An N-aryl (2-carboxamidobenzoyl) amino amide compound, a preparation method and use thereof

Abstract

This invention discloses an N-aryl(2-acylaminobenzoyl)aminoamide compound, its preparation method, and its uses. This compound is generated by reacting Boc-amino acids and aromatic amines in dichloromethane under the action of EDCI, DMAP, and triethylamine. The N-Boc-aminobenzoyl compound is then acid-hydrolyzed with trifluoroacetic acid to obtain an aminobenzoyl compound. Next, the aminobenzoyl compound is reacted with indomethacin anhydride in acetonitrile under the action of potassium carbonate to generate a diamide compound. Finally, the diamide compound is reacted with an acyl halide in the action of triethylamine to obtain the N-aryl(2-acylaminobenzoyl)aminoamide compound. The raw materials used in the synthesis are inexpensive and readily available, and the synthesis method is simple. This compound exhibits good inhibitory activity against crop pathogens, particularly against Sclerotinia sclerotinia, Phytophthora blight, Fusarium head blight, rice blast fungus, gray mold, sheath blight, and rot fungus.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an N-aryl(2-acylaminobenzoyl)aminoamide compound, its preparation method, and its uses. Background Technology

[0002] Polyamides are a hot topic in pharmaceutical and pesticide research, attracting significant attention due to their broad bioactivity and diverse structures, and finding wide application in medicine, pesticides, and fine chemicals. In pesticides, they serve as highly effective insecticides, fungicides, and herbicides, playing a crucial role in ensuring healthy crop growth and increasing agricultural yields. For example, in 2021, YilmazÖ et al. synthesized and tested the antibacterial activity of diamides, clearly identifying (1S,2S)-4,5-dimethyl-N... 1，N 2 -Diphenylcyclohexyl-4-ene-1,2-dicarboxamide (Va) exhibits antibacterial activity against Staphylococcus aureus, while (1S,2S)-4,5-dimethyl-N 1，N 2 -bis(2-(trifluoromethyl)phenylcyclohexyl-4-ene-1,2-dicarboxamide (Ve) exhibited antibacterial activity against *E. aerogenes* strains. In 2017, Ramachandran et al. reported a potent, cellularly active, and orally bioavailable diamide compound that can be used as a CSF1R inhibitor. It exerts antitumor, immune-enhancing, angiogenesis-inhibiting, and tumor metastasis-inhibiting effects by inhibiting the recruitment and function of tumor-associated macrophages (TAMs), showing potential applications in cancer treatment. In 2020, Luo Chunyan et al. synthesized a novel cyclopropyl-containing isophthalamide compound, which showed 100% insecticidal activity against *Plutella xylostella* at a test concentration of 1 mg / L and 100% insecticidal activity against *Taxodium difficile* at a test concentration of 5 mg / L.

[0003] However, with the increasing demand for practical applications and the ever-increasing requirements for compound performance, although there are many reports on polyamide compounds, reports on triamide compounds are still relatively rare. Therefore, this invention focuses on the synthesis of triamide compounds and their antibacterial activity research, in order to provide new ideas. Summary of the Invention

[0004] This invention provides an N-aryl(2-acylaminobenzoyl)aminoamide compound, its preparation method, and its uses. The preparation method of this type of compound is simple, the raw materials are readily available, and it has good antibacterial activity against crop pathogens, especially against Fusarium head blight, Phytophthora blight, rice blast fungus, sclerotinia sclerotinia, gray mold, sheath blight, and rot fungus, which effectively ensures the yield of crops.

[0005] To solve the above-mentioned technical problems, the basic concept of the technical solution adopted by the present invention is as follows:

[0006] In one aspect, this invention provides an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (I).

[0007] ;

[0008] In the formula, R1 is one of hydrogen atom, alkyl, alkoxy or halogen atom; R2 is one of hydrogen atom, alkyl or aryl; R3 is hydrogen atom or halogen atom; and R4 is one of hydrocarbon group, aryl, heterocyclic group or substituted aryl.

[0009] Preferably, R1 is either methoxy or methyl; R2 is either hydrogen or methyl; R3 is a hydrogen atom; and R4 is either aryl, heterocyclic, or substituted aryl.

[0010] Preferably, the compound having the general structural formula (Ⅰ) is specifically selected from one or more of the following compounds:

[0011] N-(4-Tolyl)-(2-(4-tert-butylbenzoamide)benzoyl)glycine:

[0012] ;

[0013] N-(3-methoxyphenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine:

[0014] ;

[0015] N-(4-Bromophenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine:

[0016] ;

[0017] N-(4-Tolyl)-(2-(2-Naphthoylamino)benzoyl)glycine:

[0018] ;

[0019] N-(4-Tolyl)-(2-(4-bromobenzoylamino)benzoyl)glycine:

[0020] ;

[0021] N-(4-Tolyl)-(2-(2-methyloxaloylamino)benzoyl)glycine:

[0022] ;

[0023] N-(4-Tolyl)-(2-(1-Adamantanecarbamoylamino)benzoyl)glycine:

[0024] ;

[0025] N-(4-Tolyl)-(2-Bromoacetamido)benzoyl)glycine:

[0026] ;

[0027] N-(4-Tolyl)-(2-(2-phenoxypropionylamino)benzoyl)glycine:

[0028] .

