methyl (D25) and ethyl (D26), the antibacterial activity of the compound against wheat take-all pathogen was significantly reduced; the introduction of a strong electron-withdrawing group into the phenyl group at the 2-position of thiazole in compound D9 was more beneficial to the compound in inhibiting the growth of wheat take-all pathogen (D30 VS D9, D27, D28), when fluorine atoms were introduced into the 3rd or 4th position of the phenyl group at the 2nd position of thiazole in compound D9, the EC50 values ​​of compounds D30 and D38 against Psoralea tritici were 0.41 and 0.96 μM, respectively, which were 0.7 and 2.9 times higher than those of compound D9, respectively; therefore, we also introduced fluorine atoms into other positions of the 4-fluorophenyl group at the 2nd position of thiazole in compound D30. It is exciting that when the 3rd and 4th positions of the phenyl group at the 2nd position of thiazole in the compound were simultaneously replaced by fluorine atoms, the antibacterial activity of the compound against Psoralea tritici was further improved, 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 2nd position of thiazole in compound D9 was replaced by other heterocyclic rings, it was not conducive to the compound's inhibition of the growth of Psoralea tritici (D9 VSD33-36).

[0383] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, 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 I and Formula II: Among them, the is a five-membered heterocyclic ring; The R 2 Including hydrogen, alkyl with 1 to 5 carbon atoms, benzyl or phenyl; The R 1 including hydrogen, alkyl, alkyloxy, cyano, carbonyl, amino, nitro, hydroxyl, mercapto or halogen; The R 3 These include aliphatic, furan, thiophene or pyridine, as well as aliphatic, cyano, carbonyl, amino, nitro, trifluoromethyl, hydroxyl, mercapto or halogen-substituted phenyl.

2. The five-membered heterocyclic amide compound according to claim 1, characterized in that: The five-membered heterocyclic ring includes furan, thiophene, pyrazole, isoxazoline, isoxazole, oxazole, thiazole, triazole or oxadiazole substituted with an aliphatic group and / or an aromatic group.

3. The five-membered heterocyclic amide compound according to claim 1 or 2, characterized in that: Said and R 3 The aliphatic groups in are independently aliphatic groups having 1 to 6 carbon atoms.

4. The five-membered heterocyclic amide compound according to claim 1, characterized in that: Has any of the following chemical structures:

5. The method for preparing the five-membered heterocyclic amide compound according to any one of claims 1 to 4, characterized in that: The following steps are involved: The five-membered heterocyclic carboxylic acid ester is sequentially hydrolyzed and acidified to obtain a five-membered heterocyclic carboxylic acid; The five-membered heterocyclic carboxylic acid, amino acid ester, organic base catalyst and condensation agent are mixed to carry out condensation reaction to obtain the five-membered heterocyclic amide compound; The amino acid ester structure has the structure shown in Formula III: Where R 1 , R 2 As defined in Formula II and Formula I; The five-membered heterocyclic carboxylate structure has a structure shown in Formula IV or Formula V: Where R is Me or Et, As defined in formula I; Where R 3 As defined in Formula II.

6. The preparation method according to claim 5, characterized in that: The organic base catalyst includes 4-dimethylaminopyridine, N-hydroxybenzotriazole or N-hydroxysuccinimide; the condensing agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-tetramethyluronium hexafluorophosphate or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

7. The preparation method according to claim 5, 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 condensation agent is 1-1.1:0.2-0.4:1.3-1.

5.

8. The preparation method according to claim 5, characterized in that: The temperature of the condensation reaction is 0-25° C. and the time is 8-12 hours.

9. Use of the five-membered heterocyclic amide compound according to any one of claims 1 to 4 or the five-membered heterocyclic amide compound prepared by the preparation method according to any one of claims 5 to 8 in the prevention and control of agricultural diseases.

10. A bactericide, characterized in that: It comprises an active component and a bactericidal component; the molar concentration ratio of the active component to the bactericidal component is 1:1-10; the active component is the five-membered heterocyclic amide compound described in any one of claims 1 to 4 or the five-membered heterocyclic amide compound prepared by the preparation method described in any one of claims 5 to 8.

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