[0029] Another aspect of the present invention provides a method for synthesizing N-aryl(2-acylaminobenzoyl)aminoamide compounds having the general structural formula (Ⅰ), as shown in the appendix. Figure 1-2 The illustration shows that N-aryl(2-acylaminobenzoyl)aminoamide compounds with general structural formula (I) are prepared by reacting a diamide compound with an acyl halide under the action of triethylamine.

[0030] .

[0031] The method specifically includes the following steps:

[0032] S1) A Boc-amino acid with structural formula (V) is reacted with an aromatic amine with structural formula (VIII) in dichloromethane under the action of EDCI, DMAP, and triethylamine to obtain an N-Boc-aminoacyl aromatic amine compound with structural formula (Ⅳ).

[0033] ;

[0034] S2) Reaction of N-Boc-amino acyl amine compounds with structural formula (Ⅳ) in dichloromethane under the action of trifluoroacetic acid yields amino acyl amine compounds with structural formula (Ⅲ).

[0035] ;

[0036] S3) An N-amino amide with structural formula (Ⅲ) is reacted with indigo anhydride with structural formula (Ⅶ) in acetonitrile under the action of potassium carbonate to obtain a diamide compound with structural formula (Ⅱ):

[0037]

[0038] S4) A diamide compound having general structural formula (II) is reacted with an acyl halide (IV) in the presence of triethylamine to prepare an N-aryl(2-acylaminobenzoyl)aminoamide compound having general structural formula (I):

[0039] ;

[0040] In the formula, R1 is one of hydrogen atom, alkyl, alkoxy or halogen atom; R2 is one of hydrogen atom, alkyl or aryl; R3 is hydrogen atom or halogen atom; and R4 is one of hydrocarbon group, aryl, heterocyclic group or substituted aryl.

[0041] Preferably, R1 is either methoxy or methyl; R2 is either hydrogen or methyl; R3 is a hydrogen atom; and R4 is either aryl, heterocyclic, or substituted aryl.

[0042] Preferably, step S1) specifically involves: weighing a Boc-amino acid of general formula (V), adding EDCI, DMAP, and triethylamine to a 250 mL round-bottom flask, and dissolving it in 50 mL of dichloromethane. The aromatic amine of general formula (VIII) dissolved in dichloromethane is then slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, the reaction yields an N-Boc-aminoacyl aromatic amine compound of formula (Ⅳ).

[0043] In this invention, in step S1), the preferred reaction molar ratio of the addition of Boc-amino acid having general structural formula (V), aromatic amine having general structural formula (VIII), EDCI, DMAP and triethylamine is 1.5:1:1.5:0.15:1.5, the preferred temperature is 25°C, and the preferred reaction time is 3 hours.

[0044] Preferably, step S2) specifically involves: weighing N-Boc-aminoarylamine of general formula (Ⅳ) and adding it to a 100 mL round-bottom flask. Trifluoroacetic acid dissolved in dichloromethane is slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, the reaction yields an aminoarylamine compound with general formula (Ⅲ).

[0045] In this invention, in step S2), the preferred reaction molar ratio of the addition of N-Boc-aminoacylamine having general formula (Ⅳ) and trifluoroacetic acid is 1:5, the preferred temperature is 0°C, and the preferred reaction time is 6h.

[0046] Preferably, step S3) specifically involves: weighing N-amino amide of general formula (Ⅲ), indigo anhydride of general formula (Ⅶ), and K2CO3 into a 100 mL round-bottom flask, adding 30 mL of acetonitrile to dissolve them, and heating the reaction solution to react and obtain a diamide compound of formula (Ⅱ).

[0047] In this invention, in step S3), the preferred reaction molar ratio of the addition of N-aminomethylarylamine having general structural formula (Ⅲ) and indigo anhydride having general structural formula (Ⅶ) and potassium carbonate is 1.2:1:1.2, the preferred temperature is 50°C, and the preferred reaction time is 18h.

[0048] Preferably, step S4) is as follows: Weigh 1 mmol of II and 1.2 mmol of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Add 1.2 mmol of an acyl halide with general structural formula (VI) dissolved in dichloromethane slowly through a constant-pressure dropping funnel in an ice-water bath, and allow the reaction to proceed for 3 hours after the addition is complete. After the reaction is complete, add an appropriate amount of deionized water and a small amount of Na₂CO₃ / NaHCO₃ solution and stir continuously for at least 30 minutes to quench the reaction system. Then, remove the organic solvent under reduced pressure. The resulting solid and aqueous solution are extracted with hot EA to separate the organic phase, and the aqueous phase is extracted with EA (30 mL × 3 times). The combined organic phases are retained, dried with anhydrous Na₂SO₄, and the solvent is removed by rotary evaporation under reduced pressure to obtain an N-aryl(2-acylaminobenzoyl)aminoamide compound with general structural formula (I).

[0049] In this invention, the purpose of adding triethylamine is to remove acidic components (such as hydrochloric acid, hydrobromic acid, etc.) that may be present in the reaction.

[0050] Preferably, the solvent is an organic solvent, and more preferably dichloromethane.

[0051] Preferably, the molar ratio of the added acyl halide to the key reactant (such as II-1) is 1:1.2-1.8, preferably 1:1.2, and more preferably 1:1.5.

[0052] Preferably, the molar ratio of triethylamine to key reactant (such as II-1) is 1:1.2-1.8, preferably 1:1.2, and more preferably 1:1.5.

[0053] Preferably, the reaction solvent is preferred in different steps. For the synthesis step of compound I, dichloromethane is used as the main solvent; for the synthesis step of compound II, acetonitrile is used as the main solvent.

[0054] Preferably, the acyl halide mixture is added to a mixed solution containing reactants (such as II-1) such that the molar ratio of reactants to acyl halides is 1:1.2-1.8, preferably 1:1.2-1.8, for example 1:1.5.

[0055] In this invention, the reaction temperature for obtaining the acyl halide mixture is 0-10 °C, preferably 0-5 °C, more preferably 0-2 °C; for example, an ice-water bath temperature range. The reaction time is 1-7 h, preferably 2-5 h, more preferably 3-4 h.

[0056] In this invention, the separation is achieved by filtration and extraction; preferably, the separation is achieved by repeated extraction with water and ethyl acetate.

[0057] Preferably, the present invention further includes drying the extracted organic phase, preferably using anhydrous Na2SO4.

[0058] Preferably, the present invention further includes a solvent removal process for the dried product, preferably using rotary evaporation under reduced pressure.

[0059] In another aspect, the present invention provides the use of an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (I), or an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (I) prepared by the above method, for the purpose of using the N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (I) for antibacterial purposes on crops or for the preparation of antibacterial drugs for crops; specifically, for the inhibition of one or more pathogens selected from Fusarium head blight, rice blast fungus, Phytophthora blight, Sclerotinia sclerotinia, gray mold, sheath blight, and rot fungus, or for the preparation of antibacterial drugs.

[0060] Preferably, the N-aryl(2-acylaminobenzoyl)aminoamide compounds having the general structural formula (V) are used to inhibit *Rhizoctonia solani*, *Pseudomonas rotundus*, *Sclerotinia sclerotiorum*, or to prepare antibacterial drugs.

[0061] By adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art.

[0062] 1. The N-aryl(2-acylaminobenzoyl)aminoamide compound with general structural formula (Ⅰ) of the present invention is a novel compound, and the compound has very good antibacterial activity; in particular, it has a significant inhibitory effect on the pathogens of Fusarium head blight, Phytophthora, rice blast fungus, sclerotinia, gray mold, and sheath blight.

[0063] 2. The method for preparing N-aryl(2-acylaminobenzoyl)aminoamide compounds with general structural formula (Ⅰ) provided by the present invention has the advantages of inexpensive and readily available raw materials, simple synthesis method, high yield, and easy separation and purification of products.

[0064] The specific embodiments of the present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0065] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention, but do not constitute an undue limitation of the invention. Obviously, the drawings described below are merely some embodiments, and those skilled in the art can obtain other drawings based on these drawings without creative effort. In the drawings:

[0066] Figure 1 This is a structural diagram of an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general formula (Ⅰ) described in this invention.

[0067] Figure 2 This is a synthetic circuit diagram of N-aryl(2-acylaminobenzoyl)aminoamide compounds having the general structural formula (Ⅰ) according to the present invention.

[0068] It should be noted that these accompanying drawings and textual descriptions are not intended to limit the scope of the invention in any way, but rather to illustrate the concept of the invention to those skilled in the art by referring to specific embodiments. Detailed Implementation

[0069] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below with reference to the accompanying drawings. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0070] The structural formula of the final product of this invention is shown in Table 1 below.

[0071] Table 1. Structural Formulas of End Products

[0072]

[0073] The chemical reagents used in the various embodiments of this invention are sourced from the following sources:

[0074] Shanghai Mairui Chemical Technology Co., Ltd.: Boc-glycine (CAS: 4530-20-5), indomethacin (CAS: 118-48-9), DMAP (CAS: 122-58-3), anhydrous sodium sulfate (CAS: 7757-82-6), acetonitrile (CAS: 75-05-8), EDCI (CAS: 25952-53-8), trifluoroacetic acid (CAS: 76-05-1), anhydrous potassium carbonate (CAS: 584-08-7), 3 -Methoxyaniline (CAS: 536-90-3), p-Toluidine (CAS: 106-59-0), 4-tert-butylbenzoyl chloride (CAS: 1710-98-1), 4-Nitrobenzoyl chloride (CAS: 122-04-3), 4-Methylbenzoyl chloride (CAS: 874-60-2), 2-Naphthoyl chloride (CAS: 2243-83-6), 4-Bromobenzoyl chloride (CAS: 586-75-4), Benzoyl chloride (CAS: 98-88-4)

[0075] Xilong Chemical Co., Ltd.: Triethylamine (CAS: 121-44-8).

[0076] Guangdong Guanghua Technology Co., Ltd.: Ethyl acetate (CAS: 141-78-6), dichloromethane (CAS: 75-09-2).

[0077] Hunan Huihong Reagent Co., Ltd.: Anhydrous ethanol (CAS: 64-17-5).

[0078] Example A1

[0079] Synthesis of N-(4-tolyl)-(2-(4-tert-butylbenzoamide)benzoyl)glycine:

[0080] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0081] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0082] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0083] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Slowly add 0.236 g (1.2 mmol) of 4-tert-butylbenzoyl chloride dissolved in dichloromethane through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine.

[0084] 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.07 (s, 1H), 9.28 (t, J =5.9 Hz, 1H), 8.68 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.84 (d, J =8.4 Hz, 2H), 7.59 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.49 (d, J =8.4 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 4.11 (d, J =5.8 Hz, 2H), 2.24 (s, 3H), 1.27 (s, 9H).

[0085] 13 C NMR (101 MHz, DMSO-d6) δ 170.29, 168.00, 165.45, 155.88, 140.37,137.35, 132.83, 131.25, 130.07, 127.82, 127.15, 126.63, 126.20, 123.69,121.22, 120.19, 44.30, 35.61, 31.75, 21.38.

[0086] Example A2

[0087] Synthesis of N-(3-methoxyphenyl)-(2-(4-tert-butylbenzoamide)benzoyl)glycine:

[0088] Weigh out m-methoxyaniline (1.23 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) and add them to a 500 mL round-bottom flask. Dissolve the flask in 50 mL dichloromethane and place it in an ice-water bath. Weigh out triethylamine (1.52 g, 15 mmol) and dissolve it in dichloromethane. Add the triethylamine slowly dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the flask to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate the solution by column chromatography to obtain a white solid 3-methoxyphenyl(N-Boc)glycine.

[0089] 1.40 g (5 mmol) of 3-methoxyphenyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction, followed by desolvation under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The combined organic phases were dried over anhydrous Na₂SO₄, and the solvent was removed by rotary evaporation under reduced pressure. The dried product yielded a white solid, 3-methoxyphenylglycine.

[0090] Weigh 0.649 g (3.6 mmol) of 3-methoxyphenylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 3-methoxyphenyl(2-amino-benzoyl)glycine.

[0091] Weigh 0.299 g (1 mmol) of 3-methoxyphenyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Slowly add 0.236 g (1.2 mmol) of 4-tert-butylbenzoyl chloride dissolved in dichloromethane through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid N-(3-methoxyphenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine.

[0092] 1H NMR (400 MHz, Chloroform-d) δ 11.89 (s, 1H), 8.71 (d, J = 8.3 Hz,1H), 8.47 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.69 (t, J = 5.4 Hz, 1H), 7.61(d, J = 7.7 Hz, 1H), 7.46 (d, J = 8.5 Hz, 3H), 7.24 (s, 1H), 7.13 (t, J = 8.1Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.64 (dd, J =8.3, 2.4 Hz, 1H), 4.23 (d, J = 5.3 Hz, 2H), 3.71 (s, 3H), 1.32 (s, 9H).

[0093] 13 C NMR (101 MHz, Chloroform-d) δ 170.07, 167.00, 165.82, 160.13,155.57, 139.96, 138.47, 133.25, 131.85, 130.55, 129.75, 127.21, 125.77,123.06, 121.74, 119.61, 112.21, 110.42, 105.90, 55.26, 44.84, 34.99, 31.15.

[0094] Example A3

[0095] Synthesis of N-(4-bromophenyl)-(2-(4-tert-butylbenzoamide)benzoyl)glycine:

[0096] Weigh p-bromoaniline (1.70 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-bromophenyl(N-Boc)glycine.

[0097] 1.64 g (5 mmol) of 4-bromophenyl(N-Boc)glycamide was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction, followed by desolvation under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-bromophenylglycamide.

[0098] Weigh 0.820 g (3.6 mmol) of 4-bromophenylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-bromophenyl(2-amino-benzoyl)glycine.

[0099] Weigh 0.347 g (1 mmol) of 4-bromophenyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Slowly add 0.236 g (1.2 mmol) of 4-tert-butylbenzoyl chloride dissolved in dichloromethane through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-bromophenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine.

[0100] 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.26 (s, 1H), 9.28 (t, J =5.9 Hz, 1H), 8.66 (dd, J = 8.4, 1.1 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.82(d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.9 Hz, 3H), 7.49 (d, J = 8.5 Hz, 4H), 7.23(t, J = 7.6 Hz, 1H), 4.11 (d, J = 5.7 Hz, 2H), 1.28 (s, 9H).

[0101] 13 C NMR (101 MHz, DMSO-d6) δ 169.86, 168.02, 165.00, 155.45, 139.84,138.71, 132.88, 132.35, 132.06, 128.74, 127.33, 126.16, 123.26, 121.62,120.74, 120.69, 115.40, 43.93, 35.16, 31.31.

[0102] Example A4

[0103] Synthesis of N-(4-tolyl)-(2-(2-naphthoylamino)benzoyl)glycine:

[0104] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0105] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0106] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0107] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Add 0.228 g (1.2 mmol) of 2-naphthoyl chloride dissolved in dichloromethane slowly through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-(2-naphthoylamino)benzoyl)glycine.

[0108] 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.05 (s, 1H), 9.27 (t, J =5.9 Hz, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.07 – 7.89(m, 6H), 7.63 (d, J = 4.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.2Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 4.12 (d, J = 5.7Hz, 2H), 2.24 (s, 3H).

[0109] 13 C NMR (101 MHz, DMSO-d6) δ 170.25, 168.06, 165.70, 140.16, 137.30,135.37, 133.15, 132.92, 130.11, 130.02, 129.59, 129.30, 129.06, 128.79,128.65, 127.96, 124.35, 124.04, 121.80, 121.54, 120.28, 44.30, 21.40.

[0110] Example A5

[0111] Synthesis of N-(4-tolyl)-(2-(4-bromobenzoylamino)benzoyl)glycine:

[0112] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0113] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0114] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0115] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Add 0.264 g (1.2 mmol) of 4-bromobenzoyl chloride dissolved in dichloromethane slowly through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-(4-bromobenzoylamino)benzoyl)glycine.

[0116] 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 10.02 (s, 1H), 9.24 (t, J =5.9 Hz, 1H), 8.61 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 6.4 Hz, 1H), 7.83 (d, J =8.6 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.49 (d, J =8.3 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 4.11 (d, J =5.8 Hz, 2H), 2.25 (s, 3H).

[0117] 13 C NMR (101 MHz, DMSO-d6) δ 170.13, 167.95, 164.60, 139.99, 137.25,134.62, 133.30, 133.20, 132.85, 130.06, 129.97, 129.23, 126.79, 124.07,121.54, 121.43, 120.22, 44.20, 21.38.

[0118] Example A6

[0119] Synthesis of N-(4-tolyl)-(2-(2-methyloxalamido)benzoyl)glycine:

[0120] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0121] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0122] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0123] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Add 0.147 g (1.2 mmol) of methyl oxaloyl chloride dissolved in dichloromethane slowly through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the resulting solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-(2-methyloxaloylamino)benzoyl)glycine.

[0124] 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.02 (s, 1H), 9.19 (t, J =5.9 Hz, 1H), 8.53 (dd, J = 8.4, 1.2 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (ddd, J = 8.5, 7.4, 1.5 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.30 (t, J =7.6 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 4.08 (d, J = 6.0 Hz, 2H), 3.83 (s,3H), 2.25 (s, 3H).

[0125] 13 C NMR (101 MHz, DMSO-d6) δ 168.75, 167.46, 161.06, 154.60, 138.18,136.83, 133.00, 132.69, 129.61, 128.97, 124.50, 121.03, 120.71, 119.69,53.97, 43.50, 20.91.

[0126] Example A7

[0127] Synthesis of N-(4-tolyl)-(2-(1-adamantanecarbamoylamino)benzoyl)glycine:

[0128] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0129] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0130] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0131] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Slowly add 0.238 g (1.2 mmol) of 1-adamantaneformyl chloride dissolved in dichloromethane through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-(1-adamantaneformylamino)benzoyl)glycine.

[0132] 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.99 (s, 1H), 9.10 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 9.1 Hz, 3H), 7.13 (dd, J = 23.3, 7.9 Hz, 3H), 4.05 (d, J = 5.8 Hz, 2H), 2.25 (s, 3H), 1.97(s, 3H), 1.85 (s, 6H), 1.65 (d, J = 8.7 Hz, 6H).

[0133] 13 C NMR (101 MHz, DMSO-d6) δ 176.36, 169.62, 167.50, 139.83, 136.85,132.65, 132.52, 129.54, 128.56, 122.79, 120.87, 120.70, 119.70, 43.75, 41.81,39.06, 36.41, 28.01, 20.90.

[0134] Example A8

[0135] Synthesis of N-(4-tolyl)-(2-bromoacetamido)benzoyl)glycine:

[0136] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0137] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0138] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0139] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Slowly add 0.240 g (1.2 mmol) of bromoacetyl bromide dissolved in dichloromethane through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-bromoacetylamino)benzoyl)glycine.

[0140] 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 10.02 (s, 1H), 9.07 (t, J =5.9 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.57 – 7.52(m, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.2Hz, 2H), 4.19 (s, 2H), 4.08 (d, J = 5.9 Hz, 2H), 2.25 (s, 3H).

[0141] 13 C NMR (101 MHz, DMSO-d6) δ 168.78, 167.73, 165.42, 138.37, 136.78,132.76, 132.39, 129.62, 128.71, 123.98, 122.44, 121.07, 119.70, 43.52, 31.06,20.91.

[0142] Example A9

[0143] Synthesis of N-(4-tolyl)-(2-(2-phenoxypropionylamino)benzoyl)glycine:

[0144] Weigh p-toluidine (1.07 g, 10 mmol), Boc-glycine (2.63 g, 15 mmol), EDCI (2.87 g, 1.5 mmol), and DMAP (0.18 g, 0.15 mmol) into a 500 mL round-bottom flask, dissolve in 50 mL of dichloromethane, and place in an ice-water bath. Weigh triethylamine (1.52 g, 15 mmol) and dissolve in dichloromethane. Slowly add the solution dropwise through a constant-pressure dropping funnel in the ice-water bath. After the addition is complete, transfer to room temperature and react for 4 h. After the reaction is complete, remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid, 4-tolyl(N-Boc)glycine.

[0145] 1.32 g (5 mmol) of 4-tolyl(N-Boc)glycine was weighed and added to a 250 mL round-bottom flask. 2.85 g (25 mmol) of trifluoroacetic acid was weighed and dissolved in three times its own volume of dichloromethane. This solution was slowly added dropwise through a constant-pressure dropping funnel in an ice-water bath. After the addition was complete, the mixture was transferred to room temperature and reacted for 6 h. After the reaction was complete, 10% Na₂CO₃ solution was added dropwise to quench the reaction mixture. The solvent was removed under reduced pressure. The resulting solid-liquid mixture was extracted with EA and water to separate the organic phase. The aqueous phase was extracted with EA (30 mL × 3 times). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation under reduced pressure, and the product was dried to obtain a white solid, 4-tolylglycine.

[0146] Weigh 0.591 g (3.6 mmol) of 4-tolylglycine, 0.489 g (3 mmol) of indomethacin, and 0.500 g (3.6 mmol) of K₂CO₃ into a 100 mL round-bottom flask, and dissolve in 30 mL of acetonitrile. Transfer to a 50 °C oil bath and react for 18 h. After the reaction is complete, remove the solvent under reduced pressure, extract the solid with water (50 mL × 2 times), and extract the aqueous phase with EA (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na₂SO₄, and remove the solvent by rotary evaporation under reduced pressure. Separate by column chromatography to obtain a yellowish-white solid, 4-tolyl(2-amino-benzoyl)glycine.

[0147] Weigh 0.283 g (1 mmol) of 4-tolyl(2-aminobenzoyl)glycine and 0.122 g (1.2 mmol) of triethylamine into a 100 mL round-bottom flask, and dissolve them in 20 mL of dichloromethane. Slowly add 0.240 g (1.2 mmol) of 2-phenoxypropionyl chloride dissolved in dichloromethane through a constant-pressure dropping funnel in an ice-water bath. After the addition is complete, transfer the mixture to room temperature and react for 4 h. After the reaction is complete, cool, remove solvent under reduced pressure, and extract the obtained solid with EA and water to separate the organic phase. Extract the aqueous phase with EA (30 mL × 3 times). Combine the organic phases and dry them with anhydrous Na₂SO₄. Remove the solvent by rotary evaporation under reduced pressure. Column chromatography yields a white solid, N-(4-tolyl)-(2-(2-phenoxypropionylamino)benzoyl)glycine.

[0148] 1H NMR (400 MHz, Chloroform-d) δ 11.77 (s, 1H), 8.81 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 7.80 (t, J = 5.3 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.45(t, J = 7.9 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.18 (t, J = 7.9 Hz, 2H), 7.06(d, J = 8.2 Hz, 2H), 6.98 (dd, J = 11.3, 8.1 Hz, 3H), 6.90 (t, J = 7.3 Hz,1H), 4.73 (q, J = 6.7 Hz, 1H), 4.10 (d, J = 18.2 Hz, 2H), 2.30 (s, 3H), 1.61 (d, J = 6.7 Hz, 3H).

[0149] 13 C NMR (101 MHz, Chloroform-d) δ 171.35, 169.56, 167.20, 157.12,138.56, 134.92, 134.33, 132.99, 129.67, 129.51, 127.41, 123.50, 122.08,121.55, 120.47, 120.06, 115.83, 44.78, 20.92, 18.74.

[0150] Crop antibacterial activity test

[0151] Using an in vitro method, N-(4-tolyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine, N-(3-methoxyphenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine, N-(4-bromophenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine, N-(4-tolyl)-(2-(2-naphthoylamino)benzoyl)glycine, and N-(4-tolyl)-(2- The antibacterial activity of (4-bromobenzoylamino)benzoyl)glycamide, N-(4-tolyl)-(2-(2-methyloxalamido)benzoyl)glycamide, N-(4-tolyl)-(2-(1-adamantanecarbamoylamino)benzoyl)glycamide, N-(4-tolyl)-(2-bromoacetamido)benzoyl)glycamide, and N-(4-tolyl)-(2-(2-phenoxypropionylamino)benzoyl)glycamide was tested.

[0152] Using *Fusarium graminearum*, *Phytophthora infestans*, *Sclerotinia sclerotinia*, *Botrytis cinerea*, *Sheath blight*, and *Pseudomonas rotundus* as test materials for fungicidal activity testing, the test agents were dissolved in acetone and then diluted to 500 g / mL with 200 g / mL Sorporl-144 emulsifier. Under aseptic conditions, 1 mL of the compound solution was pipetted into a sterilized Petri dish, followed by 9 mL of sterile PDA culture medium. The mixture was then stirred to prepare the appropriate concentration of drug-containing plates. Under aseptic conditions, mycelial cakes were cut from the edge of the colony using a 4 mm diameter sterile punch. After the culture medium solidified, the mycelial cakes were inoculated into the center of the drug-containing plate using an inoculator and incubated at a suitable temperature. A blank control was prepared without the added agent. Each treatment was incubated in an incubator at 24 ± 1℃. After 72 hours, the colony diameter was observed and measured. The diameter of each colony was measured vertically once using the cross-sectional method, and the average value was taken.

[0153] Growth inhibition rate (%): (control colony diameter - treatment colony diameter) × 100 / (control colony diameter - 4 mm).

[0154] The drug concentration was 50 μg / mL. The results of the antibacterial activity test are shown in Table 2.

[0155] Table 2. Results of antibacterial activity

[0156]

[0157] Table 2 shows that the target compounds all exhibited antibacterial activity against the tested pathogens, with some showing good antibacterial activity. Among them, N-(4-tolyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine showed an inhibition rate of up to 95.5% against Sclerotinia sclerotiorum, up to 85.0% against Sheath blight, and up to 91.2% against Rot bacterium. N-(3-methoxyphenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine, N-(4-bromophenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine, and N-(4-tolyl)-(2-(2-phenoxypropionylamino)benzoyl)glycine showed inhibition rates of 75.3%, 79.0%, and 75.3% against Sclerotinia sclerotiorum, respectively. N-(4-Tolyl)-(2-(2-naphthylamino)benzoyl)glycine exhibited an inhibition rate of up to 83.8% against *Fusarium wilt* and up to 72.5% against *Sheath blight*; N-(4-Tolyl)-(2-(2-methyloxalamido)benzoyl)glycine showed an inhibition rate of up to 89.2% against *Fusarium wilt*; N-(4-Tolyl)-(2-(1-adamantanecarbamoyl)benzoyl)glycine showed inhibition rates of up to 72.6% and 70.2% against *Sclerotinia sclerotiorum* and *Fusarium wilt*, respectively; and N-(4-Tolyl)-(2-bromoacetamido)benzoyl)glycine showed inhibition rates of up to 81.6%, 75.4%, and 93.9% against *Fusarium wilt*, *Phytophthora*, and *Sheath blight*, respectively.

[0158] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An N-aryl(2-acylaminobenzoyl)aminoamide compound, characterized in that, The compound has the general structural formula (Ⅰ). ； In the formula, R1 is one of hydrogen atom, alkyl, alkoxy or halogen atom; R2 is one of hydrogen atom, alkyl or aryl; R3 is hydrogen atom or halogen atom; and R4 is one of hydrocarbon group, aryl, heterocyclic group or substituted aryl.

2. The N-aryl(2-acylaminobenzoyl)aminoamide compound according to claim 1, characterized in that, R1 is methoxy or methyl; R2 is hydrogen or methyl; R3 is a hydrogen atom; R4 is an aryl, heterocyclic or substituted aryl group.

3. The N-aryl(2-acylaminobenzoyl)aminoamide compound according to claim 1, characterized in that, The compound is selected from one or more of the following compounds: N-(4-Tolyl)-(2-(4-tert-butylbenzoamide)benzoyl)glycine: ； N-(3-methoxyphenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine: ； N-(4-Bromophenyl)-(2-(4-tert-butylbenzoylamino)benzoyl)glycine: ； N-(4-Tolyl)-(2-(2-Naphthoylamino)benzoyl)glycine: ； N-(4-Tolyl)-(2-(4-bromobenzoylamino)benzoyl)glycine: ； N-(4-Tolyl)-(2-(2-methyloxaloylamino)benzoyl)glycine: ； N-(4-Tolyl)-(2-(1-Adamantanecarbamoylamino)benzoyl)glycine: ； N-(4-Tolyl)-(2-Bromoacetamido)benzoyl)glycine: ； N-(4-Tolyl)-(2-(2-phenoxypropionylamino)benzoyl)glycine: 。 4. A method for preparing an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (Ⅰ), characterized in that, The preparation method specifically includes the following steps: S1) A Boc-amino acid with structural formula (V) is reacted with an aromatic amine with structural formula (VIII) in dichloromethane under the action of EDCI, DMAP, and triethylamine to obtain an N-Boc-aminoacyl aromatic amine compound with structural formula (Ⅳ). ； S2) Reaction of N-Boc-amino acyl amine compounds with structural formula (Ⅳ) in dichloromethane under the action of trifluoroacetic acid yields amino acyl amine compounds with structural formula (Ⅲ). ； S3) An N-amino amide with structural formula (Ⅲ) is reacted with an indigo anhydride with structural formula (Ⅶ) in acetonitrile under the action of potassium carbonate to obtain a diamide compound with structural formula (Ⅱ). ； S4) A diamide compound with general structural formula (II) is reacted with an acyl halide (VI) in the presence of triethylamine to prepare an N-aryl(2-acylaminobenzoyl)aminoamide compound with general structural formula (I); ； In the formula, R1 is one of hydrogen atom, alkyl, alkoxy or halogen atom; R2 is one of hydrogen atom, alkyl or aryl; R3 is hydrogen atom or halogen atom; and R4 is one of hydrocarbon group, aryl, heterocyclic group or substituted aryl.

5. The preparation method according to claim 4, characterized in that, R1 is methoxy or methyl; R2 is hydrogen or methyl; R3 is a hydrogen atom; R4 is an aryl, heterocyclic or substituted aryl group.

6. The preparation method according to claim 4, characterized in that, In S1), the molar ratio of Boc-amino acid with general structural formula (V), aromatic amine with general structural formula (VIII), EDCI, DMAP and triethylamine is 1.5:1:1.5:0.15:1.5, the reaction temperature is 25℃ and the reaction time is 3h. In S2), the molar ratio of N-Boc-aminoacylarylamine with general structural formula (Ⅳ) to trifluoroacetic acid is 1:5, the reaction temperature is 0℃, and the reaction time is 6h. In S3), the molar ratio of N-aminomethyl aromatic amine with general structural formula (Ⅲ), indigo anhydride with general structural formula (Ⅶ), and potassium carbonate is 1.2:1:1.2, the reaction temperature is 50℃, and the reaction time is 18h.

7. The preparation method according to claim 4, characterized in that, S4) Specifically: Weigh out a diamide compound with general structural formula (II) and triethylamine and add them to a round-bottom flask. Add dichloromethane to dissolve them. Add the acyl halide with general structural formula (VI) dissolved in dichloromethane slowly through a constant pressure dropping funnel in an ice-water bath. After the addition is complete, react for 3 hours. After the reaction was completed, an appropriate amount of deionized water and a small amount of Na2CO3 or NaHCO3 solution were added and stirred for more than 30 minutes to quench the reaction system. Then, the organic solvent was removed by vacuum extraction. The resulting solid and aqueous solution were extracted by hot EA to separate the organic phase and the aqueous phase was extracted by EA. The combined organic phases were retained and dried, and the solvent was removed by vacuum rotary evaporation to obtain N-aryl(2-acylaminobenzoyl)aminoamide compounds with the general structural formula (Ⅰ).

8. The preparation method according to claim 7, characterized in that, The molar ratio of diamide compounds with general structural formula (II), triethylamine, and acyl halide is 1:1:1.2-1.

8.

9. The use of an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (I) as described in any one of claims 1-3, or an N-aryl(2-acylaminobenzoyl)aminoamide compound having the general structural formula (I) prepared by the method according to any one of claims 4-8, characterized in that, Used for antibacterial purposes in crops or for preparing antibacterial drugs for crops.

10. The use according to claim 9, characterized in that, The fungicides used for crop control include those that inhibit one or more of the following pathogens: Fusarium head blight, rice blast fungus, Phytophthora blight, Sclerotinia sclerotinia, gray mold, sheath blight, and rot fungus. Drugs used to prepare antibacterial agents for crops include drugs for inhibiting one or more of the following pathogens: Fusarium head blight, rice blast fungus, Phytophthora blight, Sclerotinia sclerotiorum, gray mold, sheath blight, and rot fungus.

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